to the full program book with all educational

Transcription

Louisiana Society of
Health-System Pharmacists
2015 Annual Meeting
May 21-23, 2015
Hyatt Regency
601 Loyola Ave., New Orleans, LA
Program Book
Louisiana Society of Health-System Pharmacists
Board of Directors & Committee Chairs
Officers & Directors
Fancy Manton— President
Edward Stemley — Past President
Shawn Manor— President Elect
Helen Calmes— Secretary
Tommy Mannino— Treasurer
Kristian Fruge— Director at Large
Camtu Ho— Director at Large
Frank McCloy—Director at Large
Chapter Presidents
Teresa Nash— Director at Large
Liz Lafitte— NLSHP President
vacant—NELSHP President
Jennifer Smith— SCLSHP President
LaKeisha Williams— SELSHP President
vacant—SWLSHP President
Joseph Gary LeBlanc— CLSHP President
Committee Chairs
Jamie Terrell — Education & Workforce Development Chair
Michael Loftin & Michael Dorman— Pharmacy Management Chair
William Kirchain & Jeff Evans — Public Policy Chairs
Jay Schwab & Helen Calmes— Programming & Practitioner Education Chairs
Tammy Belleau—Pharmacy Practice Chairs
Dana Jamero—Publications Editor
Lisa Ross— Membership & Marketing Chair
Anne LaVance —Technician Activities
Helen Calmes—Organization Affairs & Documents Chair
Jessica Brady— University of Louisiana at Monroe Liaison
Iman Borghol— Xavier University Liaison
Liz Lafitte and Amanda Storer—Mid Year Meeting Coordinators
New Practitioner Committee—Alexis Horace
Louisiana Society of Health-System Pharmacists
Past Presidents
1944-45 Gracie A. Barr*
1945-46 Hebert J. Mang*
1946-47 Guy L. Leefe*
1947-48 John F. Thompson*
1948-51 Valerie C. Armbruster
(Bobear)
1951-52 Troy L. Carter, Jr.*
1952-53 William P. O‘Brien*
1953-54 Ernest B. Simnacher
1954-55 Frances C. Pizzolato
(Polizzi)
1955-56 Herbert J. Mang*
1956-57 Albert P. Lauve*
1957-58 Joseph P. Crisalli*
1958-59 Joseph P. Crisalli*/
Frank Hollister
1959-60 Frank W. Hollister
1960-62 Gladys M. Hebert
1962-63 John F. Kellerman
1963-64 Malcolm Claus*/
Henry Derewicz
1964-65 Henry J. Derewicz/
Lowell Pfau
1965-66 Lowell Pfau
1966-67 Troy L. Carter, Jr.*
1967-68 Willard L. Harrison
1968-69 Joseph A. Maggio, Jr.
1969-70 W. Clark Wherritt*
1970-71 Daniel H. Yeoman
1971-72 Thomas B. Himel*
1972-73 W. James Inbau, Jr.
1973-74 Jon J. Tanja
1974-75 Paul J. Comeaux
1975-76 Charles G. Eberhardt
1976-77 Thomas G. Alexander
1977-78 JoBeth Baggett
1978-79 Wesley R. Gladhart, Jr.
1979-80 Claudine J. Lackey
1980-81 Shelton E. McBride
1981-82 Michael L. Louviere
* Deceased
1982-83 John D. ―Jack‖ Harris, III*
1983-84 Andrew L. Wilson
1984-85 T. Morris Rabb
1985-86 Paul S. Knecht
1986-87 F. B. ―Brad‖ Belding
1987-88 Michael W. Walker
1988-89 Malcolm J. Broussard
1989-90 Theresa M. Miller
1990-91 Ruth A.C. ―Cookie‖ Jean
1991-92 Darryl Gould
1992-93 Myra Thomas
1993-94 Susan Webber
1994-95 Michael C. Loftin
1995-96 James Witchen
1996-97 Deborah U. Carpenter
1997-98 Janet B. Schmitt
1998-99 Charles W. Jastram
1999-00 Helen M. Calmes
2000-01 Ernest Terry
2001-02 Jay Schwab
2002-03 Mathew Thomas
2003-04 David Loftin
2004-05 Tommy Mannino
2005-06 Michael Cockerham
2006-07 Christopher Betz
2007-08 Barries Leung
2008-09 Marty Steffenson
2009-10 Keturah Robinson
2010-11 Teresa Nash
2011-12 Scott Dantonio
2012-13 Roxie Stewart
2013-14 Edward Stemley
2014-15 Fancy Manton
Table of Contents General Information & Activities
1
Hotel Meeting Room Diagram
3
Annual Meeting Program
4
Sponsors
7
Syllabus
(listed chronologically)
Trends in Prescribing in Pediatric Psychopharmacology
Mary Margaret Gleason, MD
8
Application of Epidemiology, Study Design & Methodology, and Biostatistics for Specialty Board
Preparation or Use in Literature Evaluation
Larry W. Segars, PharmD, DrPH, FCCP, FACE, BCPS, RPh
18
New and Emerging Strategies for the Treatment of Advanced Melanoma
R. Donald Harvey, PharmD, FCCP, BCOP
55
Special Situations in Patients with Type 2 Diabetes
Susan Ann Cornell, PharmD, CDE, FAPhA, FAADE
72
The Future is Yours—Advancing Practice
Christene Jolowsky, MS, RPh, FASHP, ASHP President
78
Technician Advancement: How can I Climb the Ladder? (TECHNICIAN SESSION)
Richard Ponder, MBA, CMRP, CPhT, CPP, CEPP
88
Sterile Compounding: USP <800> Hazardous Drugs
Anne P. LaVance, BS, CPhT
95
A Pharmacists Guide to Using Fluids, Vasopressors, and Inotropes in Shock
Craig Worby, PharmD, BCPS
100
Management of Invasive Fungal Infections: Applying Evidence-based Strategies and Individualizing 124
Antifungal Therapy
Kevin W. Garey, Pharm.D., M.S., FASHP
Emerging Technologies to Decrease Opioid Abuse: An Update for Pharmacists/Technicians
Gregory L. Holmquist, PharmD, CPE
139
Sterile Compounding: USP <797> Update
156
Trends in Pharmacy Law and Regulation
William R. Kirchain, PharmD, CDE
Jeffery D. Evans, PharmD
162
General Information & Activities
Registration
The Annual Meeting Registration and Information Desk is located on the third floor of the Hyatt Regency. Registration
will be open Thursday from 12:00-5:30 p.m., Friday from 7:30 a.m.-12:30 p.m. & 2:00-5:30 p.m., and Saturday from
7:30 a.m.-12:00 p.m.
Information Updates
Please read through your meeting packet, particularly the program-at-a-glance. It contains updated meeting
information as well as meeting locations.
Badges
Badges must be worn at all times. Badges are required for admittance to all Annual Meeting functions.
Registrants, staff, guests and speakers have white badges. Exhibitors have blue badges.
Meeting Locations
Most meeting sessions will be held in the Celestin Ballroom on the third floor of the Hyatt Regency. On Friday, the
student session will take place in Foster 2 and the technician session will be in Foster 1 Room on the second floor.
Welcome Reception
Come join us for the Thursday Welcome Reception from 7:00—9:30 p.m. at Rock ‗n‘ Bowl. Rock ‘n‘ Bowl is located at
3016 S. Carrollton Ave. in New Orleans. Transportation will be provided. There will be a mini bus that will begin picking
up at 6:30 pm at the rear entrance of the hotel.
Exhibit Program & Lunch
The exhibit program is located in the Storyville Hall on the third floor from 12:00-3:00 p.m. on Friday. Please take time
to visit our exhibitors and express your thanks for their participation. Additionally, please thank your local
representatives. Friday‘s lunch is provided for all paid registrants and exhibitors. Lunch will be served in Storyville Hall
for exhibitors only beginning at 11:00 a.m.
Lunch begins for registrants at 11:30 a.m. Seating and lunch service ends at 12:30 p.m.
Please see the handouts in your packet for a list of exhibitors and exhibit hall layout.
Door Prize Drawings
Cash Drawing– Four $50 cash drawings will be held throughout the exhibit hours on Friday. All registrants are
automatically entered, but you must be present to win!
Exhibitor Drawing- A door prize drawing card can be found in your meeting packet. In order to qualify for the
drawing, you must have an exhibitor from each company on your card sign or initial the appropriate space on the card.
After completing your card, sign it and return it to the registration desk. The drawing will be held at 2:45 p.m. Friday
in the Exhibit Hall. You must be present to win.
New Mentorship Program
We are developing a mentorship program to aid in the professional growth of new practitioners. The New Practitioner
Committee is formalizing this program state-wide to provide consistent oversight and leadership. The goal of the
program is to provide mentorship opportunities to leaders and future leaders of the society through a program
designed to develop, inspire, and encourage involvement in the profession. In doing so, this will allow new
practitioners, students and their mentoring pharmacists to expand their professional network, share and learn from
experience, and develop the future generation of our profession. The Mentorship Program is available to both students
and New Practitioners. Mentors and their mentees will have an opportunity to meet face-to-face at the Annual Meeting
at 4:00 pm on Friday, May 22 after the Student Session in Foster 2 room.
LSHP Annual Pharmacy Student Ice Cream Social
Moderator: Lisa M. DiGioia-Ross ,Pharm. D.
Sponsor: Robert D. Ross ,M.D., APMC
All students are invited to attend the student listening session and reception at 4:30 p.m. on Friday (immediately
following the Mentorship Program.) This will be held in Foster 2 Room on the second floor. Ice cream will be
served.
Awards
All awards will be presented at the General Membership Meeting on Friday, May 22 from 9:00-10:00 am.
Past Presidents’ Breakfast
The Past Presidents‘ Breakfast has been scheduled for Saturday from 7:00-8:00 a.m. in the in Foster 1 Room. This
function is by invitation only.
1
General Information & Activities, continued
Activity Evaluations
Activity evaluations are extremely important in the development of educational needs assessment for future
activities. Please take a moment to evaluate each activity you attend; we appreciate and value your input. A
booklet of evaluations was included in your registration packet. Please turn in your evaluation packet at the
end of the activity, or after attending your last activity. Please also fill out the Annual Meeting Survey, which
helps us know what you enjoyed or didn‘t enjoy about the meeting and the facility. Thank you in advance for
your participation!
Continuing Education Credit
The Louisiana Society of Health-System Pharmacists, American Society of Health-System Pharmacists,
and the American Association of Diabetes Educators are accredited by the Accreditation Council for
Pharmacy Education as providers of continuing pharmacy education.
Certification of Continuing Education Hours/ How to Receive Credit:
To receive credit for continuing education activities at the Annual Meeting registrants must:
1. Register and pay all applicable fees.
2. Attend the activity.
3. Complete the Continuing Education Credit Report included in the registration packet.
4. Initial next to each activity that you attend. PARTIAL CREDIT WILL NOT BE GIVEN FOR ANY ACTIVITY.
(For example, if you attended only 1 hour of a 2 hour activity, then you will not get any credit for it.)
5. Complete and sign the form and submit to the registration desk at the end of the conference or after
attending your last activity. Include on the form your month of birth in ―MM‖ format (for example, January is
―01‖) and day of birth in ―DD‖ format (for example, the 3rd of the month is ―03‖). Also include your NABP eProfile ID.
Due to ACPE credit recordation requirements, LSHP no longer issues statements of credit. Your CE
credit will be recorded by the LSHP office electronically via CPE Monitor (see details below) within 60
days after the meeting.
CPE Monitor is a national, collaborative effort by ACPE and the National Association of Boards of Pharmacy
(NABP) to provide an electronic system for pharmacists and pharmacy technicians to track their completed
continuing pharmacy education (CPE) credits. All pharmacists and pharmacy technicians must obtain their
NABP e-Profile ID by going to www.nabp.net. Your NABP e-Profile ID is required to receive credit for the
LSHP Annual Meeting. After the Annual Meeting, LSHP will send to NABP and ACPE (via the CPE Monitor)
the amount of credit you received (using your e-Profile ID) at the Annual Meeting. Once this information is
received by NABP, pharmacists and pharmacy technicians will be able to log in to access information about
their completed CPE.
To receive credit, registrants must attend activities designated for their credential. Activities acceptable for
pharmacists are indicated by a ―P‖ suffix in the activity number. Programs acceptable for pharmacy technicians
are indicated by a ―T‖ suffix in the activity number.
ACPE credit will not be given by LSHP for the following activities. Information will be given to participants at
these sessions on how to receive credit.
 Friday, May 22: 8:00—9:00 am: New and Emerging Strategies for the Treatment of Advanced Melanoma
(0204-0000-15-413-L01-P)
 Friday, May 22: 10:00—11:30 am: Special Situations in Patients with Type 2 Diabetes
 (0069-9999-14-148-L01-P)
 Saturday, May 23: 8:00—9:00 am: Management of Invasive Fungal Infections: Applying Evidence-based
Strategies and Individualizing Antifungal Therapy (0204-0000-15-412-L01-P)
2
Hyatt Regency Layout
Second floor
Legend:
Foster 1 (second floor)
Technician Session on Friday;
and Past President‘s Breakfast on
Saturday
Foster 2 (second floor)
Student sessions on Friday
♠
Celestin Foyer (third floor)
Registration
♥
♣
Celestin A-C (third floor)
General Session
Storyville Hall (third floor)
Exhibit Hall and Friday lunch
Celestin D (third floor)
Reverse Expo
Strand 13 (second floor)
Pharmacy Directors Forum
Third floor
♣
♥
♠
3
Program
Thursday, May 21, 2015 Schedule
12:00—5:30 p.m.
Registration open
Celestin Foyer
1:00—3:00 p.m.
Pharmacy Directors Forum (for pre-registered pharmacy directors and clinical managers only)
Strand 13
3:00—5:00 p.m.
Reverse Expo (for pre-registered pharmacy directors, clinical managers, and exhibitor reps only)
Celestin D
2:45—3:00 p.m.
Welcome & Announcements
Celestin A-C
3:00—4:00 p.m.
0179-0000-15-003-L04-P / 0179-0000-15-003-L04-T
1 contact hour (0.1 CEU)
Celestin A-C
4:00—5:30 p.m.
Application of Epidemiology, Study Design & Methodology, and Biostatistics for Specialty Board
Preparation or Use in Literature Evaluation
0179-0000-15-004-L04-P
1.5 contact hours (0.15 CEUs)
Celestin A-C
7:00—9:30 p.m.
LSHP Welcome Reception at Rock ‘n’ Bowl
3016 South Carrollton Ave., New Orleans, LA 70118
Sponsored by: FFF ENTERPRISES
Transportation will be provided. A mini bus will arrive at 6:30 pm at the rear entrance to the hotel.
Thank you to MORRIS & DICKSON for being an educational sponsor!
Program continued on next page.
4
Program (continued)
Friday, May 22, 2015 Schedule
7:30 a.m.—12:30 p.m. and 2:00—5:30 p.m.
Registration Open
Celestin Foyer
7:30—8:00 a.m.
Breakfast
Celestin Foyer
8:00—9:00 a.m.
0204-0000-15-413-L01-P
This activity is planned and conducted by ASHP Advantage and supported by an educational grant from Merck.
Celestin A-C
9:00—10:00 a.m.
General Membership Meeting
Celestin A-C
10:00—11:30 a.m.
0069-9999-14-148-L01-P
1.5 contact hours (0.15 CEU)
This program is supported by an educational grant from Novo
Nordisk Inc.
Celestin A-C
11:30—12:30 p.m.
Lunch
Sponsored by a grant from NOVO NORDISK, INC.
Storyville Hall
12:00—3:00 p.m.
Exhibits
Storyville Hall
2:00—3:00 p.m.
Poster Session: Focus on Patient Safety
0179-0000-15-010-L05-P / 0179-0000-15-010-L05-T
1.0 contact hour (0.1 CEU)
Storyville Hall
3:00—4:00 p.m.
Christene Jolowsky, MS, RPh, FASHP, ASHP President
0179-0000-15-005-L04-P / 0179-0000-15-005-L04-T
Celestin A-C
5
TECHNICIAN BREAKOUT
SESSION
3:00—4:00 p.m.
Technician Advancement: How can I Climb
the Ladder?
Richard Ponder, MBA, CMRP, CPhT, CPP,
CEPP
0179-0000-15-011-L04-T
Foster 1—2nd floor
STUDENT SESSION
3:00-4:00 p.m.
Financial Planning
Scott LaCaze, CPA
Foster 2 Room—2nd floor
4:00—4:30 p.m.
Mentorship Program
4:30 p.m.
LSHP Annual Pharmacy Student
Ice Cream Social
Moderator: Lisa M. DiGioia-Ross ,Pharm. D.
Sponsor: Robert D. Ross ,M.D., APMC
All students are invited to attend
Program continued on next page.
Program (continued)
4:00—5:00 p.m.
Anne P LaVance, BS, CPhT
0179-0000-15-006-L04-P / 0179-0000-15-006-L04-T
Celestin A-C
5:00—7:00 p.m.
0179-0000-15-008-L01-P / 0179-0000-15-008-L01-T
Celestin A-C
Saturday, May 23, 2015 Schedule
7:30 a.m. —12:00 p.m.
Registration Open
Celestin Foyer
7:30—8:00 a.m.
Continental Breakfast
8:00—9:00 a.m.
Management of Invasive Fungal Infections: Applying Evidence-based Strategies and Individualizing
Antifungal Therapy
0204-0000-15-412-L01-P
Celestin A-C
9:00—11:00 a.m.
Emerging Technologies to Decrease Opioid Abuse: An Update for Pharmacists/Technicians
0179-0000-15-009-L01-P / 0179-0000-15-009-L01-T
Celestin A-C
11:00 a.m.—12:00 p.m.
0179-0000-15-007-L04-P / 0179-0000-15-007-L04-T
Celestin A-C
12:00—1:00 p.m.
Trends in Pharmacy Law and Regulation
William R. Kirchain, PharmD, CDE and Jeffery D. Evans, PharmD
0179-0000-15-012-L03-P / 0179-0000-15-012-L03-T
Celestin A-C
6
Sponsors
The success of LSHP‘s Annual Meeting depends, in large part,
on the participation and support of pharmaceutical and related
interests. LSHP is very appreciative of the companies listed
below that have generously supported the 2015 Annual Meeting
by educational or event sponsorship.
ASHP Advantage
Merck
Novo Nordisk
Program Management Services, Inc.
7
Louisiana Society of Health System Pharmacists
2015 Annual Meeting
Thursday, May 21
3:00—4:00 p.m.
Associate Professor, Psychiatry and Behavioral Sciences
Tulane University School of Medicine
0179-0000-15-003-L04-P / 0179-0000-15-003-L04-T
Knowledge-based activity
Technician Objectives:
 Discuss trends in prescribing psychotropic
medications for young children nationally
 Discuss trends in prescribing psychotropic
medications for young children in
Louisiana
Pharmacist Objectives:
 Describe trends in prescribing
psychotropic medications for young
children nationally
 Describe trends in prescribing
psychotropic medications for young
children in Louisiana
 Recognize medication classes with FDA
indications or empirical evidence for use
in children
Speaker has disclosed that she has no relevant financial relationships.
8
 Abramson
Preschool
Psychopharmacology
Working Group



Louisiana Society of Health System
Pharmacists
Mary Margaret Gleason MD FAAP
[email protected]
Tulane University School of Medicine









Graham J. Emslie, MD
Helen L. Egger, MD
Laurence L. Greenhill, MD
Robert A. Kowatch, MD PhD
Alicia Lieberman, PhD
Joan Luby, MD
Judith Owens, MD
Lawrence D. Scahill, MSN PhD
Michael S. Scheeringa, MD MPH
Brian Stafford, MD MPH
Brian Wise, MD MPH
Charles H. Zeanah, MD
 Louisiana’s
Early
Childhood Supports
and Services Teams
 Tulane Institute of
Infant and Early
Childhood Mental
Health
Patients
and
parents who
teach us
Mary Margaret Gleason MD [email protected]
 Will
 No
be discussing off label medications
financial conflicts of interest
 Be
familiar with pediatric psychotropic
prescription patterns


Nationally
in Louisiana
 Be
able to recognize medication classes
with FDA indications or empirical evidence
for use in children.
A state of well-being in which every individual
 realizes his or her own potential
 can cope with the normal stresses of life
 can work productively and fruitfully
 and is able to make a contribution to her or
his community.
 WHO 2014
 Provide
overview of pediatric indications for
psychopharmacologic treatment
 Present prescribing trends in pediatric
psychopharmacology especially in young
children
 Review developmentally-specific issues in
preschool mental health
 Review evidence supporting
psychopharmacological interventions in young
children
9
A state of well-being in which every individual
 realizes his or her own potential
 can cope with the normal stresses of life
 can work productively and fruitfully
 and is able to make a contribution to her or
his community.
 WHO 2014

and Statistical Manual (US)
Classification of Diseases (UK
and billing)
 Diagnostic Classification: 0-3R (children
under 36 months)
 International
 These
are just parenting problems (or school
problems or our culture in the 21st century)
Psychiatric illnesses are just created by PHARMA
to increase sales



 Diagnostic
Quality research demonstrates that psychiatric
disorders have high heritabillity, that diagnostic
criteria can differentiate healthy from non-healthy
children, and that there is stability over time
Best practices recommend non-pharmacologic
treatment for many disorders


 If
we just disciplined children more, they
wouldn’t have these problems
These are just phases


Many psychiatric illnesses have biological
correlates
Rates of disorders are more similar across the
globe than different
Prevalence of psychiatric disorders increases with age
Most adults with psychiatric illness had onset in
childhood or adolescence

Corporal punishment is associated with higher
rates of aggression
16
14
12
10
8
6
4
2
0
Anxiety
Disorders
Depressive
disorder
ADHD
Disruptive Any disorder
behavior
Polanczyk et al 2015 JCPP
Verlust et al 2003 AJP
10
14
16
13.5
14
12
12.5
Prevalence (%)
Prevalence (%)
13
10
Diagnosis
12
Severe Emotional
Disability
11.5
Diagnosis
8
Severe Emotional
Disability
6
4
11
2
10.5
0
Preschool
School age
Preschool
Adolescent
Egger 2006 JAACAP ; Merkingas 2014 Pediatrics
School age
Adolescent
18
16
Lack of
empathy
14
Impulse
control
Attention
Prevalence (%)
12
Diagnosis
10
8
Psychosis
Severe Emotional
Disability
6
Social
impairm
ent
4
2
0
Preschool
School age
Mood
(sad/irrit
able)
Problems
Anxiety
Substance
use disorder
Adolescent

Strong validity










ADHD
Oppositional Defiant
Disorder
Conduct Disorder
Anxiety disorders
Posttraumatic stress
disorder
Depression
Bipolar disorder (in
adolescence)
Autism
Tic disorders
Eating Disorders
Strong

Moderate validity




Limited data

Strong validity

Schizophrenia/Schizophr
eniform


Intermittent explosive
disorder






Moderate
ADHD
Disorder
Conduct Disorder
Anxiety disorders
disorder
Depression
Bipolar disorder (in
adolescence)
Autism
Tic disorders
Eating Disorders
Strong
11

Moderate validity


Schizophrenia/Schizophr
eniform
Limited data

disorder
Moderate

Strong validity






ADHD
Disorder
Conduct Disorder
disorder
Depression
Autism

Moderate validity
80%
Anxiety disorders
Eating/Feeding
disorders
60%






10
20%
disorder
Bipolar disorder
Tic disorders
(Psychosis)
**
8
No
diagnosis 6
Diagnosis 4
40%
Limited data

12
**
No
diagnosis
Diagnosis
2
0
0%
Percent Impaired
Impairment Score
 Children
Strong
who meet criteria for a disorder are
more impaired than those who do not
Moderate
** p<0.01, Egger et al 2006
 Multiple
informants (child and parent minimally)
sessions for younger children
 Multiple modes of assessment (interview,
observations, structured measures of symptoms
and development)
 Consider biological, developmental, family,
social, and environmental factors
 Fluoxetine,
sertraline, (es)citalopram
(paroxetine)
 Uses: Anxiety, depressive disorders
 FDA Indications: Anxiety disorders, OCD, MDD
 Multiple

(lower limit age range 6-8; case reports in
preschoolers)
 Clinically


important adverse effects
Increased suicidality (Black box)
Mania
FDA.gov
Methylphenidate, amphetamines
Uses: ADHD, severe, impulsive aggression
 FDA Indications

 Guanfacine,

 Uses:



Methylphenidate (> 6; explicitly warns against
preschool use)
Amphetamines (> 3 yo)
Empirical support



clonidine
ADHD, aggression, sleep (clonidine)
 FDA indications: Hypertension (immediate
release), ADHD (extended release, children >
6)
 Empirical support
1 major RCT for mph in preschoolers
Extensive RCT’s in school age and adolescents


Clinically important adverse effects




 Clinically
Anorexia
Sleep disturbance
Emotionality
Does NOT increase risk of substance abuse
RCT’s in children > 6
Case reports (guanfacine) in preschoolers



FDA.gov; parentsmedguide.org
important adverse effects
Hypotension/death in overdose
Sedation
Rebound hypertension
12
FDA.gov
Atomoxetine
Uses: ADHD (anxiety)
FDA indication: ADHD
(> 6)
 Empirical support:
RCT’s in children 4+
 Clinically important
adverse effects





Buproprion
Uses: Depression,
ADHD
 FDA indication

•
•
•
•
•
Emotionality
Appetite suppression
Liver failure
•
•
FDA.gov
FDA.gov
18
Depression, (ADHD)
 FDA indication: None in youth
 Empirical support: RCT for ADHD, Depression
 Clinically important adverse effects

Sedation
Obesity
Lipid and glucose problems
Hyperprolactinemia
 Uses:

Aripiprazole, asenpine, olanzapine,
olanzapine/fluoxetine, quetiapine, risperidone,
ziprasidone (iloperidone; paliperidone,
lurasidone)
Uses: psychosis, bipolar disorder (aggression,
eating disorder)
FDA indications: Bipolar disorder (> 10),
schizophrenia (> 14 yo); irritability in children
with autism (> 5)
Important adverse effects
•
16
14
12
1995-1998
1999-2002
2003-2006
2007-2010
10
Seizures
suicidality
8
6
4
2
0
Visit for
psychotropic
FDA.gov
Visit for
psychotherapy
Visit to
psychiatrist
7
6
girls 0-5
boys 0-5
girls 6-10
boys 6-10
girls 11-14
boys 11-14
girls 15-18
boys 15-18
5
4
3
2
1
Figure Legend:
0
1998
1999
2000
JAMA
Psychiatry.
2014;71(1):81-90. doi:10.1001/jamapsychiatry.2013.3074
Date
of download:
4/11/2015
Olfson et al 2014 JAMA Psychiatry
13
2001
2002
(Delate 2004)
 Represents
64% of children 4-18 in LA
received medication for ADHD
 10 yo white boys highest rates 35.8%
 Children born in September were 26%
more likely to receive medication for
ADHD
 12.9%
Visser 2015 presentation to LA DHH
Bilbo DHH 2015
 Most
preschoolers with a psychiatric
diagnosis do not receive any treatment
 Children receiving prescriptions are
impaired
 Prescriber profession varies

Pediatricians, psychiatrists, child psychiatrists,
and family practitioners
 Class
of medications


Stimulant rates have plateaued
Antipsychotic agent rates are increasing
dramatically

(Debar et al., 2003; Lavigne et al 2009, Luby et al 2007; Zito
et al 2007, Patel et al 2005, Olfson et al 2011)
14

Parent Beliefs


Perception of the problem
Acceptability of treatment options

Race/Ethnicity

Socioeconomic status

Geography
Central > North= South= West > Northeast
X2=398.7, p<0.001




Complex associations
Higher rates of use in Medicaid population
DosReis et al., 2003; Gleason et al 2011; Krain et al., 2005a;
Zito 2000; Bennett 1996; Brinkman 2009; Gage and Wilson,
2000; Harrison and Saronoff, 2002 ; Hoza et al., 2000; Hughes
and Wingard, 2008; Liu 1991; Owens et al., 2003;
 Child
mental health
workforce shortage
 Limitations of
mental health care
by insurers
 Stigma
 Regulatory approval
 Impact of out of
home care
 Preschoolers




Bilbo DHH 2015
Optimal
Development
are different
Development
Parent-child relationship
Systems
Evidence
Adverse
outcome
0
15
5
Healthy CNS development
Normal IQ
Decreased IQ
Hyperactivity •Lead toxicity
5
0
Low IQ
Thyroxin
5
0
Fisher J PEDS 2000)
Normal Cortisol diurnal rhythm
Increased IQ
Low IQ
Quality foster care
5
0
Extreme cortisol diurnal rhythm Dyadic therapy
5
0
Adverse outcome
?
Adverse outcome
?
?
?
5
0
5
0
16
Adverse outcome
?
?
?
5
0
 Relationship
quality can buffer biological and
environmental risk
 Symptoms may be relationship specific




 If

first line medication fails
Reassess diagnosis and level of impairment
 Track
symptoms systematically using
structured measures
 Plan discontinuation trial
 Practice within the scope of training and
experience
Parent-child
Teacher-child
 Parent
5
0

Adverse outcome
?
attributions
What do the symptoms mean about the child?
What do the symptoms mean about the parent?
What does the medication mean?
Researchers to examine safety and efficacy of
psychopharmacological and psychotherapeutic
interventions for preschoolers
 Funders (private and public) to fund this
research
 Clinicians and parents to advocate for improved
access to quality assessment and treatment
 Vocal advocate for access to appropriate
evidence based treatments through insurance
advocacy, legislative and other policy
interventions

17
2015 Annual Meeting
Thursday, May 21
4:00-5:30 p.m
Application of Epidemiology, Study Design & Methodology, and Biostatistics for
Specialty Board Preparation or Use in Literature Evaluation
0179-0000-15-004-L04-P
Associate Dean, College of Biosciences, and
Associate Professor of Pharmacology, Dept. of Pharmacology/Microbiology,
College of Osteopathic Medicine
Kansas City University of Medicine and Biosciences
Kansas City, Missouri
Application-based activity
Pharmacist Objectives
 Delineate and differentiate the various study designs and methodologies commonly utilized in
observational and interventional studies. Strengths and weaknesses of each design will be
reviewed.
 Delineate, calculate and interpret common elements associated with medical screenings, measures
of disease frequency and measures of association for diseases and practice their interpretations.
 Delineate and demonstrate the selection process for appropriate statistical tests for data
comparisons.
Speaker has disclosed that he has no relevant financial relationships.
18
Specialty Board Review:
Screenings in Medicine
Practice Board‐style Questions
Measures of Association & Disease Frequency (Epi.)
Biostatistics
Study Designs & Methodology
Associate Dean of the College of Biosciences
Associate Professor of Pharmacology
Kansas City University of Medicine & Biosciences
3
4 Possible Outcomes to Screening
Screening Test Result
Screenings in Medicine
“Truth”
Disease Presence
Yes
No
Total
Positive
A
B
A + B
Negative
C
D
C + D
Total
A + C
B + D
A + B +
C + D
• True Positive (TP)
– Test is positive and the patient does have the disease
• True Negative (TN)
– Test is negative and the patient does not have the disease
19
• False Positive (FP)
– Test is positive but the patient does not have the • False Negative (FN)
– Test is negative but the patient does have the disease
disease
10
SUMMARY
5 Knowledge Elements of Screenings
•
•
•
•
•
• Calculation of the 5 primary elements associated with medical screenings is straight forward
• Understanding how to explain/describe each (and their converse) is the more advance skill to acquire
Sensitivity
Describes accuracy of TEST RESULT
(from known disease status)
Specificity
Positive Predictive Value
Predicts accuracy of DIAGNOSIS
(from known test result)
Negative Predictive Value
Diagnostic Accuracy
Describes Total Accuracy of
CORRECT TEST RESULTS
(from total study population)
11
12
QUESTIONS?
Measures of Association
20
Measures of Disease Frequency
 Absolute Risk Reduction (ARR) [a.k.a. Attributable Risk (AR)]
o Example: 14.0% – 17.8% = 3.8% absolute risk difference
Building a Mental Understanding of Risks
 The AR defines the excess risk of the outcome among the group with the exposure being studied
Risk:
 Relative Risk Reduction (RRR)
o (ARR)  Runexposed
o Example: 3.8% ÷ 17.8% = 21.35% relative reduction in risk
o PROBABILITY of outcome
Risk is a PROPORTION…a simple PERCENTAGE…“part over whole”
Risk Ratio (RR) (a.k.a. Relative Risk (RR))
o RATIO of the RISKS from 2 different groups
The measure‐of‐choice commonly utilized in COHORT studies
NEJM 2000;342(3):145‐153.
Number Needed to Treat (NNT) / Number Needed to Harm (NNH)
Building a Mental Understanding of Odds
o “# of patients needed to be treated to receive the stated benefit/harm”
 1 ÷ Absolute Risk Reduction (ARR; in decimal format)
Odds:
o Example: 1 ÷ 0.038 (3.8%) = 27 patients will need to be treated with ramipril to reduce 1 AMI/CVA/Death from CV causes
o FREQUENCY of an outcome occurring vs. it NOT occurring
Odds is a RATIO, NOT a percentage/proportion
Odds Ratio (OR)
o RATIO of the ODDS from 2 different groups
The measure‐of‐choice commonly utilized in CASE‐CONTROL studies
 Interpreting Ratio’s – Risk (RR), Odds (OR), Hazard (HR):
When Interpreting Ratio’s [RR/OR/HR], look for…:
o =1.0 = no difference (no increase/decrease) in risk/odds/hazard
o >1.0 = Increased Ratio (RR/OR/HR)
1. Direction of words
a. Increased / Decreased
 +1.0001 to +1.99 = use decimal value and convert to % for interpretation
2. Magnitude
a. 80% (1.8 times) / 20% (0.8 times)
• If RR = 1.53, then a 53% INCREASED (GREATER) risk in the comparator group
RR = 1.8
3. Group Comparison Orientation
o ≥2.0 = use phrase “x” times greater for interpretation
a. Ramipril vs. Placebo / Placebo vs. Ramipril
 +2.0 to ∞
• If OR = 6.18, then comparator group is 6.18 times GREATER odds
o <1.0 = Decreased Ratio (RR/OR/HR)
When looking at the CI for “Ratio’s” (RR/OR/HR), if both values are on the SAME SIDE of 1.0, it is always
statistically significant!
 0.00001 to 0.99 = subtract decimal value from 1, then convert answer to % for interpretation
• If HR = 0.73, then a 27% LOWER probability of the hazard outcome
21
19
Example Board Question
• Incidence
– New occurrences of an outcome/disease
• Prevalence
– Existing occurrences of an outcome/disease
• Includes old and new cases, collectively
Both are a PROPORTION…a simple PERCENTAGE…“part over whole”
Epidemiology 2012;23:677‐85.
Both frequencies are customarily compared to the “at risk” (incidence) or “base” (prevalence) population, to provide a reference
Interpret this OR
Incidence (a.k.a.; Risk, Attack Rate, Cumulative Incidence):
o [# new cases of the outcome (during a defined time period)  # persons at risk of the outcome (during the same time period)]
https://www.youtube.com/watch?v=2_qKgbLOlyY
• ALWAYS subtract out (from the starting population), those who already have the disease or are immune to the disease (not “at risk”)
https://www.youtube.com/watch?v=1jzZe3ORdd8g
Prevalence:
• Incidence Rate (a.k.a. Incidence Density):
o [# existing cases of outcome  # persons in population]
– [# new cases of the outcome  person‐time (a.k.a., total (net) time) people were at risk
 The denominator includes those with the outcome and those at risk of getting the outcome
of the disease]
• Appropriate for dynamic populations
o Point Prevalence
 Prevalence at a given point in time
• e.g., on Dec. 31st
o Period Prevalence
 Prevalence over a given period of time
• e.g.; during 2012 (1 year)
22
25
26
QUESTIONS?
SUMMARY
• Risk and Odds are easily determined from 2x2 tables
– although not mathematically calculated the same
• RR and OR are simply ratio’s of 2 risks or odds and interpreted exactly the same (as is HR)
• Measures of association are commonly determined from Observational studies or statistical analyses (regression’s)
• Measures of disease frequency are easily determined by focusing on values included in the denominator & numerator of each
Biostatistics
It’s All About the Data!
2 Key Attributes of Data Measurement (variables)
1. Magnitude (or Dimensionality)
 Bigger is more, Lower is less
2. Consistency of scale (or Fixed Interval)
 Equal, measurable spacing between units
3. Rational/Absolute Zero
 No negative numbers
Each attribute can be assessed with a “Yes” or “No” response
Algorithm‐style
23
4 KEY QUESTIONS
to Selecting the Correct Statistical Test
1. What TYPE OF DATA is being collected/evaluated?
a. Does the data have MAGNITUDE? (yes/no)
b. Does the data have a fixed, measureable INTERVAL
along the entire scale? (yes/no) (units?)
Flow Sheet‐style
3 Key Levels of Measurement
Nominal (Dichotomous/Binary; Non‐
Ranked/Ordered Categories)
Ordinal (Ranked Categories; Non‐Equal‐Distance)
o Yes Magnitude / No Consistency of scale / No Rational Zero
o No Magnitude / No Consistency of scale / No Rational Zero (usually just names of groups/categories)
 Level of Intimidation
 Can you describe others?
 Gender & Death & Pharma. companies
Interval Data
Interval/Ratio (Order/Magnitude & Equal Intervals‐of‐scale)
 Required Assumptions for Interval/Ratio:
o Normally‐distributed (around a known mean)
o Equal variance (SD)
o Yes Magnitude / Yes Consistency of scale / No or Yes Rational Zero (No‐Interval; Yes‐Ratio)
• Use Bartlett, Levene, or Kolmogorov‐Smirnov tests to assess for equal variances
 Number of Days Hospitalized & Age (years)
o Randomly derived and Independent
24
Key Levels of Measurement
Changing Levels of Measurement of Data
o After data is collected, we can appropriately go down in specificity/detail of data measurement (levels), but never up!
Flow Sheet‐style
 Can you provide examples of converting data to other levels?
4 KEY QUESTIONS
b. Does the data have a fixed, measureable INTERVAL along the entire scale? (yes/no)
Algorithm‐style
The remaining 3 QUESTIONS get you around
the other portions of each individual sheet
4 KEY QUESTIONS
4 KEY QUESTIONS
2. What TYPE OF COMPARISON/ASSESSMENT is a. Does the data have MAGNITUDE? (yes/no)
desired?
2. What TYPE OF COMPARISON/ASSESSMENT is desired?
– Outcome Prediction/Association (OR)
– Predicting Future Outcome/Group Membership
a regression
– Correlation a correlation test
– Time‐to‐Event (Survival)/Event‐Occurrence a survival test
25
regression
4 KEY QUESTIONS
Regressions
Regressions
2. What TYPE OF COMPARISON/ASSESSMENT is o Provide a measure of the relationship between variables by allowing the prediction about the dependent, or outcome, variable (DV) knowing the value/rank of others independent variables (IV’s)
o Also able to calculate OR for a Measure of Association
desired?
– Outcome Prediction/Association (OR)
regression
– Nominal Regression test = Logistic Regression
– Ordinal Regression test = Multinomial Logistic Regression
– Interval Regression test = Linear Regression
4 KEY QUESTIONS
4 KEY QUESTIONS
2. What TYPE OF COMPARISON/ASSESSMENT is 1. What TYPE OF DATA is being collected/evaluated?
– Correlation
desired?
correlation test
– Correlation
correlation test
– Provides a quantitative measure of the strength & direction of a relationship between variables
4 KEY QUESTIONS
4 KEY QUESTIONS
2. What TYPE OF COMPARISON/ASSESSMENT is 1. What TYPE OF DATA is being collected/evaluated?
– Correlation
desired?
correlation test
– Time‐to‐Event / Event‐Occurrence
– Nominal Correlation test = Contingency Coefficient
– Ordinal Correlation test = Spearman Correlation
– Interval Correlation test = Pearson Correlation
– NOTE: p>0.05 for a Pearson Correlation just means there is no linear
correlation; there may still be non‐linear correlations present!
 All Correlations can be run as a “partial correlation” to control for confounders
26
survival test
4 KEY QUESTIONS
“Survival” tests
Compares the proportion of, or time‐to, event occurrences between groups (over time)
2. What TYPE OF COMPARISON/ASSESSMENT is o Commonly represented by a Kaplan‐Meier curve
desired?
– Time‐to‐Event / Event‐Occurrence
survival test
– Nominal Survival test = Log‐Rank test
– Ordinal Survival test = Cox‐Proportional Hazards test
– Interval Survival test = Kaplan‐Meier test
 All can be represented by a Kaplan‐Meier curve
4 KEY QUESTIONS
– Frequencies/Counts/Proportions*
3. *HOW MANY GROUPS are being compared?
o 2 or 3 or more groups
4. *Is the data INDEPENDENT or RELATED (PAIRED)?
o Data from different groups (independent) or the same (paired)
*KEY WORDS FOR “PAIRED” or “RELATED” DATA:
“Pre‐ vs. Post‐”, “Before vs. After”, “Baseline vs. End”, etc…
4 KEY QUESTIONS
–
–
–
–
Correlation
a correlation test
Time‐to‐Event (Survival)/Event‐Occurrence a survival test
Predicting Future Outcome/Group Membership
a regression
Frequencies/Counts/Proportions*
3. *HOW MANY GROUPS are being compared?
o 2 or 3 or more groups
4. *Is the data INDEPENDENT or RELATED (PAIRED)?
Large, individual versions available at end of slide set
o Data from the same (paired) or different groups (independent)
27
Accepting or Rejecting Hypothesis
Type 1 & Type 2 Errors
o An error can be made when incorrectly accepting or rejecting the Null Hypothesis
TRUTH
Statistical Test
Do NOT reject H0 (p>0.05)
DO reject H0
Large, individual blank‐versions available at end of slide set for practice, if desired
(p<0.05)
p value
H0 True
H1 True
CORRECT
Type 2 Error
Type 1 Error
CORRECT
Statistical Significance
Statistical tests compare differences in variables or to evaluate relationships between them
If the p value is lower than the pre‐selected a priori value (customarily 5% (0.05))* then we say it’s statistically significant
1. A test statistic value is calculated, then
2. The test statistic value is compared to the appropriate table of probabilities for that test, then
3. A probability (p) value is obtained; based on the probability of observing, due to chance alone, a test statistic value as extreme or more extreme than actually observed if the groups were equal (not different)
o Based on an acceptably‐low probability (less than 5%) that the value of the test statistic could be as large as it is by chance alone if the groups were similar
 if < the a priori percentage‐risk of error, we REJECT the Null Hypothesis
 The risk of experiencing a Type 1 error is acceptably low (less than 5%)
 The probability is selected by investigators before the study starts (a priori)
Interpretation of a pre‐set (a priori) p value:
Comparisons of groups generates only a statistical estimate of the “true” yet unknown difference between groups (a point estimate)
o The probability of making a Type 1 error if the Null Hypothesis is rejected
o The probability of erroneously claiming a difference between groups if one does not really exist
o The probability of the outcome of the group’s differences occurring by chance
o The probability of obtaining group differences as great or greater if the groups were actually the same/equal
 The probability of obtaining a test statistic as high/higher if the groups were actually the same/equal
28
QUESTIONS?
Interpretation of a 95% CI
o We are 95% confident that the “true” difference between the groups is contained within the confidence interval range.
63
64
Research Design & Methodology
Quantitative vs. Qualitative
Study Design & Methodology
Numbers used to Represent Data
Words used to Represent Data
Interventional vs. Observational
Forced allocation to study groups
2 KEY QUESTIONS
No forced allocation to study groups
2 KEY QUESTIONS
65
to Selecting the Correct Study Design
66
to Selecting the Correct Study Design
1. Is researcher FORCING GROUP ALLOCATION?
1. Is researcher FORCING GROUP ALLOCATION?
a. Yes – Interventional (sample size/focus)
b. No – Observational (‘outcome’/‘exposure’)
a. Yes – Interventional (sample size/focus)
b. No – Observational (‘outcome’/‘exposure’)
2. For Observational studies, how were groups Considering OUTCOME vs. EXPOSURE……,
Look for what is KNOWN vs. being SOUGHT
ORGANIZED?
Considering OUTCOME vs. EXPOSURE……,
Look for what is KNOWN vs. being SOUGHT
a. By Disease Status – Case‐Control/Nested Case‐Control
b. By Exposure Status – Cohort
c. By Common Factor – Cohort or Cross‐Sectional
29
Study Designs
Research Evidence Pyramid
Pre-Clinical
Cases*
(Reports/Series)
Phase 1
Ecological*
Phase 2
Cross-Sectional
Phase 3
Case-Control
Phase 4
Pragmatic Trials
Randomized Trials
Cohort
Case‐Control
Cross‐Sectional
Ecological
Case Series
Case Reports
Increasing Strength
of Evidence
*
Meta‐Analyses
Systematic Reviews
Increasing Evidence
Increasing Evidence
Interventional Observational
Animal Research
Cohort
In vitro (test‐tube) Research
69
70
Case‐Control Study
Cohort Study
Commonly utilized 2x2 Table for study summary:
Exposure
Disease Presence
Yes
No
Total
Yes
A
B
A+B
No
C
D
C+D
B+D
A+B+
C+D
Total
Commonly utilized 2x2 Table for study summary:
A+C
Exposure
Yes
No
Total
Yes
A
B
A+B
No
C
D
C+D
B+D
A+B+
C+D
Total
CASE‐CONTROL design useful when studying a rare disease
Disease Presence
A+C
COHORT design useful when studying a rare exposure
71
72
Study Designs
• Observational Studies:
• Study Methodology: Group allocation based on EXPOSURE
status (presence/absence)
• Definition: A group with something in common
Birth / Inception / Exposure
30
Interventional Observational
Pre-Clinical
Phase 1
Phase 2
Cases
(Reports/Series)
Cross-Sectional
Ecological
Phase 3
Case-Control
Phase 4
Cohort
Increasing Evidence
Increasing Evidence
– Cohort Study (a.k.a. Longitudinal & Follow‐up Study)
DEFINITION vs. STUDY METHODOLOGY
73
74
• Observational Studies Cont’d:
• Observational Studies Cont’d:
– Nested Case‐Control
• A Case‐Control study derived out of a completed Cohort – Cross‐Sectional Study (a.k.a.; Prevalence study)
• Purpose: Examines relationships between disease AND study
exposure (simultaneously) among individuals in a defined study population at a point in time
The diseased study subjects determined from the Cohort study becoming the Cases of a different, subsequent study
» Includes new subjects without disease, called Controls, who may A “snap‐shot” in time (across the entire study population)
Patient selection: based on inclusion in study population
or may not have necessarily come from the original Cohort study
Think of a cross‐sectional study when the information gathered represents what is going on with disease AND exposures (at the same time) a‐cross the entire (a large) study population
75
76
Study Strengths/Weaknesses (Broad)
Study Strengths/Weaknesses (Broad)
• Ability to prove Causation
• Patient Selection
• Applicability (External Validity)
– Inclusion / Exclusion criteria
• Others… (Ethics / Cost / Time requirement)
– Inclusion / Exclusion criteria
• Validity (Accuracy/Precision/Consistency)
– Measurements / Assessments / Classifications
 Induction Period / Latency Period
77
78
QUESTIONS?
SUMMARY
• Appropriate study design based on study question, purpose, and group allocation format
• Every study has its unique strengths & weaknesses
• For boards, be able to select the study design delineated in the stem and understand definitions of study‐related terms
31
Learning Objectives for Biostatistics Topics
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Be able to define, explain, and differentiate the 3 common characteristics of research data.
 Magnitude
 Interval
 Rational Zero
Be able to define, differentiate and give multiple examples of the common categories of research data.
 Nominal
 Ordinal
 Interval/Ratio
 These 3 categories can also be transformed into, or thought of in terms of, 2 broader categories:
o Categorical
o Continuous
Q: Can you place each of the initial 3 categories into its appropriate broader category?
Be able to define, differentiate and calculate the 3 common measures of central tendency for research data.
 Mean
 Median
 Mode
Be able to define, differentiate & calculate the 2 common measures of variation (spread/dispersion) for research data.
 Standard Deviation (SD)
 Variance
Be able to interpret multiple forms of visual presentations for data (e.g. pie charts, histograms, scatter and box plots, etc…).
Be able to define and differentiate the terms descriptive statistics versus inferential statistics.
Be able to identify and describe a data distribution curve as normally distributed or positively/negatively skewed especially as
it relates to the mean and median values of a research data set.
Be able to cite and list the percentages of a population represented by 1, 2 and 3 standard deviations (SDs) from the mean of a
normally-distributed data set.
Be able to define and differentiate the statistical terms skewness and kurtosis and be able to interpret values for each.
Be able to define and differentiate the following common statistical terms.
 Alpha
 Type 1 error
 Power
 Beta
 Type 2 error
Q: How does sample size affect Power?
Be able to define and appropriately interpret the statistical terms p value and 95% confidence interval (95% CI).
Be able to list and delineate the elements used to determine sample size for a research study.
Be able to describe and discuss how sample size affects power and the ability to detect a difference between populations, if a
difference truly exists.
Be able to define and differentiate between independent vs. non-independent (paired/repeated measures) data.
Be able to delineate and list the key questions to answer to determine which statistical test is most appropriate when analyzing
research data.
 What “type” of data needs to be analyzed (nominal, ordinal, or interval)?
 Is the data independent or non-independent (paired/repeated measures)?
 How many groups are being compared?
Be able to select the most appropriate statistical test based on the research data being analyzed. [NOTE: Two different
styles/versions of how to select the most appropriate statistical test for research data is provided as an additional Appendix
at the end of this document]
 Comparisons of Frequencies or Proportions:
o Chi-square / Fisher’s Exact
o Mann-Whitney
o Kruskal-Wallis
o McNemar
o Cochran
o Wilcoxon-Signed Rank
o Student t-test
o Friedman / Kendall
o Paired t-test
o Analysis of Variance (ANOVA) / Analysis of Co-Variance (ANCOVA)
o Repeated Measures ANOVA / Repeated Measures ANCOVA
o Multiple ANOVA (MANOVA) / Multiple ANCOVA (MANCOVA)
 Post-hoc tests for 3 or more groups where an initial significance was detected:
o Student-Newman-Keul
o Dunnett
o Scheffe
o Dunn
o Tukey
o Bonferroni adjustment
 Correlations:
o Pearson Correlation
o Contingency Coefficient
o Spearman/Kendall Correlation
 Regressions:
o Logistic Regression
o Linear Regression
o Multinomial Logistic Regression
 Survival tests:
o Kaplan-Meier
o Log-Rank
o Cox Proportional Hazards
 Kappa (the amount of agreement between 2 or more elements (e.g., evaluators/raters/investigators))
 Coefficient of Determination (the fraction of total variability predicted by a regression model)
 Bartlett or Levene or Kolmogorov-Smirnov tests (tests for equal variances of interval data)
32
Learning Objectives for Epidemiology Topics
1.
2.
3.
4.
5.
6.
7.
8.
9.
Be able to define and differentiate the 2 main stages of disease prevention.
 Primary
 Secondary
Be able to define and differentiate the following epidemiological terms:
 Outbreak
 Endemic
 Internal Validity
 Cluster
 Pandemic
 External Validity
 Epidemic
 Reliability
 Generalizability
Be able to calculate a ratio and proportion as measures of disease frequency.
Be able to define, differentiate and calculate each of the following terms associated with medical screenings:
 True Positive (TP)
 Positive Predictive Value (PPV) (a.k.a., Predictive Value Positive (PVP))
 True Negative (TN)
 Negative Predictive Value (NPV) (a.k.a., Predictive Value Negative (PVN))
 False Positive (FP)
 Positive Likelihood Ratio (LR+)
 False Negative (FN)
 Negative Likelihood Ratio (LR-)
 Sensitivity
 Diagnostic Accuracy
 Specificity
Task: Given the first 4 elements, be able to complete a customary epidemiological 2x2 table to calculate all remaining terms.
Be able to define, differentiate and calculate the following measures of disease frequency terms:
 Incidence (a.k.a. Attack or Risk)
 Prevalence
o Incidence Density
o Point Prevalence
o Incidence Rate
o Period Prevalence
o Cumulative Incidence
o Prevalence Rate
Q: How does disease duration affect the Prevalence of a disease?
Be able to define, differentiate and calculate the following epidemiological terms associated with comparing groups based on
measures of association for disease:
 Absolute Difference
 Absolute Risk Reduction (ARR) (a.k.a. Absolute Risk Difference)
 Relative Difference
 Relative Risk Reduction (RRR) (a.k.a. Relative Risk Difference)
 Attributable Difference
 Number Needed to Treat/Harm (NNT/NNH)
 Incidence Risk (IR)
 Odds
 Risk (Rate) Ratio/Relative Risk (RR)
 Odds Ratio (OR)
 Attributable Risk (AR)
Task: Given frequencies of exposure & disease (for 2 groups), complete a customary epidemiological 2x2 table to calculate
all remaining terms.
Be able to define and differentiate each of the following common types of bias:
 Recall bias
 Hawthorne effect
 Healthy-Worker effect
 Compliance bias
 Selection bias
 Withdrawal/Lost-to-Follow-up bias
 Participation/Responder bias
Be able to define and differentiate the following epidemiological terms:
 Association
 Confounding
 Categories of Associations:
 Types of Causal Relationships:
o Artifactual Association
o Sufficient Cause
o Non-Causal Association
o Necessary Cause
o Causal Association
o Component Cause (a.k.a., Risk Factor)
 Misclassification
 Interaction (a.k.a., Effect Modification)
o Differential Misclassification
o Non-Differential Misclassification
Q: Can you differentiate between the terms causation and association? Which study designs can demonstrate each term?
Be able to define and differentiate the following common techniques to control for bias and confounding:
 Study Design stage:
 Data Analysis stage:
o Randomization
o Stratification
o Restriction
o Multivariate Analysis
o Matching
33
Learning Objectives for Study Design & Methodology Topics
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Be able to delineate and describe the difference between Observational and Interventional (Experimental) study designs.
Be able to list, describe and differentiate the methodology of the common types of Observational study designs (specifically their
purpose/design, and patient allocation techniques).
 Case Report/Case Series
 Case-Control (and Nested Case-Control)
 Cohort
 Cross-Sectional
Be able to describe and differentiate between the common types of perspectives utilized by Observational studies.
 Prospective
 Retrospective
 Ambidirectional
Be able to list, describe and differentiate the common types of Interventional study designs (specifically their purpose, sample
size, and duration).
 Pre-Clinical Phase
 Phase 3
 Phase 1
 Phase 4
 Phase 2
Q: Which “phase” occurs after a new medication/device receives FDA approval?
Be able to recite the common elements needed in the determination of a study’s sample size.
 Margin of Error [Alpha (p-value)]
 Confidence Levels (usually 90%-99%)
 Estimated Population Size
 Standard Deviation (usually 0.5 if unknown)
Be able to describe and differentiate between the common types of study reviews.
 Systematic Reviews
 Meta-Analysis
Be able to list, in increasing order of strength of evidence, the common Observational and Interventional study designs.
Be able to describe and differentiate a population and a sample.
Be able to describe and differentiate each of the following sampling terms:
Probabilistic Sampling:
Non-Probabilistic Sampling
 Simple Random Sample
 Convenience Sample
 Systematic Random Sample
 Stratified Random Sample
Be able to describe the process and purpose of Randomization (a.k.a. group allocation/assignment).
Q: How might you determine if a study’s randomization technique was successful and met its primary goal?
Be able to describe and differentiate between the 3 common forms of Randomization.
 Simple
 Blocked
 Stratified
Be able to describe and differentiate between, and draw examples of, each of the following Interventional study designs.
 Simple vs. Factorial
 Parallel vs. Cross-Over
Be able to define the process and purpose of Blinding (a.k.a. Masking).
Be able to describe and differentiate between the 3 main levels of Blinding.
 Single-Blind
 Double-Blind
 Triple-Blind
Be able to describe and differentiate the following terms associated with Interventional studies.
 Placebo/Dummy/Double-Dummy
 Wash-out period
 Run-in/Lead-in period
 Hawthorne-effect
Be able to describe and differentiate the purpose/responsibilities of the following entities associated with Interventional studies.
 Investigational Review Board (IRB)
 Data & Safety Monitoring Board (DSMB)
Be able to describe and differentiate the common methods of handling lost-to-follow up/drop-outs associated with Interventional
and Observational studies.
 Intent-to-Treat
 Per Protocol
Be able to define and develop examples of the common statements of research hypothesis used by researchers.
 Null Hypothesis
 Alternative Hypothesis
34
APPENDIX
Glossary of Example Terms Related to Study Methodology, Epidemiology & Biostatistics
AMBIDIRECTIONAL: A study conducted using both a retrospective and a prospective focus (See Retrospective and Prospective).
This type of study looks back in time for occurrences/events, and then looks forward in time for future occurrences/events.
ARTIFACTUAL (FALSE) ASSOCIATION: A false, incorrect relationship or connection between an exposure and a disease (See
Association).
ASSOCIATION: A relationship or connection between an exposure and a disease. Associations can be categorized as Artifactual (false),
Non-Causal, or Causal (See Artifactual Association, Non-Causal Association and Causal Association).
BASELINE: Information gathered from or about the study subject at the initial time point in a clinical trial, just before a participant starts
to receive their assigned study intervention.
BIAS: The introduction of any factor, process, or information in the design or execution of a study that leads to a spurious (false) result.
Bias is considered as a systemic distortion of the truth. In clinical studies, bias can be minimized by use of the blinding and
randomization techniques. Most biases are associated with the Selection and Information-Gathering/Measurement processes. Example
biases are selection bias and recall bias (See Blinding, Randomization and Selection Bias, Recall Bias).
BLINDING: A research technique by which one or more individuals (study subject, study clinician, study researcher) is prevented from
being informed or know which of the intervention each study subject has been assigned (also called Masked). (See Single-Blind and
Double-Blind).
BLOCKED RANDOMIZATION: A randomization process that attempts to assure a balance number of study subjects within each of
the study groups in the study (See Randomization).
BOOLEAN: Technique in database (literature) searching using the terms “and”, “or”, “not”; web-based presentations can be found at the
following websites (http://lib.colostate.edu/tutorials/advboolean.html and http://lib.colostate.edu/tutorials/boolean.html).
CAUSAL ASSOCIATION: A relationship or connection in which the antecedent event, characteristic or condition must be present prior
to the occurrence of disease (the exposure comes before the disease) (See Association). There are 3 types of causal relationships:
Sufficient Cause, Necessary Cause, and Component Cause (a.k.a., Risk Factor) (See Sufficient Cause, Necessary Cause, and
Component Cause).
CLINICAL TRIAL: A research study involving humans to answer specific questions regarding specific interventions (e.g., medications,
procedures, etc…). Clinical trials can be conducted in one of four phases (See Phase 1, Phase 2, Phase 3, and Phase 4 Trials).
COHORT: In epidemiology, a group of individuals with some characteristics in common (employment, exposure, birth place, birth year,
residence (e.g., zip code)).
COMPONENT CAUSE (a.k.a. RISK FACTOR): A characteristic that if present increases the probability (risk) of disease occurring
(See Causal Association). In other words, if the component cause is present then the disease is more likely to occur than if it is present,
but just because the component cause is present doesn’t mean the disease can’t occur of that if it is present it will occur (e.g., cholesterol
level and coronary heart disease).
COMPOSITE OUTCOME: The combining of two or more outcomes (primary, secondary, or tertiary), into a single, combined outcome
(e.g., death OR myocardial infarction OR stroke).
CONFIDENCE INTERVAL: An interval between which researchers are confident (to a preset percentage (e.g., 95%)) that the true
association or difference between groups lies.
CONFOUNDER: A 3rd variable that distorts the real, observed relationship (association) between two other variables (e.g., exposure
and disease). To be a confounder, the 3rd variable must be associated (correlated) with both of the other 2 variables (e.g., associated with
the exposure and associated with the disease) (See Correlation and Association).
CONTROL: Also known as “the comparator” to which the experimental intervention/observation is compared. (See Control Group). In
an interventional study, the control may either be an active, useful intervention or a placebo. In an observational study, a control is a
person without the exposure (in a Cohort study) or disease (in a Case-Control study).
CONTROL GROUP: The standard by which observational and interventional studies are conducted and in which other groups are
compared. In clinical trials, there is always a “comparator” group, whether they are receiving an active, known effective intervention or a
placebo, from which the experimental interventional group is compared (See Placebo and Standard Deviation).
CORRELATION: A statistical test which evaluates the degree to which one variable changes in relationship with another variable and
relates the magnitude and direction of this change and relationship (association) (See Association).
CROSS-OVER STUDY: A study in which subjects are initially randomly assigned to one of the intervention groups and during the
study are switched from their initially-assigned group to another treatment group, after a wash-out period. Switching intervention groups
can occur more than once during a study (See Wash-Out, Randomization, and Intervention).
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DATA SAFETY AND MONITORING BOARD (DSMB): An independent committee of researchers (statisticians, clinicians, nonclinicians, etc…) and non-researchers (community advocates) organized with the sole purpose of ensuring a clinical trial is ethical and
that the rights (ethical and legal) and safety of study participants are protected after the study begins (while it is being conducted) (See
Clinical Trial). A DSMB may recommend that a trial be stopped or procedures/processes changed if there are safety concerns. These
concerns could include too much risk of harm in one or more groups (not all) or too great of a benefit in one or more groups (not all).
DIFFERENTIAL MISCLASSIFICATION: Unequal/Unbalanced error in classifying study subjects in an observational study, based on
their exposure or disease status (misclassification related to study subjects disease or exposure status) (See Misclassification).
DIGITAL OBJECT IDENTIFIER (DOI): Provides an actionable, interoperable, persistent link to electronic resources; Can be found at
www.doi.org to locate articles and other electronically-based documents.
DIRECT ENDPOINT: An outcome of a study which is most clinically relevant and useful for patient quality of life/health (e.g., a
disease such as death, stroke, MI; or a patient-relevant event, such as hospitalization, prevention of dialysis). This is different from
surrogate endpoints (See Surrogate Endpoint).
DOUBLE-BLIND: A clinical trial design in which neither the participating study subjects nor the study researchers know which
intervention each study participant is receiving; also called double-masked study (See Blinding, Single-Blind, and Placebo).
DOI: See Digital Object Identifier.
DOUBLE-DUMMY INTERVENTION: Use of two placebos so that each group is receiving more than one intervention at a time.
Useful when the two (or more) interventions are customarily administered via different routes (oral, inhaled, injected, rectal, etc…). This
reduces the risk of subjects or an investigator knowing which intervention is the “active” intervention and which intervention is the
placebo.
DSMB: See Data Safety and Monitoring Board.
DUMMY INTERVENTION: See Placebo.
EFFECT MODIFIER: A 3rd variable that distorts the real, observed relationship (association) between two other variables (e.g.,
exposure and disease) by varying the relationship (association) within different layers (strata) of this 3 rd variable. (Note: It is this
underlined portion that differentiates an Effect Modifier with a Confounder). (See Correlation, Confounder, Strata and Association).
EFFICACY ANALYSIS: See Per-Protocol Analysis.
ELIGIBILITY CRITERIA: See Inclusion Criteria.
ENDEMIC: The occurrence of disease at a level that is constantly and consistently elevated for a given population compared to the
occurrence level in other populations/countries.
ENDPOINT: A time-point in which a study ends (a date or duration). Outcome variable(s) the study protocol is designed to
assess/evaluate (answers research question) (synonymous with study Outcome) (See Outcome, Direct Endpoint, Surrogate Endpoint
and Protocol).
EPIDEMIC: The occurrence of disease at a level that is clearly in excess of normal expectancy; Interpreted by most as having a larger
scope/distribution than an outbreak (See Outbreak).
EQUIPOISE: The genuine belief and confidence that an intervention may be worthwhile (risks vs. benefits) if utilized in humans;
therefore, the defense for acceptable use in interventional studies.
EXCLUSION CRITERIA: Predetermined criteria, set by investigators, that delineate the characteristics that patients may have the will
cause them to not be eligible to participate in a clinical study.
EXTERNAL VALIDITY: Extent to which results are applicable to other, non-studied, populations who also have the disease/condition
being studied. (See Generalizability).
GENERALIZABILITY: Taking the results of a study, in which only a sample of the complete study population it utilized, and confer
the same results and outcomes to the entire (full) population (external to the study’s sample population).
HAWTHORNE EFFECT: Psychological or physiological change simply due to being cared for and managed as part of a study.
Commonly considered a reason for any ‘changes’ seen/perceived from use of a placebo (See Placebo and Placebo-Effect).
HEALTHY-WORKER EFFECT: A common bias in Cohort studies where study subjects are selected only from the currentlyemployed cohort; excluding all of the existing and past ill/dead subjects who may have been exposed and may have been harmed by
disease but are no longer able to be employed (See Bias).
HYPOTHESIS: A supposition, assumption, or perspective on which to base the rationale for conducting a research study. A statement of
outcome the researcher expects to find from conducting the research study (See Null Hypothesis).
INCLUSION CRITERIA: Predetermined criteria set by investigators, which delineates the characteristics that patients need to have to
allow them to be eligible to participate in a clinical study.
INDUCTION PERIOD: Time interval between exposure which may cause a disease and the onset of the disease (could be undiagnosable at this stage).
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INFERENTIAL STATISTICS: Use of statistical tests to reach conclusions that extend beyond the immediate data derived from the
study’s sample population; using statistics to draw conclusions, generalizations, predictions, and estimations about the general population
based on data from samples (See Generalizability).
INFORMED CONSENT: The process potential study subjects undergo to learn the key facts (risks, benefits, processes, requirements,
costs, compensation, etc…) about a clinical trial before deciding whether or not to participate. It is also a continuing process throughout
the study to provide information for participants. To help someone decide whether or not to participate, the doctors and nurses involved in
the trial explain the details of the study and document in detail each step of this process.
INSTITUTIONAL REVIEW BOARD (IRB): An independent committee of researchers (statisticians, clinicians, non-clinicians, etc…)
and non-researchers (community advocates) organized with the sole purpose of ensuring a clinical trial is ethical and that the rights
(ethical and legal) and safety of study participants are protected before the study begins. All clinical trials in the U.S. must be approved,
prior to study initiation, by an IRB (See Clinical Trial).
INTENT-TO-TREAT: Analysis of clinical trial results that includes all data from participants in the groups to which they were
randomized (See Randomization) even if they never received the intervention, withdrew from the study or were lost to further follow-up.
Considered the most conservative way to manage patients who are lost-to-follow-up (See Lost to Follow-up). Missing data is commonly
treated as the last-assessment carried forward for all missed assessments, or use of the study subject’s baseline assessment for all missed
assessments going forward.
INTERACTION: See Effect Modifier.
INTERNAL VALIDITY: Extent to which results accurately reflect the true situation of the study population (study sample).
INTERVAL DATA: Data that has magnitude, a fixed, consistent spacing (interval) between all observable points, yet does not have an
absolute zero (allows negative values). Adequately described by the descriptive statistics of mean, median and mode (See Ratio Data,
Mean, Median and Mode).
INTERVENTION: A “treatment” provided to the patient as part of a clinical trial. The treatments may be medications, placebo, device,
health program, exercise or other element the study subjects will be asked to undertake.
IRB: See Institutional Review Board.
KAPPA STATISTIC: A statistical test useful in comparing assessments from two or more raters/evaluators. It looks at “agreement”
between multiple opinions/determinations. Statistic varies between +1.0 (perfect agreement) and -1.0 (perfect disagreement).
LATENCY PERIOD: Time interval between disease onset of the disease and clinical diagnosis of disease.
LEAD-IN PHASE: See Run-In Phase.
LOST TO FOLLOW-UP: Patients not completing all aspects of a study, regardless of reason(s).
MATCHING: Process of selecting pre-determined patient characteristic(s) used to select and enroll subjects enrolled in different study
groups to make them more equal on that key characteristic(s). A key way to control or adjust for confounders (See Confounder).
MASKED: See Blinding.
MAXIMUM: The highest value in a set of values.
MEAN: Average. Calculated by taking the sum of all values and dividing the sum by the total number of values. Useful for describing
Interval/Ratio data variables (See Interval Data and Ratio Data).
MEDIAN: The middle value of a group of values listed from lowest to highest. Found in an odd number of values by listing all values in
the data set from lowest to highest and finding the middle-most value (where there is the same number of values above and below this
middle value). Found in an even number of values by listing all values in the data set from lowest to highest and finding the average of the
middle two values. Useful for describing Ordinal and Interval/Ratio data variables (See Ordinal Data, Interval Data and Ratio Data).
MEDICAL SUBJECT HEADING (MeSH): MeSH is the National Library of Medicine's controlled vocabulary thesaurus. It consists of
sets of terms which name descriptors in a hierarchical structure that permits literature searching at various levels of specificity. MeSH
descriptors are arranged in an alphabetic and a hierarchical structure. At the basic level of the hierarchical structure, are very broad
headings (e.g., "Anatomy" or "Mental Disorders”). More specific headings are found at more narrow levels of the twelve-level hierarchy,
(e.g., "Ankle" and "Conduct Disorder”). There are 27,149 descriptors in the current MeSH network. There are also over 218,000 entry
terms that assist in finding the most appropriate MeSH Heading, (e.g., "Vitamin C" is an entry term to "Ascorbic Acid”). In addition to
these headings, there are more than 219,000 headings called Supplementary Concept Records (formerly Supplementary Chemical
Records) within a separate thesaurus.
MeSH: See Medical Subject Heading.
MINIMUM: The lowest value in a set of values (dataset).
MISCLASSIFICATION: Error in classifying study subjects in an observational study in terms of exposure status or disease status. The
two common types of misclassification are Differential and Non-Differential (See Differential Misclassification and Non-Differential
Misclassification).
37
MODE: The most common value in a set of values. Useful for describing Nominal, Ordinal, and Interval/Ratio data variables (See
Nominal Data, Ordinal Data, Interval Data and Ratio Data).
NECESSARY CAUSE: A condition/event which must be present prior to the onset of disease for the disease to occur yet may also be
present without causing the disease (See Causal Association). In other words, if disease occurs then the necessary cause must have been
present prior to the onset of disease, but just because the cause is present doesn’t necessary mean that disease will absolutely occur (e.g.,
Mycobacterium tuberculosis and Tuberculosis disease).
NOMINAL DATA: Data that has does not have magnitude. Classically represented by categories that do not express magnitude.
Adequately described by the descriptive statistics of mode (See Mode).
NON-CAUSAL ASSOCIATION: A relationship or connection in which the disease induces the exposure (rather than the exposure
inducing the disease) or from a confounding variable (See Association and Confounder).
NON-DIFFERENTIAL MISCLASSIFICATION: Equal and balanced error in classifying study subjects in an observational study,
regardless of exposure or disease status (misclassification unrelated to study subjects disease or exposure status) (See Misclassification).
NON-PARAMETRIC DATA: Data which is not known to meet the criteria for parametric data. Non-parametric data does not have a
normal distribution, is not randomly or independently obtained, does not contain equal variances between groups, and is not adequately
described by a mean, median and mode. (See Parametric Data, Mean, Median, Mode, Randomization & Sampling and Variance).
NON-PROBABILITY SAMPLING: A sample obtained without a non-zero probability of inclusion in the study. An example is
Convenience Sampling (just taking the first 20 people you come in contact with or willing to participate)
NULL HYPOTHESIS: Perspective taken by researchers at the start of human studies that there will be no difference between the study
groups. At the conclusion of the study, the researchers use the outcome data to either accept this perspective or reject it because they
found a statistically significant difference between groups (See Statistically Significant).
OPEN-LABEL: A clinical trial in which all participants (study researchers, clinicians, and subjects) know which intervention is being
administered to each study subject.
ORDINAL DATA: Data that has magnitude, yet does not have a fixed, consistent spacing (interval) between all observable points.
Classically represented by categories/ranges that express magnitude. Adequately described by the descriptive statistics of median and
mode (See Median and Mode).
OUTBREAK: The increase in occurrence of a disease (epidemic) that is limited in time and scope/distribution (local) (See Epidemic).
OUTCOME: A variable (assessment) which answers the study purpose/intent (answers a research question). Outcomes can either be
Primary, Secondary, Tertiary, or Composite. (See Primary Outcome, Secondary Outcome and Composite Outcome).
PANDEMIC: The occurrence of disease at a level that is clearly in excess of normal expectancy and that is also very widespread;
classically across multiple countries/continents.
PARAMETRIC DATA: Data which is known to have a normal distribution, randomly and independently obtained, contain equal
variances between groups, and is adequately described by a mean, median and mode. (See Mean, Median, Mode, Randomization &
Sampling and Variance).
PER-PROTOCOL ANALYSIS (a.k.a. EFFICACY ANALYSIS): Analysis of clinical trial results that includes only the data from
participants that completed a pre-determined percentage/fraction (e.g., 80%) of the study’s requirements (treatments, evaluations, followup, etc…) (See Randomization). It ignores the data collected to date on the patients that never received their assigned intervention,
withdrew from the study, or were lost to further follow-up before the study was completed.
PHASE 1 TRIAL: A clinical study conducted in a small number (10-30) of health individuals to determine the
pharmacokinetics/pharmacology and short-term safety of an intervention.
PHASE 2 TRIAL: A clinical study conducted in a slightly larger number of diseased subjects (compared to Phase 1 studies; 50-150) to
determine the effectiveness and short-term safety of an intervention.
PHASE 3 TRIAL: A clinical study conducted in an even larger number of diseased subjects (compared to Phase 1 & 2 studies; 150300+) to determine the effectiveness and short-to-intermediate-term safety of an intervention. This phase is intended to gather additional
information in a larger diseased population (over the Phase 2 study) to evaluate the overall benefit-risk relationship of the intervention and
is required by the FDA for intervention approval/labeling.
PHASE 4 TRIAL: Also called Post-Marketing trial and is a clinical interventional study or documentation registry (observational data
collection), conducted after a drug is approved by the FDA and marketed/sold by one or more companies. Post-marketing (Phase 4)
studies are customarily utilized to delineate additional information including the drug's longer-term risks, benefits, and optimal use when
used in a very large population.
PLACEBO: A placebo is an inactive ingredient administered in any form (tablet, capsule, liquid, inhalation, etc…) that has no
known/inherent interventional value. In clinical trials, interventions are often compared with a placebo to assess the intervention's
effectiveness. (See Placebo-Controlled).
PLACEBO CONTROLLED: A study in which a placebo is utilized (See Placebo).
38
PLACEBO EFFECT: A physical or emotional change derived from the use of a placebo. Due to the power of suggestion or the
Hawthorne Effect (See Hawthorne Effect)
POWER: The ability of a study to detect a true difference between group measurements if one actually exists (See Sample Size).
PRE-CLINICAL: Refers to the testing of experimental interventions (medications, techniques, materials, etc…) in the test tube or in
animals - testing that occurs in before trials in humans are carried out.
PRIMARY OUTCOME: The main purpose of the study. It is what the researchers consider the most important element to
assess/evaluate from the study.
PRIMARY PREVENTION: An intervention used to prevent a disease from occurring (before it occurs or becomes established).
PROBABILITY SAMPLING: A sample obtained with a known, non-zero probability of inclusion in the study. Examples include
Simple Random Sampling (e.g., using random number generator), Systematic Sampling (e.g., using all persons who last name begins with
“M”) and Stratified Sampling (e.g., random sampling by layers (strata) of a given variable (e.g., age, disease severity, etc…)) (See Strata,
Sampling and Randomization)
PROPORTION: The division of two numbers that are related (i.e., the numerator is a part, or subset, of the denominator).
PROSPECTIVE: Forward looking for study outcome (e.g., disease, as assessed in a Cohort study). At the time of study initiation, the
outcome (disease) is not known. All clinical trials are prospective in nature. Cohort studies can also be conducted retrospectively. CaseControl studies are always considered retrospective (See Retrospective).
PROTOCOL: A procedural plan-of-action on which all studies are based, planned and conducted. The plan is carefully designed
describe exactly how the study will be conducted and how the researchers plan to strive to answer specific research questions. A protocol
describes what types of people may and may not participate in the study (inclusion/exclusion criteria); the schedule of
tests/procedures/medications and their related protocols/instructions; and the length of the study (including post-study follow-up) (See
Inclusion Criteria and Exclusion Criteria).
RANDOMIZATION: A method of study subject allocation based on a known probability for study group selection. The goal/purpose of
the randomization process is to make all study groups as equal as possible (in number and characteristics) and to reduce the occurrence of
confounding/bias. Examples of the types of randomization include Simple Randomization, Blocked Randomization, and Stratified
Randomization (See Simple Randomization, Blocked Randomization and Stratified Randomization).
RANDOMIZED TRIAL: A study in which participants are randomly assigned, with a known probability of selection, to one of the
study groups (arms) of a clinical trial. (See Randomization).
RANGE: The difference (subtraction) between the lowest value and the highest value in a set of values.
RATE: The division of two numbers with time as an element of the denominator.
RATIO: The division of two numbers that are unrelated (i.e., the numerator is not a part, or subset, of the denominator).
RATIO DATA: Data that has magnitude, a fixed, consistent spacing (interval) between all observable points and contains an absolute
zero. Adequately described by the descriptive statistics of mean, median and mode (See Mean, Median and Mode).
RECALL BIAS: A difference in the way study subjects in the different study groups recall information which has occurred in the past
(See Bias).
RETROSPECTIVE: Backward looking for study outcome (e.g., exposure, as assessed in a Case-Control study or disease, as assessed in
a Cohort study). At the time of study initiation, patient disease status is already known but is not the primary focus of the observational
study. Case-Control studies are always considered retrospective. Cohort studies are either retrospective (disease status already known at
time of study initiation (yet being a Cohort study, the subjects will initially be divided based on exposure status) or prospective (disease
status (outcome) not yet known at start of study) (See Prospective).
RESTRICTION: Pre-set patient characteristics set by researchers which will not be allowed to participate in a study. A key way to
control or adjust for confounders (See Exclusion Criteria and Confounder).
RISK FACTOR: See Component Cause.
RUN-IN PHASE: The pre-defined time period prior to the start of the official interventional stage of a clinical study in which
participants are asked to limit, reduce or eliminate certain interventions or practices in order to determine a intervention-free (new)
baseline. Many studies utilize one or more placebo interventions during this phase to determine if the study subject can be compliant with
the study requirements prior to the start of the more important (“real”) intervention phase under study (Synonymous with Lead-In Phase).
SAMPLE: A number of individuals selected from all of the subjects in a particular group (population) (See Sampling, Probability
Sampling and Non-Probability Sampling).
SAMPLE SIZE: The total number of individuals needed/selected for a study (See Sample and Power).
SAMPLING: The process of selecting a pre-determined number of individuals from all of the subjects in a particular group (population)
(See Probability Sampling and Non-Probability Sampling). The goal of sampling is to draw a representative smaller number of study
subjects from the full, total population being studied.
39
SECONDARY PREVENTION: An intervention used to interrupt/minimize a disease process from progressing, more symptomatic or
from reoccurring.
SECONDARY OUTCOME: An evaluation that is not considered the most important element to assess/evaluate from the study (See
Primary Outcome), but is none-the-less still evaluable and useful to address/evaluate.
SELECTION BIAS: A non-equitable, non-balanced difference between study groups in the way study subjects are selected by the
researcher for study participation (See Bias). This bias could also be due to actions of the study subject (called Self-Selection bias).
SELF-SELECTION BIAS: A non-equitable, non-balanced difference between study groups in the way study subjects determine their
interest in study participation (See Bias).
SIMPLE RANDOMIZATION: See Randomization.
SINGLE-BLIND: A study that classically keeps the study subject unaware of what intervention the participant is receiving; also called
single-masked study (See Blinding and Double-Blind).
STANDARD DEVIATION (SD): One way to represent the spread of a data set and is calculated by taking the square root of the
variance (See Variance).
STATISTICAL SIGNIFICANCE: The probability that an event or difference occurred by chance alone; also interpreted as the
probability of making a Type 1 error if the null hypothesis is rejected (See Null Hypothesis and Type 1 Error).
STRATA: Layers or levels (categories) of a given variable or patient characteristic.
STRATIFIED RANDOMIZATION: A randomization process that attempts to assure balance in the number of study subjects within
individual layers/levels (categories) on pre-determined variable(s) or patient characteristic(s). Useful in controlling for possible
confounders (e.g., Gender (Male/Female), Disease severity (Low/Moderate/High), etc…). (See Randomization and Strata).
SUFFICIENT CAUSE: A set of minimum conditions/events required to be present to inevitably produce disease (See Causal
Association). In other words, if disease occurs then the sufficient cause must have been present prior to the onset of disease, and if the
cause is not present the disease will not occur (e.g., homozygous gene alterations and Tay-Sachs disease).
SURROGATE ENDPOINT: An outcome of a study which is an alternative to detecting disease and may be less clinically relevant and
useful for patient quality of life/health, but useful as a substitute (alternative) for disease or other patient-relevant outcomes. Examples
include cholesterol level, blood pressure, or serum creatinine. These are considered different from direct endpoints (See Direct
Endpoint).
TYPE 1 ERROR: Incorrectly rejecting the null hypothesis when in fact there really is no difference between the groups and it should
have been accepted (See Null Hypothesis).
TYPE 2 ERROR: Incorrectly accepting the null hypothesis when in fact there really is a difference between the groups and it should
have been rejected (See Null Hypothesis).
VALIDITY: The quality of being factually sound (accurate); the extent to which a concept, conclusion or measurement is well-founded
and corresponds accurately to the real world; “Determining the Truth” (See Internal Validity and External Validity).
VARIANCE: One way to represent the spread of a data set and is calculated by finding the difference in each individual value and the
mean value of the group/data set, adding these differences together and then dividing by the number of values in the data set (See Mean).
WASH-OUT: The period of time during a clinical, interventional study in which study subjects have their initially-assigned intervention
stopped. This time period allows the effects of the initial intervention to be eliminated, after which the study subjects are then given an
alternative intervention and its affects assessed (See Cross-Over Study).
40
Exposure
Outcome
Yes
No
Total
Yes
No
Total
Exposure
Outcome
Yes
No
Total
Yes
No
Total
Exposure
Outcome
Yes
No
Yes
No
Total
41
Total
Test
Disease
Present
Absent
Total
Positive
Negative
Total
Test
Disease
Present
Absent
Total
Positive
Negative
Total
Test
Disease
Present
Absent
Positive
Negative
Total
42
Total
Data Type
NOMINAL
2 Groups
Independent
Related
≥3 Groups
Independent
Proportion
of Events
(Survival)
Related
Log-Rank
(Pearson’s)
Chi-square
Fisher’s
Exact
McNemar
Chi-square
Fisher’s
Exact
Bonferroni test
of Inequality
43
Cochran
Measure of
Correlation
Prediction
or
Association
Contingency
Coefficient
Logistic
Regression
Data
Type
ORDINAL
2 Groups
Independent
Related
≥3 Groups
Independent
Proportion
with Event
(Survival)
Related
Cox
Proportional
Hazards
MannWhitney
Wilcoxon
Signed
Rank
KruskalWallis
Friedman
Student-Newman-Keul
Dunnett
Dunn
44
Measure of
Correlation
Prediction or
Association
Spearman
Correlation
Multinomial
Logistic
Regression
Data Type
INTERVAL
2 Groups
≥3 Groups
Independent
Independent
Related
Student t
or ANOVA
or
MANOVA
Paired t or
Repeated
Measures ANOVA
or Repeated
Measures MANOVA
NonParametric
Alternative
MannWhitney
NonParametric
Alternative
Wilcoxon
Signed
Rank
ANOVA
or
MANOVA
Non-Parametric
Alternative
Kruskal-Wallis
If
Confounder
is present
ANCOVA
or
MANCOVA
Bonferroni t or Tukey or Scheffe or Dunn
or Student-Newman-Keul or Dunnett
Time to
Event or
Survival
Measure of
Correlation
Kaplan-Meier
product-limit
estimate
Pearson
Correlation
NonParametric
Alternative
Cox
Proportional
Hazards
NonParametric
Alternative
Spearman
Correlation
Related
Repeated
Measures
ANOVA or
Repeated
Measures
MANOVA
NonParametric
Alternative
Friedman
If
Confounder
is present
Repeated Measures
ANCOVA or Repeated
m45
easures MANCOVA
Membership
Prediction
or
Association
Linear
Regression
NonParametric
Alternative
(Multinomial)
Logistic
Regression
Is the data
Nominal?
Figure
1
No
Do you wish
to check for
correlation?
Yes
No
Do you wish to
assess for
associations or
predict group
membership?
No
Yes
Log Rank
Yes
Logistic
Regression
How
many
groups?
2
Are groups
or their
assessments
independent
Yes
Does any cell
have an
expected
frequency of
<5?
No
Chi-square
Yes
No
Yes
Contingency
Coefficient
Do you wish to assess
for proportion to event
(survival)?
Do you wish to
compare
frequencies or
proportions?
Report
Results
≥3
No
Does any
cell have an
expected
frequency of
<5?
Chi-square
No
46
Is test
significant?
No
Is the
Data
Interval?
Yes
Go to
Figure 3
No
Yes
McNemar
Fisher’s
Exact
Go to
Figure 2
Are groups or
their
assessments
independent?
No
Yes
Yes
Is the
Data
Ordinal?
Cochran
Yes
Fisher’s
Exact
Yes
Bonferroni test
of Inequality
Is the data
Ordinal?
Figure
2
No
Do you
wish to
check for
correlation?
No
Do you wish to
assess for
proportion with
event (survival)?
Yes
Yes
Spearman
Correlation
Cox
Proportional
H a z a r ds
Do you wish to
assess for
associations or
predict group
membership?
Do you wish to
compare
frequencies or
proportions?
No
Yes
No
No
Is the
Data
Nominal?
Yes
How
many
groups?
Yes
Multinomial
Logistic
Regression
2
Are groups or
their
assessments
independent?
Yes
MannWhitney
No
Wilcoxon
Signed
Rank
Yes
KruskalWallis
Yes
Student-Newman-Keul
Dunnett
Dunn
47
Go to
Figure 1
No
Yes
Yes
Go to
Figure 3
≥3
Are groups or
their
assessments
independent?
Is the
Data
Interval?
Friedman
Is test
significant
No
Report
Results
Figure
3
No
Do you wish to
assess for a
correlation?
Yes
Pearson
Correlation
No
Do you wish to
assess for
associations or
predict group
membership?
No
Linear
Regression
Yes
No
Are groups or
their assessments
independent?
Paired t [or
Repeated Measures
ANOVA or Repeated
Measures MANOVA]
No
ANOVA; IF
Confounding is
present use
ANCOVA
Yes
Is there
>1 DV?
MANOVA; IF
Confounding is
present use
MANCOVA
Is test
No
significant? 48
Go to
Figure 1
Is there
>1 DV?
No
Yes
Report
Results
Is the Data
Nominal?
Yes
No
Yes
Student t [or
ANOVA or
MANOVA]
Yes
Go to
Figure 2
≥3
No
Yes
Is the
Data
Ordinal?
No
How many
groups?
Are groups or
their assessments
independent?
Bonferroni t
Tukey
Scheffe
Student-Newman-Keul
Dunnett
Dunn
No
Is data normally
distributed?
2
Yes
Is the data
Interval?
Yes
Yes
Do you wish to
assess for time to
event or survival?
Kaplan-Meier
product-limit
estimate
Do you wish to
compare
means?
Yes
Repeated
Measures
ANOVA; IF
Confounding is
present use
Repeated
Measures
ANCOVA
Yes
Repeated
Measures
MANOVA; IF
Confounding is
present use
Repeated
Measures
MANCOVA
Data Type
NOMINAL
2 Groups
Independent
Related
≥3 Groups
Independent
49
Proportion
of Events
(Survival)
Related
Measure of
Correlation
Prediction
or
Association
Data
Type
ORDINAL
2 Groups
Independent
Related
≥3 Groups
Independent
Related
50
Proportion
with Event
(Survival)
Measure of
Correlation
Prediction or
Association
Data Type
INTERVAL
2 Groups
≥3 Groups
Independent
Independent
Measure of
Correlation
Membership
Prediction or
Association
NonParametric
Alternative
NonParametric
Alternative
NonParametric
Alternative
Related
Non-Parametric
Alternative
NonParametric
Alternative
Related
Time to
Event or
Survival
NonParametric
Alternative
NonParametric
Alternative
If
Confounder
is present
If
Confounder
is present
51
Is the data
Nominal?
Figure
1
No
Do you wish to
assess for
associations or
predict group
membership?
No
2
Yes
How
many
groups?
Are groups
or their
assessments
independent
No
Yes
Yes
No
Report
Results
No
No
52
Go to
Figure 2
≥3
Does any
cell have an
expected
frequency of
<5?
Is test
significant?
Is the
Data
Ordinal?
No
Is the
Data
Interval?
Yes
No
Yes
No
Yes
Yes
Are groups or
their
assessments
independent?
Does any cell
have an
expected
frequency of
<5?
No
Yes
Yes
Yes
Do you wish
to check for
correlation?
Do you wish to assess
for proportion to event
(survival)?
Do you wish to
compare
frequencies or
proportions?
Yes
Yes
Go to
Figure 3
Is the data
Ordinal?
Figure
2
No
No
Do you
wish to
check for
correlation?
Do you wish to
assess for
proportion with
event (survival)?
Do you wish to
assess for
associations or
predict group
membership?
Do you wish to
compare
frequencies or
proportions?
No
Yes
No
No
Is the
Data
Nominal?
Yes
How
many
groups?
Yes
2
Yes
Are groups or
their
assessments
independent?
Yes
Yes
No
Yes
Go to
Figure 1
No
Yes
Yes
Is test
significant
No
Report
Results
53
Yes
Go to
Figure 3
≥3
Are groups or
their
assessments
independent?
Is the
Data
Interval?
Figure
3
No
Do you wish to
assess for a
correlation?
Do you wish to
assess for
associations or
predict group
membership?
Do you wish to
compare
means?
No
Is the data
Interval?
No
Yes
Is data normally
distributed?
Yes
Yes
Yes
No
2
Are groups or
their assessments
independent?
Do you wish to
assess for time to
event or survival?
Are groups or
their assessments
independent?
Is there
>1 DV?
Yes
Is test
No
significant? 54
Yes
Report
Results
Go to
Figure 1
Is there
>1 DV?
No
Is the Data
Nominal?
Yes
No
Yes
No
Yes
Go to
Figure 2
≥3
No
Yes
Is the
Data
Ordinal?
No
How many
groups?
No
Yes
Yes
Yes
2015 Annual Meeting
Friday, May 22
8:00—9:00 a.m.
0204-0000-15-413-L01-P
Please see the following pages for educational materials for this activity and
instructions on how to receive credit.
55
New and Emerging Strategies
for the Treatment of Advanced
Melanoma
LSHP Annual Meeting 2015 – New Orleans, LA – May 22, 2015
Planned and conducted by ASHP Advantage and supported by an
educational grant from Merck
56
Activity Overview
According to the National Cancer Institute and the American Cancer Society, over 75,000 people will be
diagnosed with melanoma in the United States in 2014, with 9710 deaths. The increasing number of people in
the US over 65 along with longer life expectancy generally will lead to greater numbers of patients diagnosed
with melanoma over the coming decade. Although knowledge about prevention of melanoma has become
more prevalent, death due to advanced disease has doubled over the past 30 years. Inevitably, the aging US
population and improvement in treatments will increase the number of patients with melanoma and present
new challenges. A number of novel treatments have been approved and are in development for patients with
melanoma. Oral agents that target molecular drivers of the disease have produced robust response rates,
however, they come with a number of challenges for patients and providers, specifically drug interactions, food
effects, and unique side effects. Along with new oral agents, drugs that activate the immune system have also
been approved for use, with impressive activity. These agents also have specific adverse event profiles that all
pharmacists should be familiar with. Faculty will discuss current agents and regimens used to treat melanoma,
highlighting recently approved agents and treatment controversies. Management principles and key resources
for pharmacists will also be discussed.
Learning Objectives
At the conclusion of this application-based educational activity, participants should be able to
•
•
•
•
•
Review the pathophysiology of BRAF-mutant melanoma.
Design a first- line therapeutic plan for a patient who has BRAF-mutated metastatic melanoma.
Compare and contrast the mechanism of action and toxicity profile of interleukin 2, ipilimumab, and
pembrolizumab.
Describe common adverse effects associated with immunotherapy as well as strategies for managing
them.
Discuss future directions in the treatment of melanoma therapy with regard to treatment options and
tumor genomic sequencing.
Continuing Education Accreditation
The American Society of Health-System Pharmacists is accredited by the Accreditation Council for
Pharmacy Education as a provider of continuing pharmacy education. This activity provides 1.0
hour (0.1 CEU – no partial credit) of continuing pharmacy education credit (ACPE activity #02040000-15-413-L01-P).
Participants will process CPE credit online at http://elearning.ashp.org/my-activities, with the option of printing
a CE certificate. CPE credit will be reported directly to CPE Monitor. Per ACPE, CPE credit must be claimed no
later than 60 days from the date of the live activity or completion of a home study activity.
57
Activity Faculty
R. Donald Harvey, Pharm.D., FCCP, BCOP
Associate Professor, Hematology/Medical Oncology
Director, Phase 1 Clinical Trials Section
Winship Cancer Institute
Emory University
Atlanta, Georgia
R. Donald Harvey, Pharm.D., FCCP, BCOP is Director, Phase 1 Clinical Trials Section at Winship Cancer Institute of
Emory University and Associate Professor, Department of Hematology and Medical Oncology at the Emory
University School of Medicine in Atlanta, Georgia. Dr. Harvey also serves as Co-chair of the Data Safety and
Monitoring Committee and as a Pharmacology representative on the Clinical and Translational Research
Committee for the cancer center, as well as preceptor for the Emory PGY-2 oncology residency.
He received his Bachelor of Science in Pharmacy and Doctor of Pharmacy degrees from the University of North
Carolina (UNC) in Chapel Hill. He subsequently completed a pharmacy practice residency at the University of
Kentucky Medical Center and College of Pharmacy and a Hematology/Oncology specialty residency at UNC
Hospitals and School of Pharmacy.
Dr. Harvey is a board certified oncology pharmacist and a fellow of the American College of Clinical Pharmacy
(ACCP). He has authored or co-authored over 40 peer-reviewed publications, and is section editor for original
research for the Journal of Hematology Oncology Pharmacy. He serves as a reviewer for the British Journal of
Cancer, Journal of Pharmaceutical and Biomedical Analysis, Cancer, Annals of Oncology, Pharmacotherapy,
and the Journal of Clinical Pharmacology. Dr. Harvey was President of the Hematology/Oncology Pharmacy
Association (HOPA) from 2010-2013 and now serves as Vice Chair of the HOPA Research Foundation.
358
Disclosure Statement
In accordance with the Accreditation Council for Continuing Medical Education’s Standards for Commercial
Support and the Accreditation Council for Pharmacy Education’s Guidelines for Standards for Commercial
Support, ASHP Advantage requires that all individuals involved in the development of activity content disclose
their relevant financial relationships. A commercial interest is any entity producing, marketing, re-selling, or
distributing health care goods or services consumed by, or used on, patients. A person has a relevant financial
relationship if the individual or his or her spouse/partner has a financial relationship (e.g., employee, consultant,
research grant recipient, speakers bureau, or stockholder) in any amount occurring in the last 12 months with a
commercial interest whose products or services may be discussed in the educational activity content over which
the individual has control. The existence of these relationships is provided for the information of participants
and should not be assumed to have an adverse impact on presentations.
All faculty and planners for ASHP Advantage education activities are qualified and selected by ASHP Advantage
and required to disclose any relevant financial relationships with commercial interests. ASHP Advantage
identifies and resolves conflicts of interest prior to an individual’s participation in development of content for an
educational activity.
•
The faculty and planners report no financial relationships relevant to this activity.
59
Disclosures
• The faculty and planners report no financial
relationships relevant to this activity.
R. Donald Harvey, Pharm.D., FCCP, BCOP
Associate Professor, Hematology/Medical Oncology
Director, Phase 1 Clinical Trials Section
Winship Cancer Institute
Emory University
Atlanta, Georgia
Planned and conducted by ASHP Advantage
and supported by an educational grant from Merck
Learning Objectives
At the conclusion of this activity, participants should be able to
•
Review the pathophysiology of BRAF‐mutant melanoma.
•
Design a first‐line therapeutic plan for a patient who has BRAF‐mutated metastatic melanoma.
•
Compare and contrast the mechanism of action and toxicity
profile of interleukin 2, ipilimumab, and pembrolizumab. •
Describe common adverse effects associated with
immunotherapy as well as strategies for managing them.
•
Discuss future directions in the treatment of melanoma
therapy with regard to treatment options and tumor genomic sequencing.
Pathophysiology of Melanoma and Drug Approval
Risk Factors
Melanoma Epidemiology
• UV Radiation
• Previous sunburns
• 3% of skin cancer cases
– 80% of skin cancer deaths
•
•
•
•
– > 4 severe by 15 yr
~60,000 new US cases each year
~8,000 will die
High cure rates if treated early
14% of patients with metastatic melanoma
have 5‐year survival rate
• Outdoor lifestyles
•
•
•
•
•
•
•
•
Miller AJ et al. N Engl J Med. 2006; 355: 51-65.
Age
Male Gender
Past hx of melanoma
Xeroderma
pigmentosum
Dysplastic nevi
Fair skin
Family History of
melanoma
Immunosuppressed
Miller AJ et al. N Engl J Med. 2006; 355: 51‐65.
60
ABCDEs of Melanoma
Patient Presentation
A
B
C
D
E
• Median Age of diagnosis 45‐55 years
• Diagnosis at presentation
– 82‐85% present with localized disease – 10‐13% regional disease
– 2‐5% with metastatic disease
Evolution of existing mole
www.skincancer.org accessed 2014 October 30 2014.
Miller AJ et al. N Engl J Med. 2006; 355: 51‐65.
Further Work Up
Biopsy
• History and physical exam
• Further dermatologic examination indicating other lesions
• >1mm thick
• Indicated for a suspicious lesion
• Full thickness excisional biopsy with 1‐3mm margins into normal skin
– Not always feasible (i.e. face, feet, large lesions)
– Full thickness incisional biopsy or punch – Baseline CXR and LFTs • Lactate dehydrogenase (LDH)
• Suspected lymph node involvement confirmation
• Radiographic evaluation at baseline based on site of symptoms
Lymph Node Involvement
Clark Level
• Important prognostic factor
• Complete lymph node dissection
• How deep the tumor has penetrated base histology
• Directly related to risk of metastasis to nodes
• Level I‐V
– Labor intensive
– Unable to stain every section of node and may miss area showing metastasis
– Level I is restricted to epidermis (in situ)
– Level V is metastatic
• Only 20% of patients with an intermediate thickness  regional nodal involvement
– 80% are at risk for a bad outcome from the complete dissection of the LN
• Sentinel LN = First node that melanoma spreads to
– Melanoma follows an orderly nodal distribution
Morton DL et al. Ann Surg. 2005; 242: 302‐313.
61
Breslow Thickness
Staging and 5 Year Survival Rates
• A: < 1mm thick, no ulceration, Clark II‐III
• B: < 1 mm thick with ulceration, Clark IV‐V
• Similar to Clark level but uses a micrometer to measure tumor invasion through a microscope
• 0.75 mm (Clark Level II) • > 0.75 ‐ 1.5 mm (Clark Level III) • > 1.5 ‐ 4.0 mm (Clark Level IV) • > 4.0 mm (Clark Level V) Stage I • 5yr OS: 90‐95%
• > 1 mm thick with any characteristic
Stage II • 5yr OS: 45‐78%
• Lymph node involvement
Stage III • 5yr OS: 28‐70% (depends on # of nodes)
• Metastatic Disease
Stage IV • 5yr OS: 18% (though may be increasing)
http://training.seer.cancer.gov/module_staging_cancer/unit03_sec04_part05_melanoma.html
Melanoma Molecular Subsets
Immunotherapy and Targeted Treatment and Future of Melanoma Treatment
Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved.
Sosman, J: 2011 Education Book American Society of Clinical Oncology 2011: 367-72.
Treatment Overview
Stage I or II
Cancer and Immune Evasion
Surgical removal and observation
• Individual cells and tumors have capacity to avoid immune surveillance from early in development
• Methods used
Stage III Lymph Node Positive
Diagnosis
– Production of immunosuppressive cytokines (e.g., TGF‐β, IL‐4, IL‐6, IL‐10) – Increase number and function of immune suppressor cells (e.g., macrophages, regulatory T cells [Tregs]
– Changes in cell signaling that leads to cancer cell death (e.g., increased IDO, reduced MHC receptors)
– Limit immune effectors and create inhibitory checkpoints Surgical removal and IFN
If BRAF positive, vemurafenib, dabrafenib +/‐trametinib or immunotherapy or trial
Stage IV Metastatic
If BRAF negative, Ipilimumab first line, HD‐IL2, or trial
IFN=interferon
HD-IL2=high-dose interleukin-2
IDO=indoleamine 2,3-dioxygenase
MHC=major histocompatibility complex
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2015. NCCN.org
http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf.Accessed November 2014.
62
Current Immunotherapies in Melanoma
General Immunotherapy Approaches
• Active
• Direct immune stimulation
– Vaccination
– Interleukin‐2 (IL‐2) used for metastatic disease – Interferon alfa‐2B (IFN) for adjuvant therapy
• Autologous
• Allogenic
• Inhibition of immune checkpoints – Cytokines
• Interferon, interleukin‐2, GM‐CSF, denileukin diftitox
– Cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4)
• Passive
• Ipilimumab approved for metastatic melanoma in 2011 – Conventional naked (e.g., rituximab) and loaded (e.g., ado‐trastuzumab emtansine) monoclonal antibodies
– Programmed cell death protein 1 (PD‐1) receptor
• Pembrolizumab approved for patients who failed ipilimumab in 9/4/2014
• Nivolumab approved for same indication 12/22/2014
• Passive leading to active
– Ipilimumab, pembrolizumab, nivolumab
HD IL‐2 Therapy: Durable Responses
•
•
•
Metastatic Melanoma (N = 270)
0.8
0.6
0.4
0.2
0.0
0
• High‐dose IL‐2 benefits patients, but:
– Toxic
– Impractical: must be delivered as an inpatient
• Use remains limited to selected patients treated at experienced centers
• Efforts to develop more tolerable IL‐2 based regimens unsuccessful • Efforts to better select patients who might benefit from HD IL‐2 therapy have produced modest advances
• Proof of principle that immunotherapy can produce durable benefit in patients with solid tumor malignancies
Metastatic RCC (N = 255)
1.0
CR (n = 17)
PR (n = 26)
CR + PR (n = 43)
10 20 30 40 50 60 70 80 90 100 110 120 130
Duration of Response (Months)
Probability of Continuing Response
1.0
CR
PR All
0.8
0.6
0.4
0.2
0.0
0
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180
Duration of Response (Months)
Atkins MB et al. J Clin Oncol. 1999;17:2105‐2116. McDermott DF et al. Expert Opin Biol Ther. 2004;4:455‐468.
Ipilimumab in Metastatic Melanoma: Durable Survival
Comparison of CTLA‐4 vs PD‐1
CTLA‐4 pathway
PD‐1 pathway
Exclusively on T cells
On T, B, and NK cells
Ligands: CD80 and CD86
Ligands: PD‐L1 and PD‐L2
Ligands only expressed on APCs
Ligand expressed on APCs and tumor cells
CTLA‐4–deficient mice suffer early, fatal autoimmune syndrome
PD‐1–deficient mice develop strain‐specific autoimmunity late in life
Previously Treated Patients
Median
OS, Mos
Ipi + gp100 10.0
Ipi
10.1
gp100
6.4
100
Previously Untreated Patients
HR P Value
0.68 < .001
0.66
.003
80
60
40
Blockade enhances CD8+ T cells greater than Blockade enhances proliferation of CD4+ and CD8+ T cells with increase in ratio to regulatory CD4+ with increase of CD8+ to Tregs and T cells
cytotoxicity of CD8+
20
0
4
8 12 16 20 24 28 32 36 40 44 48 52 56
60
Ipilimumab + dacarbazine
Placebo + dacarbazine
40
20
Ipilimumab + gp100 vs
OS=Overall survival
0
4
8
12 16 20 24 28 32 36 40 44 48
Mos
Mos
Greenwald RJ et al. Ann Rev Immunol. 2005; 23:515-548. Chambers CA et al. Ann Rev Immunol. 2001;19:565-594. Dong
H et al. Nat Med. 2002; 8:793-800. Curran MA et al. Proc Natl Acad Sci U S A. 2010; 107:4275-80. Pilon-Thomas S et al.
J Immunol. 2010;184:3442-3449.
80
0
0
APC=antigen presenting cells
Est 1, 2, 3-Yr
P
Median
Survival, %
OS, Mos
HR Value
47.3, 28.5, 20.8 0.72 < .001
11.2
Ipi + D
36.3, 17.9, 12.2
Placebo + D 9.1
100
Patients Survival (%)
Probability of Continuing Response
HD IL‐2 Therapy in Melanoma and RCC
HD IL‐2 produces durable responses in 6% to 10% of patients with advanced melanoma or renal cell carcinoma (RCC)
Few relapses in patients responding for over 2.5 years (therefore, can be considered cured)
FDA approval in 1992 (RCC) and 1997 (melanoma)
gp100[1]
Ipilimumab vs Placebo[2]
Adapted from Hodi FS et al. N Engl J Med. 2010; 363:711-723.
Robert C et al. N Engl J Med. 2011;364:2517-2526.
63
Ipilimumab: Immune‐Related Adverse Events
System
GI tract
Skin
Symptoms
Management
Diarrhea
Abdominal pain
Dark, bloody stools
Moderate enterocolitis: hold ipilimumab, administer antidiarrheal.
Persistent diarrhea (> 1 wk): systemic corticosteroids. 7+ stools/day:
start methylprednisone, permanently discontinue ipilimumab.
Consider infliximab for corticosteroid-refractory patients
Rash (± itching)
Blistering/peeling
Oral sores
Moderate/nonlocalized rash: hold ipilimumab,
start topical or systemic corticosteroids. Severe dermatitis:
permanently discontinue ipilimumab, start corticosteroids
Jaundice
Nausea/vomiting
Assess ALT/AST, bilirubin, and thyroid function before each dose and
as necessary. Hold ipilimumab if ALT/AST > 2.5 x but ≤ 5 x ULN;
permanently discontinue if AST/ALT > 5 x ULN or bilirubin > 3 x ULN.
The immunosuppressant mycophenolate can be used for
hepatotoxicity in corticosteroid-refractory patients
Weakness in extremities
Numbness/tingling
Sensory changes
Moderate neuropathy: hold ipilimumab. New or worsening neuropathy:
permanently discontinue ipilimumab. Consider corticosteroids
Headaches
Fatigue
Behavior/mood changes
Menstruation changes
Dizziness/light-headedness
Moderate endocrinopathy: hold ipilimumab, start corticosteroids.
Endocrine abnormalities can be difficult to detect, due to nonspecific
symptoms. Consider having an endocrinologist follow the patient
Liver
CNS
Endocrine
Eyes
Vision problems
Irritation
Ipilimumab Adverse Effects
#2
#3
#4
Monitor for redness suggesting uveitis, treat with topical steroidal eye drops
Ipilimumab adverse reaction management guide. Available at: http://hcp.yervoy.com/pages/rems.aspx.
Reprinted with permission. © 2012 American Society of Clinical Oncology. All rights reserved.
Weber JS et al. J Clin Oncol. 2012; 30:2691-7.
CTLA‐4 and PD‐1 Pathways
Nivolumab Phase I Trial Design
Phase 1 Dose Escalation
of anti-PD-1 antibody
N=296 patients
 Melanoma (n = 104)
 NSCLC (n = 122)
 Renal cell carcinoma (n = 34)
 Prostate cancer (n = 17)
 Colorectal cancer (19)
BMS-936558
All patients had a ECOG
performance status of < 2 and
measurable disease
Ipilimumab
0.1 to 10 mg/kg IV every 2
weeks for up to 12 cycles
or until disease progression or
complete response where
therapy could continue
Tumor samples analyzed for
PD-L1 expression using
immunohistochemistry (IHC)
• Cohorts of 3‐6 patients enrolled in each cohort
– 0.1, 0.3, 1.0, 3.0, and 10 mg/kg
• Expansion groups enrolled after no maximum tolerated dose was found
Nivolumab
Pembrolizumab
Brahmer JR. J Clin Oncol. 2013; 31:1021-8.
Topalian S et al. N Engl J Med. 2012; 366:2443-54.
Selected Toxicity
Summary of Results
Toxicity
• Antitumor activity was seen at all dose levels
• Objective response rate (complete or partial)
– 28% in melanoma
– 27% in renal cell carcinoma
– 18% in NSCLC
• 65% of the responses were durable for 1 year or more in patients with > 1 year follow up
• IHC staining for PD‐L1 predicted response rate
Anti‐PD‐1 Antibody all dose levels
All grade
Grade 3 and 4
Diarrhea
11%
1%
Infusion reaction
3%
1%
Hypothyroidism
2%
1%
Increased AST
4%
1%
Pneumonitis
3%
1% (3 deaths)
Skin Toxicity
– 0 of 17 responses in PD‐L1 negative tumors
– 9 of 25 responses in PD‐L1 positive tumors
Topalian S et al. N Eng J Med. 2012; 366:2443-54.
Rash
12%
0%
Pruritus
29%
1%
Vitiligo
8%
0%
Urticaria
2%
0%
Topalian S et al. N Eng J Med. 2012; 366:2443-54.
64
Clinical Development of Inhibitors of the PD‐1 Immune Checkpoint Target
PD‐1
Antibody Molecule
Development Stage
Nivolumab
(BMS‐936558)
Fully human IgG4 Approved
Pembrolizumab
(MK‐3475)
Humanized IgG4
Approved
Pidilizumab (CT‐011)
Humanized IgG1
BMS‐936559
Fully human IgG4
MedI‐4736
Engineered human IgG1
Phase I
MPDL‐3280A
Engineered human IgG1 Phase I‐II
PD‐L1
Activity of Anti‐PD‐1/PD‐L1 in Patients With Advanced Melanoma
6‐Mo PFS, %
12‐Mo PFS, %
Median PFS, Mos
1‐Yr OS, %
2‐Yr OS, %
41
36
3.7
62
43
NA
NA
> 7
81
NA
Pts, n
ORR (at Optimal Dose), %
Grades 3/4 Tx‐Related AEs, %
Nivolumab
(anti‐PD‐1)[1‐3]
104
31
(41)
22
Pembrolizumab
(anti‐PD‐1)[4,5]
135
38
(52)
13
Phase II multiple tumors
BMS 936559
(anti‐PD‐L1)[6]
55
17
5
NA
NA
NA
NA
NA
Phase I
MPDL3280A
(anti‐PD‐L1)[7]
44
29*
36
43
NA
NA
NA
NA
Agent
*Includes 4 patients with UM without a response.
1. Topalian SL et al. J Clin Oncol. 2014; 32:1020-30. 2. Sznol M et al. ASCO 2013. Abstract 9006.
3. Topalian SL et al. N Engl J Med. 2012; 366:2443-54. 4. Ribas A et al. ASCO 2013. Abstract 9009.
5. Hamid O et al. N Engl J Med. 2013; 369:134-44. 6. Brahmer JR et al. N Engl J Med. 2012; 366:2455-65.
7. Hamid O et al. ASCO 2013. Abstract 9010.
Nivolumab + Ipilimumab: Phase I Study Comparison of Anti‐PD‐1 Agents
FDA Approval Date
Type of Antibody
Approved Dosing
Dose forms
Approved Indication
Pembrolizumab
Nivolumab
September 4, 2014
December 22, 2014
Humanized, , IgG4 kappa immunoglobulin
Human, IgG4 kappa immunoglobulin
2 mg/kg over 30 minutes every 3 weeks
3 mg/kg IV over 60 minutes every 2 weeks
50 mg lyophilized powder in single use vial and 100mg/4mL solution in single use vial
40 mg/4mL and 100 mg/10mL solution in single‐use vial
• Concurrent therapy study design:
Patients with stage III or IV melanoma with ≤ 3 previous therapies
(n = 53)
Weeks 0-9
Ipilimumab
+ Nivolumab
q3w x 4 cycles
Weeks 24-108
Ipilimumab
+ Nivolumab
q12w x 8 cycles
Weeks 12-21
Nivolumab
q3w x 4 cycles
Escalating doses of nivolumab (0.3‐10 mg/kg) and ipilimumab (1‐10 mg/kg)
• Sequenced therapy study design
Patients with stage III or IV melanoma with
≥ 3 previous doses of ipilimumab
(n = 33)
FDA accelerated approval for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor
Nivolumab (1 or 3 mg/kg)
q2w for up to 48 doses
Wolchok JD et al. N Engl J Med. 2013; 369:122-33.
Wolchok JD et al. ASCO 2013. Abstract 9012.
Nivolumab + Ipilimumab
Adverse Events
Nivolumab + Ipilimumab: Tumor Response With Concurrent Therapy
Treatment-Related AE,
Number of Patients (%)
Change in Target Lesions From
Baseline (%)
250
200
150
100
ORR: 40%
Highest dose ORR: 53%
(by investigator-assessed irRC
with confirmation)
50
0
-50
-100
Patients
Objective responses were observed in patients with either PD-L1–positive tumor samples
(6 of 13 patients) or PD-L1–negative tumor samples (9 of 22) (P > .99)
irRC=immune-related response criteria
Wolchok JD et al. N Engl J Med. 2013; 369:122-33.
Concurrent
All Cohorts (n = 53)
Sequenced
All Cohorts (n = 33)
All Grades
Grades 3/4
Al Grades
Grades 3/4
Any adverse event
49 (93)
28 (53)
24 (73)
6 (18)
Rash
29 (55)
2 (4)
3 (9)
0
Pruritus
25 (47)
0
6 (18)
0
Fatigue
20 (38)
0
3 (9)
0
Diarrhea
18 (34)
3 (6)
3 (9)
0
Nausea
11 (21)
0
1 (3)
0
Pyrexia
11 (21)
0
1 (3)
0
AST increase
11 (21)
7 (13)
0
0
ALT increase
11 (21)
6 (11)
1 (3)
0
Lipase increase
10 (19)
7 (13)
4 (12)
2 (6)
1 (3)
Amylase increase
8 (15)
3 (6)
1 (3)
Cough
7 (13)
0
2 (6)
Vomiting
6 (11)
1 (2)
0
0
Vitiligo
6 (11)
0
0
0
Headache
6 (11)
0
0
0
0
Wolchok JD et al. N Engl J Med. 2013;369:122-33.
65
Combining Immunotherapy and Targeted Therapy for Melanoma
Improved Survival With
Ipilimumab[1]
Ipi + gp100
Ipi
gp100
Vemurafenib (n = 336)
6 mos OS: 84%
80
60
40
12
20
28
Mos
36
44
52
0
0 1 2 3 4 5 6 7 8 9 101112
Mos
Immunotherapy
Combination???
Percent Alive
Percent Alive
Targeted Therapy
0
1
Yrs
2
3
0
1
Yrs
2
3
Doses of
Ipilimumab
Before ALT-AST
Elevation, n
Time to Onset of
ALT-AST
Elevation After
First Dose
Ipilimumab, Days
Treatment
Time to
Resolution of
ALT-AST
Elevation,
Days
Toxicity
Relapse
With
Repeated
Ipilimumab
4
1
21
Vem discontinued for 5 days then restarted with
dose reduction; Ipi permanently discontinued
4
NA
5
2
26
dose reduction; Ipi continued (2 doses)
6
No
6†
1
21
dose reduction; Ipi continued (1 dose)
6
No
8
1
19
dose reduction; Ipi continued (1 dose)
12
Yes
10
1
15
dose reduction; Ipi permanently discontinued (1
dose)
10
NA
16§
1
13
Vem and Ipi permanently discontinued
20
NA
Cohort 1*
Dacarbazine (n = 336)
6 mo OS: 64%
20
0 4
Patient
Number
Improved Survival With
Vemurafenib[2]
100
OS (%)
100
80
60
40
20
0
Ipilimumab + Vemurafenib Liver Toxicities in Phase I Testing
Cohort 2‡
0
1
Yrs
2
*Cohort 1: 1-month run-in of single-agent vemurafenib 960 mg BID followed by 4 infusions of ipilimumab 3 mg/kg every
3 wks plus vemurafenib.
†Patient also had grade 2 increase in total bilirubin.
‡Cohort 2: vemurafenib 760 mg BID plus ipilimumab 3 mg/kg every 3 wks.
§Patient also had grade 3 increase in total bilirubin.
Ribas A et al. N Engl J Med. 2013;368:1365-1366.
3
Adapted from Hodi FS et al. N Engl J Med. 2010; 363:711-723.
Chapman PB et al. N Engl J Med. 2011; 364:2507-2516.
Which of the following is true regarding single agent immunotherapy in melanoma?
Adverse events seen with ipilimumab and PD‐1 antagonism include:
a. High response rates are commonly seen, but are of short duration
a. Rash, cardiotoxicity, and myelosuppression
b. All produce low response rates of short duration
c. Cardiotoxicity, hepatotoxicity, and
myelosuppression
c. Long‐term responses can be seen, but are in
less than 20% of patients
d. Diarrhea, hepatotoxicity, and myelosuppression
b. Rash, hepatotoxicity, and diarrhea
d. Responses are seen in over 50% and are very durable
Treatment Overview
Stage I or II
BRAF Mutant Melanoma
• Found in 40‐50% of cutaneous melanoma
– Nearly 60% of melanoma in skin without chronic sun‐
induced damage
– 80‐90% are the V600E and 5‐12% are V600K
– Generally non‐overlapping with other mutations
Stage III Lymph Node Positive
Diagnosis
Surgical removal and IFN
• Results in enhanced BRAF kinase activity and
subsequent MAPK activation
If BRAF positive, vemurafenib, dabrafenib +/‐trametinib or immunotherapy or trial
Stage IV Metastatic
• Current FDA approved therapies:
If BRAF negative, Ipilimumab first line, HD‐IL2, or trial
– BRAF inhibitors: Vemurafenib and Dabrafenib
– MEK inhibitor: Trametinib
IFN=interferon
HD-IL2=high-dose interleukin-2
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2015. NCCN.org
http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed November 2014.
66
Phase III Vemurafenib vs. Dacarbazine
R
A
N
D
O
M
I
Z
A
T
I
O
N
N = 675
Previously untreated, unresectable Stage IIIC or IV melanoma with BRAF V600E mutations
Phase III Vemurafenib vs. Dacarbazine
• Overall Survival (6 months)
Vemurafenib 960 mg PO BID
– Vemurafenib: 84% (95% CI, 78%‐89%)
– Dacarbazine: 64%(95% CI, 56%‐73%)
– HR: 0.37 (0.26‐0.55), p< 0.001
Dacarbazine 1000 mg/m2 IV every 3 weeks • Estimated Progression‐Free Survival
– Vemurafenib: 5.3 months
– Dacarbazine: 1.6 months
– HR: 0.26 (0.20‐0.33), p< 0.001
• Co‐primary endpoints: Progression‐free survival (PFS) and overall survival (OS)
• Secondary endpoints: Response rate (RR), response duration and safety
• Stratification by stage, performance status, LDH level and geographic region
• Enrolled January 2010 to December 2010 in 12 countries
BRAF Inhibitor Dermatologic Effects
Vemurafenib and Dacarbazine Toxicity
Toxicity
Vemurafenib
Arthralgia
Maculopapular rash with
keratoacanthomas
Dacarbazine
Grade 2
Grade 3
Grade 2
Grade 3
18%
3%
< 1%
< 1%
Nausea
7%
1%
11%
2%
Fatigue
11%
2%
12%
2%
Diarrhea
5%
< 1%
1%
< 1%
Keratoacanthoma
2%
6%
0%
0%
Hyperkeratosis
5%
1%
0%
0%
Cutaneous SqCC
N/A
12%
N/A
< 1%
Pustular “white head” reactions
treated like traditional acne
The majority of all toxicities were grade 2 or less.
Most common events in the vemurafenib arm were cutaneous events,
arthralgia and fatigue.
N/A = not applicable
sqCC=squamous cell carcinoma
Photo courtesy of Dr. Walko, used with patient permission
Vemurafenib Relapse
BRAF + MEK vs. BRAF alone
N = 704 Previously untreated, unresectable Stage IIIC or IV melanoma with BRAF V600E or V600K mutations
Baseline before
therapy
15 weeks of therapy
with vemurafenib
R
A
N
D
O
M
I
Z
A
T
I
O
N
Dabrafenib 150 mg PO BID + Trametinib 2 mg PO daily
Vemurafenib 960 mg PO BID
• Primary endpoint: Overall survival
• Secondary endpoint: Progression free survival
• Preplanned interim survival analysis performed after 77% of the total number of expected events
23 weeks of therapy
with vemurafenib
Reprinted with permission. © 2011 American Society of Clinical
Oncology. All rights reserved.
Wagle N et al. J Clin Oncol. 2011; 29:3085-96.
Robert C et al. N Engl J Med. 2015; 372:30-9.
67
BRAF + MEK vs. BRAF alone
BRAF‐Targeted Selected Toxicities
• Median overall survival at 12 months
Toxicity
– Dabrafenib + trametinib: 72%
– Vemurafenib: 65%
– HR 0.69 (95% CI 0.53‐0.89), p = 0.005
• Median progression free survival
– Dabrafenib + trametinib: 11.4 months
– Vemurafenib: 7.3 months
– HR 0.56 (95% CI 0.46‐0.69), p < 0.001
Vemurafenib
Grade 3 and 4
All grade
Grade 3 and 4
Pyrexia
21%
1%
53%
4%
Rash
43%
9%
22%
1%
Diarrhea
38%
< 1%
32%
1%
Hand Foot Syndrome
25%
< 1%
4%
0%
Hyperkeratosis
25%
1%
4%
0%
Cutaneous SqCC
18%
17%
1%
1%
Decreased ejection fraction
0%
0%
8%
4%
Patient Case
BRAF Mutated Melanoma: Summary
• Resistance to BRAF inhibitors typically occurs after 6‐7 months in most BRAF mutant metastatic melanoma patients
• Combination of a BRAF and MEK inhibitors may suppress downstream resistance mechanisms
• WK is a 38 yo female who was initially diagnosed with stage IIIC melanoma of the neck
– Modified radical neck dissection
– 2 months of adjuvant interferon before stopping due to toxicity
– Combination therapy had longer mPFS compared with monotherapy
– Median overall survival not yet reached
• PET scan at 6 months shows numerous sites compatible with metastatic disease
• Pathology notable for the 1799 T>A (V600E) mutation in the BRAF gene
• She is willing to travel for a clinical trial.
• Combination therapy resulted in higher occurrence of pyrexia, chills, nausea and vomiting but less skin toxicities
• Potential place in therapy: – First line for BRAF positive metastatic melanoma
mPFS=median progression free survival
Dabrafenib + Trametinib
All grade
Flaherty KT et al. N Engl J Med. 2012; 367:1694-703.
What therapy would be most beneficial for this patient?
Compared to a BRAF inhibitor alone, which toxicity is LESS likely with combination BRAF + MEK inhibition?
a. Single agent trametinib
a. Pyrexia
b. Single agent vemurafenib
b. Rash
c. Combination dabrafenib and trametinib
c. Peripheral edema
d. Combination vemurafenib and dabrafenib
d. Squamous cell carcinoma
68
Future Challenges and Directions
Genetic Assessment: Patient Case
• 71 yo man diagnosed with metastatic melanoma in April 2013 when he presented with a lesion on the left chin and also had nodal involvement. • Treatment Hx
• Optimal sequencing of therapy for BRAF‐
positive patients
• Optimal use of PD‐1 or PD‐L1 inhibitors
– Surgical resection of primary site and lymphadenectomy – Ipilimumab x 3 doses 11/2013 – complicated by ipilimumab ‐induced colitis requiring high‐dose steroids and infliximab
– Radiation therapy to the neck area and left lung from 11/2013 ‐1/2014
– CT scan in July 2014 demonstrated recurrent disease
– Sequential therapy
– Combination immunotherapy
– Combination with BRAF inhibitors
• Somatic genetic analysis:
• Managing drug resistance
– Lymph node from 08/11/2014
• Clinical Question
– Genetic tumor profiling
– Future treatment options
Somatic Genetic Analysis
Gene
Variant
Notes
NRAS
Amplification
• NRAS activating mutations have been reported to
activate the RAF/MEK/ERK and PI3K pathways leading to hyperactivation of CDK4/6. • Numerous clinical trials available targeting this pathway with various combinations of inhibitors
CDK4
Amplification
• Amplification of CDK4 may lead to excessive
protein expression and activity, resulting in unrestricted cell cycle progression.
• Several CDK4/6 inhibitors are currently being studied in clinical trials
MDM2
amplification
• This gene encodes a nuclear‐localized E3 ubiquitin ligase and regulates the tumor suppressor p53. Controls entry into S‐phase and ultimately mitosis
• Putative amplification of MDM2 has been reported in 4% of cases in the Skin Cutaneous
Melanoma TCGA dataset.
• Phase I clinical trial with MDM2 inhibitor
currently enrolling
Potential Trial Considerations
NCT ID
Title
A Phase Ib/II, Multicenter, Open Label, Study of LEE011 in Combination With NCT01781572
MEK162 in Adult Patients With NRAS Mutant Melanoma
A Phase Ib Study of MEK162 Plus BYL719 in NCT01449058 Adult Patients With Selected Advanced Solid Tumors
Modular Phase II Study to Link Targeted Therapy to Patients With Pathway NCT02187783 Activated Tumors: Module 8 ‐ LEE011 for Patients With CDK4/6 Pathway Activated Tumors
A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and NCT02065063
Anti‐Cancer Activity of Trametinib in Combination With Palbociclib in Subjects With Solid Tumors
Conclusions
• Genetic testing is a standard part of the metastatic melanoma
work up
– BRAF V600E or K positive patients are eligible for treatment with BRAF‐inhibitors with or without MEK‐inhibitor directed therapy
– Patients lacking the BRAF mutation should be directed towards immunotherapy with HD‐IL2, ipilimumab or PD‐1 therapy
• Novel targeted and immunotherapy agents have unique side effect profiles that provide opportunities for pharmacists in terms of patient education and supportive care
• Ongoing clinical trials are aimed at addressing optimal sequencing and combinations of therapy for both BRAF‐
positive and negative patients. 69
Target
Compound
MEK, CDK4/6
LEE011 and MEK162
MEK, PI3K
BYL719 and MEK162
CDK4/6
LEE011
MEK, CDK4/6
Trametinib
Palbociclib
Self-assessment Questions
1. Which of the following is true regarding single agent immunotherapy in melanoma?
a. High response rates are commonly seen, but are of short duration
b. All produce low response rates of short duration
c. Long-term responses can be seen, but are in less than 20% of patients
d. Responses are seen in over 50% and are very durable
2. Adverse events seen with ipilimumab and PD-1 antagonism include:
a. Rash, cardiotoxicity, and myelosuppression
b. Rash, hepatotoxicity, and diarrhea
c. Cardiotoxicity, hepatotoxicity, and myelosuppression
d. Diarrhea, hepatotoxicity, and myelosuppression
3. What therapy would be most beneficial for this patient?
a. Single agent trametinib
b. Single agent vemurafenib
c. Combination dabrafenib and trametinib
d. Combination vemurafenib and dabrafenib
4. Compared to a BRAF inhibitor alone, which toxicity is LESS likely with combination BRAF + MEK inhibition?
a. Pyrexia
b. Rash
c. Peripheral edema
d. Squamous cell carcinoma
Answers
1.
2.
3.
4.
c
b
c
d
70
Instructions for Processing CE Credit with Enrollment Code
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Date of
Activity
5/22/15
Activity Title
Enrollment
Code
New and Emerging Strategies for the Treatment
of Advanced Melanoma
NEED HELP? Contact [email protected].
71
16
Credit
Hours
1.0
2015 Annual Meeting
Friday, May 22
10:00—11:30 a.m.
0069-9999-14-148-L01-P
This program is supported by an educational grant from Novo
Nordisk, Inc.
72
A knowledge-based CE program for nurses, dietitians, and pharmacists
Disclosures to Participants
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to ensure independence, balance, objectivity, scientific rigor, and integrity in all of their continuing
education activities.
The planning team and faculty must disclose to the participants any significant relationships with the
commercial companies whose products or devices may be mentioned in the activity or with the supporter
of this continuing education activity. The information is for participant information; it is not assumed that
these relationships will have a negative impact on the content of the activity.
Activity Speaker
Susan Ann Cornell, BS, PharmD, CDE, FAPhA, FAADE, has no disclosures to report.
Activity Planning Team Members

Jerry Meece, RPh, CDE, FACA, FAADE, reports that he is a speaker for Lilly, Novo Nordisk Inc,
J&J, Pfizer, Lifescan, and Janssen Pharmaceuticals. He consults for Novo Nordisk Inc, J&J, and
Lifescan. Mr. Meece also receives grants from Novo Nordisk Inc, Pfizer, and Lifescan.

Virginia Peragallo-Dittko, APRN, BC-ADM, MA, CDE, FAADE, has no actual, potential or
perceived conflict of interest to report.

Gretchen Youssef, MS, RD, CDE, reports that she is on an advisory committee for Janssen
Pharmaceuticals

Marguerite K. York, PhD, has no actual, potential or perceived conflict of interest to report.

Peter Macholdt, BS, has no actual, potential or perceived conflict of interest to report.
Non-Endorsement of Products:
Accredited status does not imply endorsement by AADE, ANCC, ACPE or CDR of any commercial
products displayed in conjunction with this educational activity.
Off-Label Use:
Speakers will notify participants about any product used for a purpose not approved by the US Food and
Drug Administration.
This program is supported by an educational grant from
Novo Nordisk Inc.
73
This activity is intended for nurses, dietitians and pharmacists involved in
Date: May 22, 2015
Time: 9:30 AM - 12:30 PM
Location: Hyatt Regency
601 Loyola Avenue
New Orleans, LB 70112
Schedule Of Events
9:30 AM - 10:00 AM : Registration
To Register On-Line
Click the link below or open your browser and go to:
http://www.mycecenter.com
1) Click on the orange colored Registration button that says: "Click Here To Register For CE Programs"
2) Click on the Register link for the program you wish to attend
3) Please make sure you are selecting the correct program
For problems or questions regarding online registration, contact us at: 800-232-4422
Speaker: Susan Ann Cornell, PharmD, CDE, FAPhA, FAADE
Susan Cornell, BS, Pharm.D, CDE, FAPhA, FAADE is the associate director of experiential education and an associate
professor in the department of pharmacy practice at Midwestern University Chicago College of Pharmacy in Downers
Grove, Illinois. Dr. Cornell is also a clinical pharmacy consultant and certified diabetes educator, specializing in community
and ambulatory care practice. Dr. Cornell’s current clinical practice is with the Access Community Health Network in
Chicago. Dr. Cornell received her bachelor of pharmacy at the University of Illinois, College of Pharmacy and her Doctor of
Pharmacy at Midwestern University. She has received numerous awards and recognitions, including the 2014 Bowl of
Hygeia, 2011 Outstanding Faculty Advisor Award, and 2010 Teacher of the Year Award, to list a few. She is an active
member of the American Diabetes Association, and the American Association of Diabetes Educators, where she served on
their board of directors from 2004 to 2007. Dr. Co
Target Audience: This activity is intended for nurses, dietitians and pharmacists involved in
Program Goal: The goal of this knowledge-based activity is to provide participants with the skills necessary to manage
special situations that may arise in patients using insulin therapy.
74
Program Objectives
Identify special situations that necessitate lifestyle modifications and individually tailored glucose-lowering regimes for
adults with type 2 diabetes
2. Describe monitoring, lifestyle modifications, and glucose-lowering regimen changes that are important for maintaining
glucose control in special situations
3. Discuss resources that provide guidance for making lifestyle modifications and glucose-lowering regimen changes in
special situations
Important Notice
To obtain continuing education contact hours for this event, be sure to obtain the “Instruction Page” from the program
planner. This Instruction Page will outline the process for completing online fulfillment and printing of your CE Statement
of Credit.
There are no fees for this program.
75
This continuing nursing education activity was approved by the American Association of Diabetes
Educators, an accredited approver by the American Nurses Credentialing Center's Commission on
Accreditation. This program 2014-055-RN is approved for 1.50 contact hours.
American Association of Diabetes Educators, (AM001) is a Continuing Professional Education (CPE)
Accredited Provider with the Commission on Dietetic Registration (CDR). Registered dietitians (RD)
and dietetic technicians, registered (DTR) will receive 1.50 continuing professional education units
(CPEU) for completion of this program. Continuing Professional Education Provider Accreditation
does not constitute endorsement by CDR of a provider, program, or materials.
The American Association of Diabetes Educators is accredited by the Accreditation Council for
Pharmacy Education as a provider of continuing pharmacy education. This program provides 1.50
contact hours (0.15 CEU’s) of continuing education credit.
ACPE Universal Program Number: 0069-9999-14-148-L01-P
Program Release Date: 10/1/2014
Program Expiration Date: 10/1/2016
The approval of this educational offering by AADE does not imply endorsement of specific therapies, treatments, or
products discussed in the presentation.
This program is supported by an educational grant from Novo Nordisk Inc.
76
2015 Annual Meeting
Friday, May 22
2:00 – 3:00 p.m.
Focus on Patient Safety
Interactive Poster Session
0179-0000-15-010-L05-P / 0179-0000-15-010-L05-T









Describe the concepts of patient safety.
Review outstanding health-system pharmacy
practices or best practices in health-system
pharmacy.
Describe the impact of patient safety and safe
medication practices.
Discuss Continuous Quality Improvement and
processes utilize to achieve quality in
Pharmaceutical Care.
Utilize national standards, evidenced-based
medicine and pharmacy literature to improve
safety and efficacy.
List the ways that national accreditation agencies
may positively impact the overall practice of
pharmacy in health-systems.
List what the high-risk drugs are and how to handle
them throughout the continuum of care.
Describe the impact of educational programs on
safety and pharmacy practice improvement.
Review the impact pharmacist or pharmacy
technicians may have in patient safety.




Review the concept of Patient Safety
List what the high-risk drugs are and how to handle
them throughout the continuum of care
Review programs in insulin, chemotherapy,
anticoagulation and sedatives and introduce the
safety practices into your practice setting
Outline how technicians may assist the pharmacist
in identifying opportunities to improve medication
safety.
To earn ACPE credit for the poster session, you must:
1. Attend the interactive portion of the poster session.
2. Complete the questions for each program in the poster packet provided.
3. Submit the completed poster packet to the registration desk by the end of the
Annual Meeting.
4. Indicate your attendance for the poster session on your Continuing
Education Report Form.
77
2015 Annual Meeting
Friday, May 22
3:00 – 4:00 p.m.
Christene Jolowsky, MS, RPh, FASHP
Executive Director, Applied and Experiential Education
University of Minnesota College of Pharmacy
President, ASHP
0179-0000-15-005-L04-P / 0179-0000-15-005-L04-T
 Describe changes roles and practice for
Describe the roles and scope of practice
pharmacy technicians
for pharmacists, based on patient needs.

Identify
expanded roles for pharmacy
Compare how practice in an acute care
technicians
setting may differ from an ambulatory care
 Identify resources that are available to support
setting.
expanded services and roles




Identify activities and resources that you
have available to expand services.
Focus on the transition to ambulatory
care, identifying challenges and changes.
78
Disclosure:
The Future Is Yours
Advancing Practice
I have nothing to disclose commercially regarding this presentation.
Louisiana Society of Health System Pharmacists – 2015 Annual Meeting Christene Jolowsky, MS, RPh, FASHP
President – ASHP
Executive Director, Applied and Experiential Education
University of Minnesota College of Pharmacy
Learning Objectives for Pharmacists
Objectives
• Describe the scope of practice for pharmacists, • Trends that will affect our future
• ASHP initiatives to position pharmacy for a key based on patient needs. • Compare how practice in an acute care setting role in health care
may differ from an ambulatory care setting.
• ASHP strategic plan
• PPMI update
• Identify metrics that could be used to demonstrate outcomes of expanded services
Focus on the transition to ambulatory care, identifying challenges and changes • Hospital
• Amb Care
•
Think about practice
Learning Objectives for Technicians
Practice Will Change
• Describe changes in the roles and practice for Code of Ethics prior to 1969
“The pharmacist does not discuss the therapeutic effects or composition of a prescription with a patient. When such questions are asked, he suggests that the qualified practitioner is the proper person with whom such matters should be discussed”
(APhA, 1952, p. 722).
pharmacy technicians. • Identify expanded roles for pharmacy technicians.
• Identify resources that are available to support expanded services and roles
79
Trends That Will Change Our Practice
Practice Will Change
“ To bring about change within a diverse profession such as pharmacy, one needs a large number of people pulling in the same direction. Before one can get folks pulling in the same direction, one needs general agreement about the best direction in which to move.” …
• Technological revolution
• Health care reform
• Evolution of pharmacy workforce
• Growing complexity and cost of medications and medication use systems
• Further move to corporate governance
William A. Zellmer
Our Patients and Their Care
ASHP Strategic Plan
•
•
•
•
•
•
•
•
•
•
•
Three sections, which focus on professional, operational, and leadership & management
PPMI
Provider Status
Expand Pharmacy Practice in Ambulatory Clinics and Other Primary Care Settings Advance Patient Care and Pharmacy Practice in Small, Rural, and Underserved Settings (new 2015)
Address the Needs and Interests of Pharmacists Who Practice in Multihospital Systems (new 2015)
Address Issues Related to Specialty Pharmacy (new 2015)
Compounding
Medication Safety
Drug Shortages
Expansion of Residencies
New Programs, Products, and Services
•
•
•
•
Tech Portal
Certification
Expansion of Residency
Meetings
PPMI
•
Hospital Self ‐
Assessment
•
•
•
•
Ambulatory Care Growth and its Impact on Pharmacy Practice
State Grants
Large health systems engagement
Messaging
•
•
•
Communications plan
Presentations at state meetings, health systems, and others
Social media
National Dashboard
80
Overview
• State of the ambulatory care environment
• Challenges and opportunities in ambulatory care
• The ASHP Ambulatory Care Conference and Summit
2013 AAMI/FDA Healthcare Technology in Nonclinical Settings Summit
Source: Alvere Health analysis of American Hospital Association Annual Survey data, 2011, for community hospitals. Available at: http://www.aha.org/research/reports/tw/chartbook/2013/table4‐2.pdf
CDC, NCHS Data Brief, Multiple Chronic Conditions Among Adults Aged 45 and Over: Trends Over the Past 10 Years, http://www.cdc.gov/nchs/data/databriefs/db100.htm, Accessed January 3, 2014
Marketplace Trends
Health Care Reform
• 40% of physicians are employed or practice is owned 2010‐2013 ‐ Initiation
by health system.
• Growth in the number of NCQA recognized medical homes: 38 in 2008 to 6,000 in 2013
• Ambulatory care pharmacy related services on the rise.
• “Aging in place” will drive home health care industry (Impact on home infusion?)
• Specialty pharmacy growth
• Other trends?
2014‐2017 – Market Expansion
•Medicare market basket reductions •Payer Reform—new insurance rules
•Medicare and Medicaid sponsor earliest payment innovations •Rapid coverage expansion
•New federal money for new Medicaid eligibles
•Capacity constraints emerge in ED, primary care, discretionary specialty services
81
ASHP Strategic Plan
Identifying and Addressing Challenges and Opportunities in Ambulatory Care
4. Convene a consensus conference to study
and make recommendations to enhance the
ambulatory care services provided by
pharmacists.
Ambulatory Care Feedback: Challenges
• #1 – Efficiency in documentation
 EMRs don’t meet amb care needs
• Effectively place pharmacists on the health care team
 Not just physicians, case managers, care navigators…
• Address community pharmacists moving from a dispensing •
•
environment into a cognitive environment
 Training, other opportunities
Demonstrate pharmacists’ value in ACOs and PCMHs
State‐level information – to advance roles for pharmacists
http://www.ashp.org/amcare
New Opportunity: Medicare Wellness Visits
Wellness Visits
• Supplement to the “Welcome to Medicare Visit”
• Provided by “…other licensed practitioner… working Yearly "Wellness" visits/ steps: •
•
•
•
•
•
•
•
under the direct supervision of a physician.”
• ASHP members are providing and billing for these Patient has had Part B for longer than 12 months
Patient completes “Health Risk Assessment” as part of visit. Develop a personalized prevention plan Develop/ update a list of current providers and prescriptions
Take height, weight, blood pressure, other routine measurements
Review potential risk for depression and level of safety
Develop a list of risk factors and treatment options
Visit is covered once every 12 months • 11 full months must have passed since the last visit
services:
•
•
82
HCPCS code G0438 for first Annual Medicare Wellness Visit • Medicare payment approximately $172 in 2011
HCPCS code G0439 for subsequent visits • Medicare payment approximately $111 in 2011
Medicare Wellness Visits
Resources:
•
•
•
http://www.ajhp.org/content/71/1/44.full.pdf
http://www/cms.gov/Outreach‐and‐education/medicare‐
learning‐network‐
mln/mlnprodcuts/downloads/awv_chart_icn905706.pdf
http://www.cms.gov/outreach‐and‐education/medicare‐
learning‐network‐
mln/mlnproducts/downloads/annualwellnessvisit‐
icn907786.pdf
http://connect.ashp.org/ambulatorycareconference14/
The Conference
•
•
•
•
Outcomes of the Summit
• Consensus: important step for ASHP & ASHP Navigating the Future: Patient Care Delivery and Integration
Develop the Possibilities: Sustainable Business Models
Make It Matter: Outcomes Evaluation
It Starts with Us: Defining and Advancing Ambulatory Care
Foundation Pharmacy Practice Model Initiative
• Post‐Summit follow‐up survey to all ASHP members
• Input on the Summit recommendations
• Final report published in AJHP August 15, 2014
• Ambulatory Self‐Assessment (Spring 2015)
• ASHP meeting presentations and discussions (Summer meetings!)
• Inclusion of Ambulatory Pharmacy Practice Model in ASHP Foundation‐supported research
Provider Status
Other ASHP Initiatives
• ASHP: Member of the Patient Access to Pharmacists' Care Coalition
• Bi‐partisan Legislation: H.R. 592 and S. 314 introduced
• Amend the Social Security Act
• Recognize pharmacists as providers in medically underserved areas under Medicare Part B
83
Drug Shortages
Compounding
• ASHP in collaboration with the University of • ASHP has been a leader in developing Utah and FDA – leading provider of information and advocacy for over 10 years
• Legislation was passed in 2012 giving FDA enhanced authority
• ASHP continuing to working with various stakeholders to find long‐term solutions
guidelines and advocating on this issue for over 20 years
• Legislation recently passed clarifying and increasing FDA authority
• ASHP working with stakeholders to influence regulations
Expansion of Residencies
• Residency capacity stakeholders conference in 2011
• Offering workshops on starting a residency at ASHP meetings
• Tools and resources on starting residency programs
Center for Pharmacy Practice Accreditation (CPPA)
• Partnership between APhA, NABP, and ASHP
• Develops and implements comprehensive programs of pharmacy practice site accreditation
• Initial focus on community pharmacy accreditation
• Other ongoing explorations
In 2014 appx 20% of graduates (2411) are seeking PGY1 positions
And 5% (129) are graduates before 2014
84
Technician Portal
Pharmacy Technicians
• Pharmacytechce.org
• Pharmacy Technician Accreditation • Individual or group subscriptions
• 20 hours of “T designated” CE
• Live webinars plus online anytime
Commission (PTAC)
• Partnership between ACPE and ASHP
• Task: Assure and advance the quality of pharmacy •Podcasts
•Live webinars
•On‐Demand
•CE Monographs
technician education and training programs
• PTAC will conduct document reviews and site surveys
• Pharmacy Technician Certification Board
• PTCB’s new requirements
• Group subscription with admin function
• ASHP, NABP, APhA, ICHP, MPA
•Tracking completion of CE
Transforming how pharmacists care for patients
PPMI is a profession‐led initiative that is empowering the pharmacy team to take responsibility for patient outcomes. Care Team Integration
•
Promotes a team‐ based approach to health care
•
Shifts the roles of the health care team to enable pharmacists to optimize their time with patients across the continuum of care
•
Goal 1
Goal 2
Goal 3
Goal 4
Goal 5
Pharmacist
roles,
practices, and
activities will
improve
medication use
and optimize
medication
related
outcomes.
Pharmacy
technicians
will prepare
and distribute
medications
and perform
other functions
that do not
require a
pharmacist's
professional
judgment.
 Pharmacists
and pharmacy
technicians will
have
appropriate
training and
credentials for
the activites
performed
within their
scope of
practice.
Pharmacy
departments
utilize available
automation
and
technology to
improve patient
safety and
improve
efficiency.
Pharmacists
will
demonstrate
leadership in
exercising their
responsibility for
medication use
systems and
will be
accountable for
medicationrelated patient
outcomes.
2014:
20
40 50 60
70
30
80
90
10
0
100
64%
2011
59%
50 60
40 60
70
30
40
20
80
90
10
0
100
20
40 506060
70
30
40
80
90
10
0
100
30
20
40 50 60
60
40 50
60
70
3040
20
80
70
80
90
10
0
0
100
XX%
17%
27%
64%
17%
24%
44%
90
10
100
48%
41
50%
85
•
Elevates the reputation of the pharmacy team •
Ensures pharmacists, residents, and students have training and credentials for activities performed within their scope of practice now and in the future
•
Empowers the pharmacy team to ensure that pharmacy technicians perform all traditional preparation and distribution activities
•
Urges technicians to handle non‐traditional and advanced responsibilities and activities to allow •
pharmacists to take greater responsibility for direct patient care
Enhances the relationship between pharmacists and patients by positioning pharmacists as providers
•
PPMI National Dashboard
Pharmacist Credentialing & Training
Leveraging Pharmacy Technicians
Promotes technician training and certification requirements, such as the need for uniform standards for advanced technician roles
Promotes the use of credentials to provide services at the top of the scope of practice Leadership in Medication Use
Technology
•
Evaluates the available technologies to support patient safety and quality of care
•
Encourages use of available automation and technology to improve patient safety, quality and efficiency, while also reducing costs
•
Identifies emerging technologies to improve pharmacy practice
•
Empowers pharmacists to take responsibility for patient outcomes
•
Positions pharmacists to promote health and wellness, optimize therapeutic outcomes, and prevent adverse medication events
•
Emphasizes that given their extensive education and training, pharmacists are integral in helping achieve the best outcomes
Challenge…
Support…
• Complete the survey
• Students: ask at your site
• Use this in department planning
• Be a member
• Be involved
•
Think Locally!
• Support initiatives
Research and Education Foundation (REF)
ASHP Foundation
Focus: Leadership Development/Practice Advancement Research & Tools for Pharmacists
Key Leadership Programs
ASHPFoundation.org
• Student Leadership Speakers Bureau
• Whitney Lectures/Conversations Videos
• Residents Visiting Leaders Program
• Pharmacy Leadership Academy • Pharmacy Leadership Institute
• Leadership Resource Center • Pharmacy Forecast 2015‐2019 • C‐Suite Toolkit
ASHP Foundation
PAC (Political Action Committee)
Focus: Leadership Development/Practice Advancement Research & Tools for Pharmacists
Research/Practice Advancement Programs
• Legislative Issues
• Provider Status
• Drug Shortages Bill
• Compounding • Supporting Pharmacy Practice
• ASHP.org Advocacy
• Residents Research Tips/Webinars
• PGY1 & Master’s Residents Grant Programs
• New Investigator Grants & Residency Expansion Grants
• Complexity Index Research‐ 23 preventable ADEs
• Traineeships‐ Crit. Care/Oncol./Pain/Med. Home/Anticoag
• Practice Tools‐ Insourcing/Outsourcing/Antithrombotic Assessment/Insulin Safety 86
Audience Questions
Audience Question
Why is obtaining provider status important?
• For Technicians?
• For Pharmacists?
As you are looking at advancing
practice, what are some of the
criteria you would take into account
in expanding into an ambulatory
setting?
Audience Question
Bring It Home – Practice Model Initiatives
What are some differences in pharmacist roles in an ambulatory care setting v. an acute care setting?
• Care for the patients
• Role at transition points • Assessment of your practice
• Personal plan
• Work plan
• Know your resources
What are some roles that technicians can perform to support ambulatory‐based pharmacy services?
What are your questions? (and thank you … again)
[email protected]
[email protected]
87
2015 Annual Meeting
Friday, May 22
3:00 – 4:00 p.m.
**Technician Session**
Technician Advancement: How can I Climb the Ladder?
Senior Advisor, Advisory Services
VHA
0179-0000-15-011-L04-T
Discuss background information related to technician career ladders, benefits and challenges
Describe how to design a technician advancement program, ladder levels, criteria for
advancement, advancing beyond a ladder
 Discuss implementation of technician advancement program


88
Objectives
• Describe background information related to
technician career ladders, benefits and challenges.
• Describe how to design a technician advancement
program, ladder levels, criteria for advancement
and advancing beyond a ladder.
Technician Advancement:
How can I Climb the Ladder?
• Discuss implementation of technician
advancement program.
Senior Advisor, Advisory Services
VHA
LSHP 2015 Annual Meeting
When you think about a
traditional Pharmacy
Technician role, what comes
to mind?
Current “Technician” Role
• Varies significantly among hospitals
When you think about an
advance Pharmacy
Technician, what roles comes
to mind?
• Traditional functions:
–
–
–
–
–
–
–
–
–
–
–
–
–
Fill prescriptions
Compound products
Prepare IVs
Restock automated dispensing cabinets
Order medications and supplies
Receive order/invoices
Restocking and repackaging
Maintain inventory area
Borrow/Loan
Billing – departments, pt. charges, coding, etc
Reports, Audits, Analytical task
Work with automation systems
Perform any and all tasks assigned
89
Current “Advanced” Roles
Barriers
• Advance roles:
• Human Resource Department
–
–
–
–
–
–
–
–
–
–
–
Medication Reconciliation
Transition of Care Technician
Patient Assistance Program
Research Technician
340B Program Management
Decentralized Nursing Liaison
Informaticists
Tech-Check-Tech
Pharmacy Concierge Technician
Specialty Pharmacy Technician
Business/Operation Manager/Director
– value, background, knowledge, and
skills
• “Don’t we have a department for that?”
• “Why would we want a technician to do
that, doesn’t pharmacist, nurse, etc.
already do that?”
Barriers Continued
Barriers Continued
• Pharmacy Support
• Professional Development
– value, perception
– Education, certifications, additional
training
• “Do you want that technician to interact
with a patient?”
– Lack of Pharmacy and/or Healthcare
specific training
• “The technician did not go to school for
that.”
• “All you do is play on the computer and
talk on the phone.”
• “How did you get a promotion/pay increase
when we never have anything on the
shelves?”
A Pharmacy Purchasing
Professional
An individual working with pharmacy who
leverages his/her knowledge and experience in
the purchasing of products and services
required to provide all customers with quality
cost effective healthcare.
Advanced Role - Pharmacy
Purchasing Professional
90
Pharmacy Purchasing
Professional’s Role
Justification – How?
• Traditional functions
• Professional – more work & documentation
–
–
–
–
–
• Provides Pharmacy with expertise in:
–
–
–
–
–
–
–
–
–
Business
Contracts
Logistics and Distribution
Project Management
Process Improvement
Quality Controls
Supplier Relations
Customer Relations
Technology
Position description vs. current responsibilities
What do I need to know?
What do I need know how to do?
“What have you done for me lately?”
Internal Proposal
• Management – ROI
– Executive Summary, Background & Description,
Market Analysis, Clinical and Quality Requirements,
Operational Structure & Processes, Financial
Projections, Critical Risk and Opportunities
– Job Function Analysis
– Salary, Wages and Benefits
Career Development:
Pharmacy Purchasing Professional
Career Levels
Advancement, Security and Value
• SMART
– Specific, measurable, agreed upon, realistic and
time-bound
1
Technician, Senior/Lead Technician
2
Buyer
3
Supervisor, Coordinator, Agent, Analyst
4
Manager, Regional, Corporate, GPOs, Beyond
• FAMIC
– Few in number and focused, aligned internally and
organizationally, intended to build mastery;
incremental; and controllable
• FITEMA (AFITME)
– Fairly determined, individual, task-focused, errortolerant, matched with the cadence of work and
action-oriented
Scope
Pharmacy Purchasing Professional
Position Elements
1
Scope of practice
2
Education, certification, and training
3
Experience
4
Knowledge, skills and abilities
Technician
Buyer
Supervisor
Manager
Performs a variety
of duties in addition
to purchasing.
Competent in the
core elements of
purchasing
addendums.
Fully competent in
all elements of the
operational
addendums.
Fully competent in all
elements of the
operational and
financial addendums.
Task Driven
Inventory
Management
Supply Chain
Management
Strategic
Management
91
Education/Certification/Training
Technician
Buyer
High School
diploma (or GED).
Must comply with
state specific
pharmacy
technician
regulations and
requirements.
Nationally
Certified
Technician
required.
2 year college
degree
preferred.
Nationally
Certified
Technician
preferred.
Supervisor
Experience
Manager
Technician
Nationally Certified Nationally Certified
Technician required.
Technician
required.
4 year college degree
2 or 4 year college in related area
required.
degree in related
area required.
Certification and
additional training in
Certification and
related area required.
additional training
in related area
Masters preferred.
preferred.
0 to 2 years of
pharmacy
technician
experience.
Buyer
Supervisor
3+ years of hospital
2 to 3 years of
hospital pharmacy pharmacy technician
experience.
technician
experience.
2 to 3 years of
pharmacy purchasing
Purchasing
experience in multiple
experience
acute care hospitals
preferred.
preferred.
Manager
5+ years of pharmacy
purchasing experience
in mid to large size
hospitals or health
systems.
Established success in
operational and
financial arenas.
Job Overview
Job Overview
• Essential Functions
• Essential Functions Continued
– Establish and maintain appropriate cost
effective on hand product availability
– Conducts audits and analysis of contract
compliance, invoices, charge master and
department finances
– Implement and maintain best practice in
pharmacy supply chain operations
– Prepare presentations, reports and other
documents as needed relative to cost
and assigned projects
– Work with management, purchasing,
accounts payable, business operations,
clinical departments and hospital
customers to identify opportunities of
cost savings or clinical value
– Maintain compliance
How can I become a Pharmacy
Purchasing Professional?
Resources
• No Cost
• Personal Assessment, Goals and Plan
• KSA - ABCs
– Social Media: industry specific
topics/groups
• Training Agenda
– Library: books/article on supply chain,
finance, operations
– Analytics, Business and Communications
–
–
–
–
–
Determine needs: personal and employer
Decide on type/style
Negotiate commitment
Document training
Document new skills in action
– Publications: Pharmacy related for
trends/industry news
– Employer: PowerPoint, communication
skills, excel, etc
– GPO & Wholesaler: educational
offerings
92
“The” Pharmacy Purchasing
Professional of Tomorrow
Resources
• Low Cost
• Nationally Certified Pharmacy Technician
– Membership: NPPA, ASHP, AHRMM,
APICS, PMI
– Books, podcast, book summaries
– Training/certificate courses
– Certification
– Conferences/Meetings
• Bachelor's in Business Administration or Supply
Chain Management with a minor in Management
Information Systems
• Certification in supply chain, healthcare supply
chain, project management, business analyst, etc
• High Cost
• Diverse experience – internships, volunteering,
organization involvement, etc
– Formal education
– Training programs
• Master’s in Healthcare Administration or Business
Administration
A “CPhPP” Future
Hospital
I now
have
options.
Advanced Role - Medication
Reconciliation Technician
Business Manager
Operation Manager
Supply Chain
Finance/Revenue Analyst
Industry
Regulatory
Sales
GPO
Consulting
Insurance
Instructor
Automation
Policy
Patient Safety
Leadership
cGMP
Med Rec Selection & Training
Med Rec Financial Justification
• Technician Candidate for Med Rec Program
Average # of discrepancies / med errors per patient
Adaptation of a template based on data at Northwestern Memorial Hospital
–
–
–
–
–
Strong communication skills
Attention to detail
Self motivated
Hospital work experience
Knowledge of commonly prescribed outpatient
medications
43,312
Potential medication errors per year that can be avoided
95,286
% of medications that were potentially harmful to patient during
hospitalization
Number of harmful medication errors avoided per year
$11,434,320
Avg pharmacist time requirement per admission
One on One Pharmacist lead training
Overview of program and EHR
Role observation
Responsibility and procedure review
Instruction in patient interview techniques and EHR
documentation
2.5%
2,382
Annual gross savings to Hospital ($4,800 per harmful error)
• Training might include:
–
–
–
–
–
2.2
Number of inpatient admission per year
21 minutes
Additional pharmacist FTE needed to provide service (based on
115 admission daily)
~ 5 FTE
Cost of additional pharmacist FTE (salary = benefits)
$625,000
Annual Net Savings/Cost Avoidance
$11.4M
Replacing Rx for Tech could expand service at no net increase
1rx = 2 tech
Source: Part of this template was presented by Steve Rough, MS, RPh at ASHP Summer meeting, 6/6/06.
93
Technician Resources
Conclusion
• Associations/Boards/Societies
• Organizations should support the hiring,
development and retaining of quality Pharmacy
Technicians
– American Society of Health-System Pharmacists
• www.ashp.org
– American Association of Pharmacy Technicians
• www.pharmacytechnician.com
• Continuous education and training is needed for
the advancement of the profession
– Healthcare Information and Management Systems Society
• www.himss.org
– Louisiana Society of Health-System Pharmacists
• www.lshp.org
• Each Pharmacy Technician is responsible for the
promotion and advancement of their profession
– National Pharmacy Technician Association
• www.pharmacytechnician.com
– National Pharmacy Purchasing Association
• www.pharmacypurchasing.com
– Pharmacy Technician Educators Council
• www.pharmacytecheducators.com
– Pharmacy Technician Certification Board
• www.PTCB.org
Any Questions?
Email: [email protected]
94
2015 Annual Meeting
Friday, May, 22
4:00—5:00 p.m.
Director - Pharmacy Technician Program
Delgado Community College
New Orleans, LA
0179-0000-15-006-L04-P / 0179-0000-15-006-L04-T
 Identify the primary areas of focus for the
health and safety management system for HDs
 Describe Primary and Secondary Engineering
Controls for compounding HD
 Identify requirements for training personnel
who handle HDs
 Identify Pharmacists responsibilities for
handling hazardous drugs
 Discuss elements of a medical surveillance
program
Controls for compounding HD
 Identify requirements for training personnel
who handle HDs
 Identify Pharmacy Technician responsibilities
for handling hazardous drugs
 Discuss elements of a medical surveillance
program
95
Learning Objectives:
Pharmacist
USP Chapter <800>:
Hazardous Drugs
• Review components of USP
Chapter <797> pertaining to the
Compounding of Hazardous
Drugs (HDs)
Pharmacy Technician Program Director –
• List Facility requirements for
• List requirements for training of
• List requirements for training of
personnel
1
Chapter <797> pertaining to the
Compounding of HDs
• Identify key USP Chapter
Compounding HDs
• Review components of USP
• Identify key USP Chapter
<800>Sections involved in the
Compounding of HDs
Pharmacy Technician
<800>Sections involved in the
Compounding of HDs
personnel
• Review purpose and
• Review purpose and requirements
of Medical Surveillance
ACPE Certified Trainer:
requirements of Medical
Surveillance
2
Sterile Compounding and Aseptic Technique
USP <797> Hazardous Drugs as
CSPs
Change from USP <797>
• Drugs are classified as hazardous if studies in
• <797>: Allows facilities that prepare a low
animals or humans indicate that exposures to them
have a potential for causing cancer, development or
reproductive toxicity, or harm to organs.
volume of HDs to place BSC or CACI in a nonnegative pressure room
• <800>(Proposed): Requires all HD
• Occupational exposure to hazardous drugs can result
in (1) acute effects, such as skin rashes; (2) chronic
effects, including adverse reproductive events; and (3)
possibly cancer.
Source: 2015 USP Compounding Compendium
compounding to be done in a separate area
designated for HD compounding
3
4
USP<800>:
Handling Hazardous Drugs
Section 1: Introduction and Scope
• Receipt
• Storage
• Compounding
• Dispensing
• Administration
• Practice and Quality Standards for handling
Hazardous Drugs (HDs)
• Applies to sterile and non-sterile compounding
• 19 sections
• Purpose: protect healthcare personnel and
patients
5
6
96
Section 2:
List of Hazardous Drugs
Health and Safety Management System /
Occupational Safety Plan
•
•
•
•
•
• Engineering Controls
• Competent personnel
• Safe work practices
• Proper use of appropriate PPE
• Policies for HD waste and disposal
NIOSH List of HDs1
Original List: 2004
Updated: 2010, 2012, and 2014
Table 1: Currently 96 Antineoplastic Drugs
Table 2: Non-Neoplastic Drugs
• Manufactures’ safe-handling recommendations
(MSHG):10 drugs
7
8
Engineering Controls
Section 5: Facilities
• C-PEC
• Designed to promote patient safety, worker safety,
environmental protection, and infection prevention.
• BSC or CACI
• Designated areas for:
• Receipt of HDs
• Storage
• Compounding
• C-SEC
• Negative Pressure room
• Externally vented
• 152 Air changes per hour
• Supplemental Engineering Controls
9
Most Current Update
10
Containment Supplemental
Engineering Controls: CSTD
• Containment Segregated Compounding Area
C-SCA
• Separate, negative pressure room with at least
12 air changes per hours
• Low/Medium-Risk
• Prepared in BSC or CACI in a C-SCA
• BUD cannot exceed 12 hours
BD PhaSeal
Equashield
ChemoClave/ChemoLock
(ICUMedical)
11
12
97
Section 6: Environmental Quality and Control
Section 7: PPE
• Wipe sampling – every 6 months
• Interior or the C-PEC and equipment within
• Staging / work areas near the C-PEC
• Areas adjacent to C-PEC
• Gloves: 2 pairs; change every 30 minutes
• Gowns: non-absorbent, back closing, long
sleeved, closed cuffs; changed every 2-3 hours
• Head, Hair, Shoe, and Sleeve Covers
• Face shield and/or goggles
13
14
Section 9: Personnel Training
Section 10: Receiving
• Training must be completed prior to handling HDs
• Validated every 12 months or when new or
significant changes in process or SOP occurs
• List of HDs and their Risks
• Review of SOPs related to HDs
• Proper use of PPE
• Proper use of equipment and devices
• Spill management
• Response to known or suspected HD exposure
• Separate from other drugs in supplier sealed
impervious plastic
• Moved to HD receiving area
• Chemo gloves
• Accessibility to Spill Kit
15
16
Section 13: Compounding
Section 15: Decontamination and Cleaning
• USP <797>
• Clean and Deactivate/Decontaminate areas
where HDs are handled, and all reusable
equipment and devices.
• Clean between compounding different HDs,
when there is a spill
• Clean under work tray monthly
• Decontamination: sodium hypochlorite,
surfactant, and thiosulfate neutralizer
• Chemo mat
• Prime tubing before compounding
• If not using a CTSD, use negative pressure
• Use ¾ rule for selecting syringe
17
18
98
Section 18: Documentation and SOPs
Section 18: Documentation and SOPs
• SOPs must be reviewed annually
•
•
•
•
•
•
• SOPs must be reviewed annually (con’t)
Hazard communication program
Occupational safety program
Labeling of HDs
Procurement of HDs
Use of proper engineering controls
Use of PPE based on activity
• Decontamination/Deactivation, cleaning and
•
•
•
•
disinfection
Transport
Environmental Monitoring
Spill Control
Medical Surveillance
19
20
Section 19: Medical Surveillance
USP <800>
• General purpose:
• minimize adverse health effects in personnel
potentially exposed to HDs
• Current revision of proposed USP General Chapter
• Initial baseline assessment of health status
<800> was posted in Dec 2014 on the USP website
and published March-April issue of the
Pharmacopeial Forum.
and medical history
• Assessment and documentation of symptom
• Open for public comment until May 31, 2015
complaints, physical findings, and lab values
• Follow up plan
• Maintained according to OSHA regulations
21
22
RESOURCES
•
1NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare
Settings, (Sept. 2104) http://www.cdc.gov/niosh/docs/2014-138/default.html
• McCarney,Lisa, BAAS, CPhT, PhTR (2012). Sterile Compounding and Aseptic
Techniques; St. Paul, MN: Paradigm Publishing Inc.
• Ochoa, Pamella S., and Vega, Jose’ A. (2015). Concepts in Sterile Preparations and
Aseptic Technique. Burlington, MA: Jones & Bartlett Learning.
• The United States Pharmacopeial Convention (2015). 2015 USP Compounding
Compendium; Update Feb 2015: <797> 43-87
• USP Briefing: (800) Hazardous Drugs – Handling in Health care Settings, PF
40(3) [May-Jun. 2013]
http://www.usp.org/sites/default/files/usp_pdf/EN/m7808_pre-post.pdf
23
99
2015 Annual Meeting
Friday, May 22
5:00—7:00 p.m.
Clinical Assistant Professor
University of New England
0179-0000-15-008-L01-P / 0179-0000-15-008-L01-T
 Differentiate between hypovolemic shock,
cardiogenic shock, and distributive shock
 Compare and contrast options for fluid
resuscitation
 Discuss the pharmacology, dosing, adverse
effects, and place of therapy for vasopressors
and inotropes
 Examine the primary literature for fluids,
vasopressors, and inotropes influencing
current and future practice
 Describe an appropriate, individualized
vasopressor/inotrope regimen for a patient in
shock
 Recognize the importance of administration of
fluids, vasopressors, and inotropes during
shock
 Explain the pharmacology and common uses
of fluids, vasopressors, and inotropes
 Identify common formulations and
concentrations of vasopressors and inotropes
100
Disclosures
• Nothing to disclose
• No conflicts of interest
A Pharmacist’s Guide to Using Fluids, Vasopressors, and Inotropes in Shock
Clinical Assistant Professor
University of New England College of Pharmacy
Clinical Pharmacist – Cardiothoracic ICU
Maine Medical Center
Pharmacist Objectives
Technician Objectives
• Differentiate between hypovolemic shock, cardiogenic shock, and distributive shock
• Compare and contrast options for fluid resuscitation
• Explain the pharmacology, dosing, adverse effects, and place of therapy for vasopressors and inotropes
• Examine the primary literature for fluids, vasopressors, and inotropes influencing current and future practice • Choose an appropriate, individualized vasopressor/inotrope regimen for a patient in shock
• Recognize the importance of administration of fluids, vasopressors, and inotropes during shock
• Explain the pharmacology and common uses of fluids, vasopressors, and inotropes
• Identify common formulations and concentrations of vasopressors and inotropes
Outline
Vascular Terminology
1.
2.
3.
4.
5.
• Mean Arterial Pressure (MAP)
Hemodynamic Principles
Shock States
Fluid Resuscitation
Using Vasopressors
Using Inotropes
– Mean pressure in central arterial bed
– Determined by CO and SVR
– MAP = ((2*DBP) + SBP)/3
• Systemic Vascular Resistance (SVR)
– Measure of impedance applied by systemic vascular system to systolic effort of left ventricle
– SVR = ((MAP‐CVP)/CO) * 80
• Afterload
– Ventricular wall tension developed during systole
– Determined by resistance or impedance the ventricle must overcome to eject end‐diastolic volume
Hoffman EW. Drug Intell Clin Pharm. 1982 Sep;16(9):657‐64.
101
Cardiac Terminology
Volume Status Terminology
• Heart Rate (HR)
• Preload
– Number of myocardial contractions per minute
– End diastolic fiber length before contraction
• Stroke Volume (SV)
– Amount of blood ejected from the ventricle with each systolic contraction
• Pulmonary capillary wedge pressure (PCWP)
– Measures pressure distal to pulmonary artery
– Reflects left ventricular filling pressures
• Cardiac Output (CO)
– Amount of blood ejected from the left ventricle per minute
– CO = SV x HR
• Central venous pressure (CVP)
• Cardiac Index (CI)
– Measures mean pressure in right atrium and reflects right ventricular filling process
– Amount of blood ejected from the left ventricle adjusted for size of the patient
– CI = CO/BSA
Normal Values
MAP = SVR * CO
Parameter
Value
Blood pressure (BP)
120‐140/80‐90 mm Hg
Mean Arterial Pressure (MAP)
80‐100 mm Hg
Cardiac Output (CO)
4‐7 L/min
Cardiac Index (CI)
2.8‐3.6 L/min/m2
Central Venous Pressure (CVP)
2‐6 mm Hg
Cardiac Output
CO = SV * HR
MAP
Heart Rate (HR)
60‐80 BPM
Pulmonary Capillary Wedge Pressure (PCWP)
5‐12 mm Hg
Stroke Volume (SV)
60‐130 mL/beat
Systemic Vascular Resistance (SVR)
800‐1400 dyne/sec/m2
Stroke Volume
SVR
MAP = SVR * CO
Inotropes (CO)
Monitoring
CO = SV * HR
• Central Venous Catheter
– Ends in the superior vena cava or right atrium
– Measures CVP
• Pulmonary Artery Catheter (Swan‐Ganz)
MAP
Vasopressors (SVR)
– Measures pulmonary capillary wedge pressure, cardiac output, SVR, and other parameters
Fluids (SV, CVP, PCWP)
102
Outline
1.
2.
3.
4.
5.
Shock
Hemodynamic Principles
Shock States
Fluid Resuscitation
Using Vasopressors
Using Inotropes
• A syndrome in which the circulatory system fails to maintain adequate cellular perfusion
• Typically accompanied by persistent hypotension
Pathophysiology
Classic Presentation
• Insult triggers cascade of events ultimately leading to organ dysfunction and cell death
• Common pathways
• Systolic blood pressure < 90 mm Hg or change in baseline > 60 mm Hg
• Tachycardia (HR > 90 BPM)
• Tachypnea (respiratory rate > 20 breaths per minute)
• Signs and symptoms of hypoperfusion
– Ischemia  endogenous inflammatory cytokine release  generation of oxygen free radicals
– Prolonged ischemia triggers initiation of anaerobic metabolism
• Decreased ATP stores
• Build up of lactic acid and other toxic substances
– Irreversible cellular damage, multi‐organ failure, death
Clinical Signs of Hypoperfusion
Types of shock
• Altered mental status
• Serum creatinine increase > 0.5 mg/dL
• Oliguria (urine output < 0.5 mL/kg/hr for 2 hours despite fluid resuscitation)
• Ileus
• Cold, clammy, mottled skin (exception: distributive shock)
• Metabolic acidosis (elevated lactate)
• Hypovolemic shock
• Distributive shock
– Septic shock
– Anaphylaxis
– Neurogenic
• Cardiogenic shock
103
Hypovolemic Shock
Distributive Shock
• Reduction in intravascular volume
• Causes:
• Loss of vascular tone causing acute tissue hypoperfusion
• Causes:
– External loss of fluid
• Trauma, bleeding
– Sepsis
– Anaphylaxis
– Neurogenic
– Third spacing
• Compensatory mechanisms
– Increased HR, contractility, and SVR
• Treatment: administration of fluids and/or blood products
Erstad BL. Hypovolemic Shock. Pharmacotherapy: A Pathophysiologic Approach. 2008; p 441‐454.
Pathophysiology
Septic Shock
• Pathophysiology
– Proinflammatory molecules upregulate adhesion molecules in neutrophils and endothelial cells
– Inflammatory mediators released by neutrophils damage endothelial cells
– Endothelial cells release nitric oxide to promote vasodilation
• Hemodynamic changes
– Decreased SVR
– Decreased PCWP
– Compensatory increase in CO, followed by decrease
Russell JA. N Engl J Med. 2006 Oct 19;355(16):1699‐713.
Cardiogenic Shock
Cardiogenic Shock
• “Persistent hypotension and tissue hypoperfusion
due to cardiac dysfunction in the presence of adequate intravascular volume and left ventricular filling pressure.”
• Causes
• Pathophysiology
– Impaired left ventricular function, reduced systolic contractility, decreased cardiac output and arterial blood pressure
– Compensatory responses
• RAAS activated
• Systemic vasoconstriction
– Nonmechanical
• Myocardial infarction
• Acute exacerbations of heart failure
• Progressive deterioration of myocardial function, worsening ischemia
– Mechanical
– Increased left ventricular filling pressures
– Pulmonary congestion and edema
• Pericardial tamponade
• Tension pneumothorax
104
Cardiogenic Shock
Hemodynamic Changes In Shock
• Hemodynamic changes
Hypovolemic
Distributive
Heart Rate



Blood Pressure


/
Cardiac Output

/

PCWP (Preload)



SVR (Afterload)



– Decreased cardiac index • CI < 2.2 L/min/m2
– Elevated pulmonary capillary wedge pressure
• PCWP > 25 mm Hg
– Systolic BP < 90 mm Hg for ≥ 30 minutes
MAP = SVR * CO
General Treatment Principles
Cardiogenic
CO = SV * HR
Choosing an Agent
• Does the patient have a Swan‐Ganz catheter?
1. Individualized care
– Does the patient have a Swan‐Ganz catheter?
– Treat the patient, not the number
– Correct abnormalities
• What is the cause of hypoperfusion?
2. Identify and treat the underlying cause
– Hypovolemia vs. sepsis vs. STEMI
– Hypovolemia – stop hemorrhage, volume repletion – Sepsis – antibiotics
– STEMI – cardiac reperfusion
• Literature and guidelines
– Surviving Sepsis
– AHA STEMI
– AHA Heart Failure
3. Restore volume
– Caution in cardiogenic shock
• Patient specific concerns
4. Hemodynamic support
– Tachycardia
– Arrhythmias
– Vasopressors
– Inotropes
Treatment of Cardiogenic Shock Secondary to Myocardial Infarction
Septic Shock Treatment
• Pulmonary Artery Catheter?
• Fluid Challenge
• Initial resuscitation (within 6 hours) – CVP 8‐12 mm Hg
– MAP ≥ 65 mm Hg
– Urine output ≥ 0.5 mL/kg/hr
– Central venous oxygen saturation ≥ 70%
– No more than 100‐250 mL at a time
– Severe LV impairment – increased intravascular volume can worsen pulmonary congestion
• Inotropes or vasopressors should be used to increase MAP and reestablish coronary perfusion
• Alternative: mixed venous oxygen saturation ≥ 65%
– May exacerbate ventricular arrhythmia and increase oxygen consumption
– Goal of therapy – MAP: 65‐70 mmHg
– Early administration of antibiotics
• Hemodynamic support/adjunctive may be needed to reach goals
• Cardiac catheterization or revascularization
• IABP or VAD
Dellinger RP. Crit Care Med. 2013 Feb;41(2):580‐637.
105
MAP = SVR * CO
AMI, ADHF
Inotropes (CO)
Patient Case: SM
CO = SV * HR
SM is an 80 year old male 5’8” 98 kg who was transferred to the ICU an hour ago after undergoing a successful aortic valve replacement with a Magna‐Ease valve.
HPI: SM presented to the hospital this morning to undergo an elective aortic valve replacement. He reports that he has been having problems walking for a year. An echo shows LV dysfunction with mild dilatation, EF = 30%, and aortic valve stenosis.
MAP
Allergies: spironolactone
Sepsis
Vasopressors (SVR)
Hypovolemia
Fluids (SV, CVP, PCWP)
PMH: Hyperlipidemia, coronary artery disease, aortic valve stenosis, CHF, atrial fibrillation
Patient Case: SM
Home Meds:
Warfarin 2 mg daily
Atorvastatin 40 mg daily
Furosemide 80 mg twice daily
Lisinopril 2.5 mg daily
Carvedilol 6.25 mg twice daily
General Treatment Principles
1. Individualized care
– Does the patient have a Swan‐Ganz catheter?
– Treat the patient, not the number
2. Identify and treat the underlying cause
– Hypovolemia
– Sepsis – Cardiogenic
3. Restore volume
4. Hemodynamic support
– Vasopressors
– Inotropes
Fluid Compartments
Intracellular Fluid (ICF)
60% Total Body Water
Fluid Resuscitation
Interstitial Fluid
75% ECF
Intravascular
space
25% ECF
Extracellular Fluid
(ECF)
40% Total Body Water
106
The Ideal Fluid
Fluids
• Predictable and sustained increase of intravascular volume
• Chemical composition resembles extracellular fluid
• Metabolized and excreted without accumulation
• No adverse effects
• Cheap
• Crystalloid fluids
– Isotonic sodium containing fluids
• Normal Saline (NS)
• Lactated ringers (LR)
• Plasma‐Lyte, Normosol‐R
• Colloids
– Large molecular weight solutions
• Albumin
• Hetastarches (Voluven, Hespan, Hextend)
• Dextran
No such fluid exists
Myburgh JA. N Engl J Med. 2013 Sep 26;369(13):1243‐51.
Crystalloid vs. Colloid
Intravascular Space
• Distribution
– Isotonic crystalloids – freely distribute to extracellular fluid compartments
0.9% Saline
• 3:1 ratio crystalloid volume to colloid volume
• Clinically the ratio is lower 1.4:1
– Colloids – expand intravascular space with minimal loss to interstitial spaces
5% Albumin
• Less volume needed to resuscitate
• Longer duration of action
• Allergic/hypersensitivity reactions
Interstitial Space
Finfer S. N Engl J Med. 2004 May 27;350(22):2247‐56.
Adapted from: Erstad BL. Hypovolemic Shock. Pharmacotherapy: A Pathophysiologic Approach. 2008; p 441‐454.
Fluid Principles
• Crystalloids preferred over colloids
• Multicenter, blinded, randomized controlled trial
• Adult patients admitted to the ICU
• Voluven vs. 0.9% saline
– Colloids show no clinical benefits over crystalloids
– Colloids are more expensive than crystalloids
– Colloids may provide a faster hemodynamic response BUT this does not correspond to improved clinical outcomes like mortality
– Hetastarches are associated with a higher risk of acute kidney injury
– 3315 received Voluven
– 3336 received 0.9% saline
• Results
– No differences in 90 day mortality
– Increased need for RRT in Voluven (7.0% vs 5.8%, RR = 1.21 95% CI 1‐1.45, p=0.04)
– Patients who received Voluven had a higher SCr
• Conclusion
– No clinical benefit to justify use of HES
Myburgh JA. N Engl J Med. 2012 Nov 15;367(20):1901‐11.
107
Hetastarches
SAFE Trial (2004)
• Multisite, double‐blind, RCT
• Adult patients predominantly trauma and sepsis
• 4% albumin vs. saline 0.9%
– 3473 patients received albumin
– 3460 patients received saline
• Primary outcome: 28 day mortality
• Results
– No difference in mortality
• Albumin vs saline: 20.9% vs. 21.1%, p=0.99
– No difference survival time, length of hospital and ICU stay
– Patients in albumin group required less fluid on day 1 and 2
• No clinical difference in hemodynamics
– Albumin may have slight mortality benefit in severe sepsis
http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm
ALBIOS Trial (2014)
Bottom Line
Albumin may have slight mortality benefit in severe sepsis (SAFE 2004)
No evidence colloids are better over crystalloids
– ALBIOS – No difference in 28 day or 90 day mortality
Crystalloids preferred due to cost
• 28 day mortality = 31.8% albumin vs 32.0% crystalloid (RR = 1.00, 95% CI 0.87‐1.14, p=0.94)
• 90 day mortality = 41.1% albumin vs 43.6% crystalloid (RR = 0.94, 95% CI 0.85‐1.05, p=0.29)
But does choice of crystalloid matter?
Caironi P, Tognoni G, Masson S. N Engl J Med. 2014 Apr 10;370(15):1412‐21.
• Primary outcome • Prospective open label sequential pilot study
– Increase in SCr from baseline to peak
– Incidence of AKI
– February 2008 – August 2008: Chloride rich solution
• NS, gelatin solutions, 4% albumin
– August 2008 – February 2009: Chloride poor solution
• Secondary outcomes
• Hartmann solution, Plasma‐Lyte, 20% albumin
– Need for dialysis
– ICU length of stay
– Mortality
• 1533 patients
– 760 patients during control period
– 773 patients during intervention period
Yunos NM. JAMA. 2012 Oct 17;308(15):1566‐72.
Yunos NM. JAMA. 2012 Oct 17;308(15):1566‐72.
108
Hartog Hamburger – Father of
“Normal Saline”
• Erroneously suggested 0.9% was the concentration of salt in human blood
• Results
– Data derived from IN VITRO experiments involving RBC lysis (1882‐1883)
– Never intended for clinical use
– Intervention group lower SCr increase (14.8 μmol/L) than control group (22.6 μmol/L) P = 0.03
– Lower risk of dialysis with intervention group (OR = 0.52 95% CI 0.33‐0.81, p = 0.004)
• Fewer intervention patients classified as at risk of AKI (3.0% vs 6.3% P = 0.002)
• No differences ICU length of stay
• No differences mortality
Hartog Hamburger –
Dutch physiologist
• Term “Normal Saline” historically referred to solutions of varying compositions NOT Hamburger’s solution
• Mystery as to how Hamburger’s solution made its way into clinical practice – easy to formulate? Inexpensive?
Awad S. Clin Nutr. 2008 Apr;27(2):179‐88.
Yunos NM. JAMA. 2012 Oct 17;308(15):1566‐72.
Human Plasma
Chloride Containing Solutions
• Supraphysiologic doses of chloride may be detrimental
• Can lead to a hyperchloremic metabolic acidosis
• Possible mechanisms of AKI
– Renal vasoconstrictive effect of tubular chloride reabsorption
– Activation of tubuloglomerular feedback triggers arterial vasoconstriction and decrease in GFR
– Enhances responsiveness to vasoconstrictor agents such as angiotension II
Albumin 5% Voluven
Normal Saline
Ringer’s Lactate
Plasmalyte
Colloid
Colloid
Crystalloid
Crystalloid
Crystalloid
Osmolarity
(mOsm/L)
291
309
308
308
280.6
294
Sodium
(mmol/liter)
135‐145
130‐160
154
154
131
140
Potassium (mmol/liter)
4.5‐5.0
5.4
5.0
Calcium (mmol/liter)
2.2‐2.6
2.0
Magnesium (mmol/liter)
0.8‐1.0
Chloride (mmol/liter)
94‐111
3.0
130‐160
154
154
111
Acetate (mmol/liter)
Lactate (mmol/liter)
1‐2
Bicarbonate
(mmol/liter)
23‐27
29
Gluconate
(mmol/liter)
Yunos NM. JAMA. 2012 Oct 17;308(15):1566‐72.
• Retrospective cohort study using claims data
• 53,448 adult patients with sepsis treated with vasopressors and crystalloids
• Patients were stratified into quintiles based on the percentage of total crystalloids that was a balanced fluid
• Primary outcome: in‐hospital mortality occurring after day 2
• Secondary outcomes: acute renal failure
98
27
23
• Results
– Balanced fluids had a lower mortality than non‐balanced fluids • 19.6% vs. 22.8% (RR = 0.86, 95% CI 0.78‐0.94, p=0.001)
• For each 10% increase in proportion of balance fluid used, mortality decreased on average by 3.4%
– No difference in acute renal failure between balanced and non‐balanced fluids
• With dialysis – 4.52% vs 4.74% (RR = 0.953, 95% CI = 0.761‐1.150)
• Without dialysis – 7.12% vs. 7.50% (RR = 0.950, 95% CI = 0.784‐
1.150)
– No difference hospital or ICU LOS
Raghunathan K. Crit Care Med. 2014 Jul;42(7):1585‐91.
Raghunathan K. Crit Care Med. 2014 Jul;42(7):1585‐91.
109
Fluids Clinical Pearls
Patient Case: SM
SM received 500 mL lactated ringer’s solution, 1500 mL isotonic saline, 500 mL albumin. A Swan‐ganz catheter is placed
• No difference in clinical outcomes between crystalloids and colloids
• Crystalloids preferred over colloids due to cost
– Chloride‐rich solutions = increased nephrotoxicity?
• Avoid hetastarch due to association with increased nephrotoxicity
What intervention would be most appropriate for the treatment of SM’s hemodynamic instability?
α1
agonism
Location
Post synaptic‐
smooth muscle, small amounts on heart muscle
α2
agonism
β1
agonism
Cardiac muscle
Pre synaptic regulating norepinephrine release into the synaptic cleft
Using Vasopressors
Physiologic effects
Constrict Vasodilation, arteries & veins sedation
↑ SVR
Hemo‐
dynamic effect ↑ MAP
Location
β2
agonism
Dopamine agonism
V1 agonism
Vascular and bronchial smooth muscle,
small amounts on cardiac muscle
Smooth muscle in renal, splanchnic, coronary, and cerebral vascular beds
Smooth muscle in blood vessels, hepatocytes, and platelets
Vasodilation
Vasodilate & increase blood flow to the kidneys
Vasoconstriction
Increase urine output
↑ SVR
↑ MAP
Physiologic effects
↓ SVR
Hemo‐
dynamic effect
↓ SVR
Inotropic effect
Chronotropic effect
↑ HR, ↑ CO Vasopressin
Epstein FH. N Engl J Med 2001;345:589.
110
Vasopressor Treatment Principles:
Common Adverse Drug Effects
Vasopressor Use Guidelines
• Ensure adequate trial of fluid resuscitation (30 mL/kg) prior to initiating vasopressors
• Administer through a central line if able
• All vasopressors that have alpha‐1 agonism
– Excessive vasoconstriction/organ ischemia
– Tissue necrosis
– Bradycardia
– Extravasation through peripheral line can cause localized skin necrosis
• All vasopressors that have beta‐1 agonism
• Titrate to the lowest possible dose to maintain adequate tissue perfusion
– Tachycardia
– Potential for arrhythmias
– Many vasopressors increase cardiac oxygen demand
– Treat the patient not the number
Norepinephrine
Septic Shock – Hemodynamic Support
• Vasopressors
–
–
–
–
• Neurotransmitter of the sympathetic nervous system
1st – Norepinephrine
2nd – Epinephrine
3rd – Vasopressin
Alternatives: phenylephrine, dopamine
– Precursor of epinephrine
• Catecholamine with both alpha and beta effects
• Inotropes (if decreased CO in the setting of adequate PCWP)
– Alpha effects > beta effects
– Dobutamine
• Causes vasoconstriction of arterioles
• Corticosteroids
– For relative adrenal insufficiency/blood pressures unresponsive to fluids and vasopressors
– Hydrocortisone 50 mg IV q6h
– Constricts both renal afferent and efferent arteriole
Overgaard CB. Circulation. 2008 Sep 2;118(10):1047‐56.
Norepinephrine. In: DRUGDEX® System [Internet database]. Updated periodically.
Norepinephrine
Norepinephrine
• Hemodynamic effects
• Usual dose
– Alpha 1: Vasoconstriction – increased SVR
– Beta 1: Mild increases in contractility and heart rate – no effect on CO
– Starting infusion rate: 0.01 – 0.05 mcg/kg/min
– May titrate up to 2 mcg/kg/min
• Dosage forms
• Increased myocardial oxygen consumption
– 1 mg/mL (4 mL) vial
• Dilute 4 mg in 250 mL (16 mcg/mL) or 8 mg in 250 mL (32 mcg/mL) in D5W or NS
• D5W protective against oxidation and degradation
111
Norepinephrine Adverse Effects
• Alpha effects
• Multisite, double blind RCT
• Comparison of dopamine vs norepinephrine as first line vasopressor in various shock states
• 1679 patients enrolled
– Excessive vasoconstriction
• Compromise of organ perfusion
– Worsening of ventricular function
• Increased afterload
– 858 received dopamine
– 821 received norepinephrine
– Tissue necrosis and sloughing
• Beta effects
– Cardiac arrhythmias
De Backer D. N Engl J Med. 2010 Mar 4;362(9):779‐89. • No significant difference in 28 day mortality (52.5% dopamine, 48.5% norepinephrine, OR 1.17 (0.97‐1.42), p = 0.10)
• Arrhythmias occurred in 24.1% dopamine patients vs 12.4% norepinephrine patients (p < 0.001)
• Statistically significant higher 28 day mortality in cardiogenic shock subgroup with dopamine use
• 1360 patients from 11 trials
– 5 trials observational
– 6 trials interventional
• No difference in mortality with dopamine in observational trials – RR = 1.09 (95% CI 0.84‐1..41, p = 0.72)
– Significant heterogeneity in outcomes, vasopressors used
• Increased mortality with dopamine in interventional trials
– RR = 1.12 (95% CI 1.01‐1.20; p = 0.035)
– Only two trials had 28 day mortality as the primary endpoint
De Backer D. N Engl J Med. 2010 Mar 4;362(9):779‐89. De Backer D. Crit Care Med. 2012 Mar;40(3):725‐30.
Epinephrine
Epinephrine
• Endogenous hormone synthesized by norepinephrine
• Circulating hormone produced and released by adrenal glands in response to stress
• α1, β1, and β2 adrenergic agonist
– Low doses (0.01 ‐0.05 mcg/kg/min)
• Activates β1 and β2 receptors
– Beta 1: Increases heart rate and contractility – increased CO
– Beta 2: Vasodilatory
– Moderate‐high doses (0.05‐3 mcg/kg/min)
• Activates α1, β1, and β2 receptors
– Primary vasoconstriction effect on small arterioles and precapillary sphincters
– Beta 1: Increases heart rate and contractility –increased CO
– Alpha 1: Vasoconstriction – increased SVR
• The most potent alpha receptor activator
Epinephrine. In: DRUGDEX® System [Internet database]. Updated periodically.
112
Epinephrine
Epinephrine Adverse Effects
•
•
•
•
•
• Usual Dose
– 0.05‐0.2 mcg/kg/min
– Max dose: 0.8 mcg/kg/min
• Dosage forms:
Hyperglycemia
Lactic acidosis
Restlessness
Headache
Alpha effects
Effects are transient, resolve after 24 hours
– Excessive vasoconstriction
• Compromise of organ perfusion
– 1 mg/mL (1 mL) vial
– Extravasation
• Dilute 1 mg in 250 mL (4 mcg/mL) or 4 mg in 250 mL (16 mcg/mL) of D5W or NS
• Beta effects
– Tachycardia
– Tachyarrhythmias
– Anginal pain
• Prospective, multisite, randomized controlled trial in Australia
• No difference in time to achieve MAP goal, vasopressor free days
• No difference in mortality in any group, subgroup
• Epinephrine associated with significant increases in tachycardia and lactic acidosis which resolved in the first 24 hours
– 139 received epinephrine
– 138 received norepinephrine
• 66% of patients not on vasopressors at enrollment
– Higher withdrawal from study due to adverse effects than norepinephrine (12.9% vs 2.8%, p = 0.002)
• No difference in supraventricular arrhythmias
Myburgh JA. Intensive Care Med. 2008 Dec;34(12):2226‐34. Epub 2008 Jul 25.
Myburgh JA. Intensive Care Med. 2008 Dec;34(12):2226‐34. Epub 2008 Jul 25.
• Prospective, multicentered, randomized, double blind study
• No difference observed in any mortality outcome (13 deaths NE+DOB, 13 deaths EPI)
• Epinephrine patients had a higher arterial pH through day 4 and higher arterial lactate concentration at day 1
• No significant differences in adverse events
– 169 received norepinephrine + dobutamine
– 161 received epinephrine
– Included patients refractory to high dose dopamine, or any dose of norepinephrine or epinephrine
• Primary Endpoints
– 28 day all cause mortality
• Secondary endpoints
– Mortality rates at day 7, 14, 90 ICU discharge, hospital discharge
– Systemic hemodynamics
– Arterial pH and lactate
Annane D. Lancet. 2007 Aug 25;370(9588):676‐84.
Annane D. Lancet. 2007 Aug 25;370(9588):676‐84.
113
Vasopressin
Vasopressin
• Dosing
• Endogenous peptide hormone
• Agonist at V1 and V2 receptors
– VASST Trial: 0.01‐0.03 units/min
– Surviving Sepsis: 0.03 units/min fixed dose adjunctive
– Vasostrict® PI: 0.01 units/min, titrate up by 0.005 units/min at 10‐15 minute intervals (Max dose: 0.07 units/min)
– Higher affinity V2 than V1
• Septic shock – relative vasopressin deficiency
– Vasoconstriction
– Associated with lower heart rates
• Dosage forms
– 20 units/mL (1 mL) vial
– 2.5 mL vasopressin in 500 mL NS or D5W (0.1 units/mL)
– Fluid restricted: 5 mL vasopressin in 100 mL NS or D5W (1 unit/mL)
• Discard unused diluted solution after 18 hours room temp or 24 hours refrigerated
• Unpunctured vials can be stored up to 12 months at room temperature
Vasopressin. In: DRUGDEX® System [Internet database]. Updated periodically.
Vasotrict(R) [package insert]. Spring Valley, NY: Par Pharmaceutical Companies Inc. 2014
Vasopressin
• Multicenter, randomized, stratified, double‐blind trial
• Included patients in septic shock unresponsive to 500 mL bolus of fluid and 5 mcg/min norepinephrine
• 778 patients randomized
• Adverse events
– Increased incidence of cardiac arrest?
– Decreased cardiac output?
– Hyponatremia
– Mesenteric ischemia
– Skin necrosis
– Digital ischemia
– 396 patients: vasopressin
– 382 patients: norepinephrine
• No difference 28 day mortality (35.4% vaso, 39.3% norepi)
– Trend favoring vasopressin in less severe septic shock
• No difference secondary outcomes
– No difference 90 day mortality
– No difference rate of organ dysfunction
• Vasopressin allowed for rapid decrease in norepinephrine dose while maintaining MAP (“catecholamine sparing”)
Russell JA. N Engl J Med. 2008 Feb 28;358(9):877‐87.
VASST Sub‐Group Analyses
• Single center, randomized controlled, open label trial
• Included patients with vasodilatory shock due to sepsis, SIRS, or cardiac surgery
• Reduced mortality in patients at risk for AKI
• Reduced mortality in patients with less severe shock
• Reduced mortality if vasopressin administered early (within 12 hours) than late
• Vasopressin + steroids use led to decreased mortality than norepinephrine + steroids
• No increase in myocardial ischemia or decreased cardiac output
– Required NE > 0.6 mcg/kg/min
• 50 patients randomized
– 25 received vasopressin 0.033 units/min
• Dose range: 2‐16 mcg/min
– 25 received vasopressin 0.067 units/min
• Primary outcome
– Hemodynamic response
• Secondary outcomes
– Differences in organ function and lab values
– AVP and prolactin levels
– ADE rate
Gordon AC. Intensive Care Med. 2010 Jan;36(1):83‐91. Epub 2009 Oct 20.
Gordon AC. Chest. 2012 Apr 19. [Epub ahead of print]
Mehta S. Crit Care. 2013 Jun 20;17(3):R117.
Torgersen C. Intensive Care Med. 2010 Jan;36(1):57‐65.
114
Dose
Baseline
1 hour
12 hour
24 hours
48 hours
P value
0.033 units
65 +/‐ 9
71 +/‐ 12
71 +/‐ 11
71 +/‐ 10
75 +/‐ 7 P = 0.06
0.067 units
65 +/‐ 9
78 +/‐ 13
69 +/‐ 14
71 +/‐ 7
75 +/‐ 7 • Results
– Mortality similar in both groups
MAP
• 6 patients in low dose, 4 patients in high dose (p=0.73)
– ADEs comparable in both groups (LD vs. HD)
•
•
•
•
NE dose
(mcg/kg/min)
0.033 units
0.98 +/‐
0.6
0.94 +/‐
0.82
0.85 +/‐
0.96
0.57 +/‐
0.39
0.4 +/‐
0.31
0.067 units
0.86 +/‐
0.34
0.64 +/‐
0.37
0.69 +/‐
0.78
0.65 +/‐
1.4
0.22 +/‐
0.16
P = 0.06
Decrease CI (25% vs. 50%, p=0.26)
Elevated LFTs (47.6% vs. 65.2%, p = 0.36)
Increased bilirubin (19% vs. 26.1%, p=0.72)
Decreased platelets (71.4% vs. 73.9%, p=1)
Phenylephrine
Phenylephrine
• Pure alpha agonist
• Usual dose: 0.2‐0.5 mcg/kg/min
• Dosage form
– Causes vasoconstriction of most vascular beds
• Alternative in patients who cannot tolerate tachycardia or arrhythmias from dopamine or norepinephrine
• Hemodynamic effect
– 10 mg/mL (1 mL, 5 mL, 10 mL) vials
– Vazculep® ‐ 10 mg/mL (1 mL, 5 mL, 10 mL) vials
– Dilute to 10 mg in 500 mL (20 mcg/mL), 50 mg in 500 mL (100 mcg/mL), or 100 mg in 500 mL (200 mcg/mL) D5W or NS
– Increases systolic, diastolic pressure and MAP
Phenylephrine. In: DRUGDEX® System [Internet database]. Updated periodically.
Phenylephrine. In: DRUGDEX® System [Internet database]. Updated periodically.
Phenylephrine
Dopamine
• Endogenous neurotransmitter in CNS and PNS
• Adverse effects
– precursor of norepinephrine
– Alpha effects
• Direct and indirect effects
• Excessive vasoconstriction
– Compromise of organ perfusion
– Direct – stimulates alpha, beta, and dopamine receptors
– Indirect – stimulates release of norepinephrine from sympathetic nerves
• Extravasation
• Reflex bradycardia
– Caution in patients with decreased CO
» Impaired preload + bradycardia = worsen CO
• Stimulates dopaminergic receptors in the splanchnic, renal, and coronary vascular beds
• Low concentration solutions at high doses = large amounts of fluid administered
– Produces vasodilation, improved renal blood flow
Phenylephrine. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
Dopamine. In: DRUGDEX® System [Internet database]. Updated periodically.
115
Dopamine
Dopamine
• Dosing
– 2 – 5 mcg/kg/min
– 0.5 – 3 mcg/kg/min
• Increases cardiac contractility and cardiac output
• No changes in heart rate, blood pressure, SVR
• Activates D1 receptors in renal vascular beds
• “Renal sparing dose”
– > 10 mcg/kg/min
• Increases blood pressure, mean arterial pressure – increased SVR
• Activates β1‐adernergic receptors
• Minimal activation of α1‐adernergic receptors
• Inotropic, chronotropic, vasoactive properties
• Mixed β1 and α1 adrenergic response
– Effects are dose dependent
– > 20 mcg/kg/min
• Stimulates dopaminergic receptors in the splanchnic, renal, and coronary vascular beds
• Predominant stimulation of peripheral α1‐adernergic receptors
Dopamine
“Low‐Dose” Dopamine
• In healthy volunteers, increases renal blood flow and induces naturesis and diuresis
• Attenuates renal injury?
• Bellomo, etal – Lancet 2000
• Dosage Forms
– Premix – 200 mg/250 mL, 400 mg/250 mL, 800 mg/250 mL in D5W
– 40 mg/mL (5 mL, 10 mL), 80 mg/mL (5 mL), 160 mg/ mL (5 mL) vials
– Double blind, placebo controlled RCT
– 328 patients with at least 1 indicator of renal dysfunction
• 163 – “low‐dose” dopamine (2 mcg/kg/min)
• 165 – Placebo
• dilute 400 mg or 800 mg in 250 mL NS or D5W
– Results
• Protect from light
• No difference in peak serum creatinine, increase in creatinine, # of patients acute renal failure, or # of patients requiring hemodialysis
• No differences in length of stay, mortality
– Do not use if yellow‐brown discoloration
•
•
•
•
•
• “Low‐Dose” dopamine cannot be recommended
Bellomo R. Lancet. 2000 Dec 23‐30;356(9248):2139‐43.
Dopamine ADRs
Midodrine
• Prodrug of desglymidodrine, a pure alpha 1 agonist
Headache
Nausea/vomiting
May impair resistance to infection
Tachyphylaxis
Alpha Effects
– Causes vasoconstriction of arteriolar and venous vasculature
• Clinical use:
– Hypertension
– Vasoconstriction
– Extravasation
– ORAL agent for patients who are unable to be weaned off LOW doses of vasopressors
• Ischemic necrosis and sloughing
• Hemodynamic effect:
• Beta Effects
– Increases systolic, diastolic pressure and MAP
– Tachycardia
– Arrhythmias
– Anginal pain
• Usual dose: 5 mg three times daily
– Up to 10 mg three times daily may be used
Midodrine. In: DRUGDEX® System [Internet database]. Updated periodically.
116
Midodrine Pharmacokinetics
Midodrine Adverse Effects
• Absorption
•
•
•
•
– Rapid and complete
– Onset of action: 1 hour
• Metabolism
– Midodrine – prodrug converted through hydrolysis in systemic circulation to desglymidodrine
– Desglymidodrine – active metabolite, responsible for therapeutic activity
Bradycardia
Piloerection (goosebumps)
Pruritus
Urinary urgency, retention, and frequency • Excretion
– Renal
– Duration of action: 2‐6 hours
• Dose adjustment
– Renal impairment: consider lower initial dose (2.5 mg) Midodrine. In: DRUGDEX® System [Internet database]. Updated periodically.
Midodrine. In: DRUGDEX® System [Internet database]. Updated periodically.
Usual Dosing and Concentrations
Receptor Affinity
Usual Dose Range
Max Dose
Adult Concentrations
Solution
Norepinephrine
Norepinephrine
0.01‐0.6 mcg/kg/min
3 mcg/kg/min
16‐32 mcg/mL
D5W or NS
Epinephrine
Epinephrine
0.8 mcg/kg/min
4‐40 mcg/mL
D5W or NS
Vasopressin
01‐0.7 units/min
0.7 units/min
0.2‐1 unit/mL
D5W or NS
Phenylephrine
9.1 mcg/kg/min
20‐200 mcg/mL
NS
Dopamine
1‐20 mcg/kg/min
50 mcg/kg/min
1600‐3200 mcg/mL
D5W or NS
Dobutamine
2.5‐20
mcg/kg/min
40 mcg/kg/min
500‐4000 mcg/mL
D5W or NS
Milrinone
0.375‐0.75 mcg/kg/min
200 mcg/mL
D5W
0.05‐3 mcg/kg/min
α1
α2
Β1
β2
D
V
+++
+++
+++
+/++
0
0
++
++
++++
+++
0
0
++++
++++
+++
+
0
0
Dopamine
0.05‐3 mcg/kg/min
0
0
+
0
++++
0
3‐10 mcg/kg/min
0/+
0
++++
+
++++
0
> 10‐20 mcg/kg/min
+++
0
++++
+
0
0
+
0
++++
++
0
0
+++
+
+
0
0
0
0
0
0
0
0
+++
Dobutamine
Phenylephrine
Vasopressin
Extravasation
General Management
• Leakage of vasopressor into soft tissue causing necrosis
• Due to large gauge needles inserted peripherally in smaller veins or areas of lower circulation
• Adrenergic agents – induce venous and arterial vasospasm reducing distal blood flow
• STOP THE INFUSION
• Leave catheter or needle in place to attempt to aspirate drug (3‐5 mL blood)
• Administer reversal agent
• Remove needle
• Elevate affected limb
• Apply WARM compresses
• Wound care
– Blanching, swelling, skin sloughing, dermal necrosis
Reynolds PM. Pharmacotherapy. 2014
Le A. Ann Pharm. 2014
117
Phentolamine
Terbutaline
• Standard of Care – only FDA approved antidote
• MoA: Competitively blocks alpha receptors
• Dose: 1 mg in 10 mL NS
– Administer SQ around extravasation site
• MoA: Beta 2 receptor agonist
– Antagonizes norepinephrine, epinephrine, phenylephrine, dopamine
– Vasodilates vasculature
• Case reports for treating extravasation of dobutamine, dopamine, epinephrine finger pricks
• No commercially available product
– Discontinued by West‐Ward in early January 2015
http://www.ashp.org/menu/DrugShortages/DrugsNoLongerAvailable/Bulletin.aspx?id=349
Stier P. Am J Emerg Med. 1999 Jan;17(1):91‐4.
Terbutaline Evidence
Nitroglycerin
Study
Type
Extravasation
Dose
Administration
Efficacy
Stier P, 1999
1 Case –
65 y/o adult
Dopamine + dobutamine
1 mg in 10 mL NS
10 mL
infiltrated into blanched areas within 1 hour
Immediate
return of blood flow, no ADRs
• Dose: 4 mm/kg (up to 1 inch) of 2% topical ointment applied to sides of extravasation
• MoA: vasodilates capillaries
• Case reports of use in dopamine extravasation in infants
• Monitor for hypotension
Stier P. Am J Emerg Med. 1999 Jan;17(1):91‐4.
Denkler KA. Plast Reconstr Surg. 1989 Nov;84(5):811‐3.
Wong AF. J Pediatr. 1992 Dec;121(6):980‐3.
Nitroglycerin Evidence
Nitroglycerin Evidence
Study
Patient
Extravasation
Dose
Study
Denkler, 1989
Infant 34 weeks gestation
Dopamine 10 mcg/kg/min
2% nitroglycerin
ointment
Wong, 1992
Infant 15 days old Dopamine 12‐20 mcg/kg/min
Wong, 1992
infant 4 day old, Dopamine 24 mcg/kg/min
Administration
Efficacy
Denkler, 1989 2% nitroglycerin
ointment
1 inch strip applied to each site of extravasation
2% nitroglycerin ointment
Blanching resolved within minutes, normal appearance within 6.5
hours
Wong, 1992
4 mm/kg applied to affect area every 8 hours x 3 doses
Some improvement noted after 8 hours, full resolution after 24 hours
Wong, 1992
4 mm/kg applied to affected area
NTG administered 1 hour after phentolamine
failure. Improvement within 15 minutes, full resolution in 2 hours
Dose
118
Vasopressor Clinical Pearls
Patient Case: SM
• Do not start vasopressors until adequate trial of fluids (30 mL/kg)
• Administer through a central line
SM received 500 mL lactated ringer’s solution, 1500 mL isotonic saline, 500 mL albumin. A Swan‐ganz catheter is placed
– Extravasations may be treated with terbutaline or nitroglycerin ointment
• Norepinephrine 1st line for septic shock
• Vasopressors that agonize alpha
– Increase SVR
– Reflex bradycardia
• Vasopressors that agonize beta
– Increase CO
– Tachycardia, arrhythmias
Patient Case: SM
Norepinephrine is initiated at 0.03 mcg/kg/min, but we still need to address the low CI.
Using Inotropes
Cardiogenic Shock
Dobutamine
• ACC/AHA STEMI Guidelines 2013
• Synthetic catecholamine designed for selective inotropic activity with minimal vascular effect
• Selective β1, β2 agonist
– “Medical support with inotropes and vasopressor agents should be individualized and guided by invasive hemodynamic monitoring”
– Only specific recommendation – avoid dopamine
• Inotropes
– Dobutamine
– Epinephrine
– Milrinone
– Weak β2, α1 effects
• Vasopressors
• β2 >>> α1
– Norepinephrine
• Reserved for severe hypotension
– Dopamine – No longer recommended (DeBacker 2010)
Dobutamine. In: DRUGDEX® System [Internet database]. Updated periodically.
O'Gara PT. J Am Coll Cardiol. 2013;61(4):e78‐e140.
119
Dobutamine
Dobutamine
• Usual dose: 2.5‐20 mcg/kg/min
• Dosage forms
– Increases contractility, stroke volume, heart rate –
increased CO
– Decreased to minimal effect on SVR, CVP, PCWP
– Premix – 250 mg/250 mL (1 mg/mL), 500 mg/250 mL (2 mg/mL), 1000 mg/250 mL (4 mg/mL)
– 250 mg/20 mL, 500 mg/40 mL vials
– Dilute vials to to premix concentrations in D5W or NS
• Effects may diminish over time due to down‐
regulation of beta receptors
Dobutamine
Milrinone
• Adverse Effects
• Inhibits cAMP phosphodiesterase found in cardiac and vascular muscles
– Beta agonism
– Increase intracellular ionized calcium and contractile force in heart muscle
• Tachycardia
• Arrhythmias
• Ischemia
• May be useful in patients who CO does not increase in response to catecholamines
– Nausea
– Anxiety
– Tremors
– Positive inotrope
• Long term use
• Increases myocardial work, oxygen consumption
– Decline in CO and HR as body downregulates β1 receptors
– Vasodilation
• decreases PVR/SVR
Milrinone. In: DRUGDEX® System [Internet database]. Updated periodically.
Milrinone
Milrinone Dose Adjustments
• Usual dose
– 0.1‐0.75 mcg/kg/min infusion
• Eliminated via kidney
– Reduce infusion rate in renal insufficiency
– T1/2 = 1‐3 hours
• Dosage forms
Creatinine Clearance
5
Infusion Rate (mcg/kg/min)
0.2
10
0.23
20
0.28
30
0.33
40
0.38
50
0.43
– Premix – 20 mg/100 mL, 40 mg/200 mL
– 10 mg/10 mL, 20 mg/20 mL, 50 mg/50 mL vials
120
Milrinone
Usual Dosing and Concentrations
• Adverse effects
– Arrhythmias
• Ventricular arrhythmias (12.1%)
– 8.5% Non‐sustained ventricular tachycardia
– 2.8% Sustained ventricular tachycardia
– 1% Ventricular fibrillation
– Hypotension (2.9%)
– Headache (2.9%)
Usual Dose Range
Max Dose
Adult Concentrations
Solution
Norepinephrine
3 mcg/kg/min
16‐32 mcg/mL
D5W or NS
Epinephrine
0.8 mcg/kg/min
4‐40 mcg/mL
D5W or NS
Vasopressin
0.3 units/min
0.2‐1 unit/mL
D5W or NS
Phenylephrine
9.1 mcg/kg/min
20‐200 mcg/mL
NS
Dopamine
1‐20 mcg/kg/min
50 mcg/kg/min
1600‐3200 mcg/mL
D5W or NS
Dobutamine
2.5‐20
mcg/kg/min
40 mcg/kg/min
500‐4000 mcg/mL
D5W or NS
Milrinone
200 mcg/mL
D5W
Mechanical Options
Inotropes Clinical Pearls
• Intraaortic Balloon Pump
• Administer through a central line
• Avoid dopamine in cardiogenic shock
• Watch for arrhythmias – may require treatment or change in inotrope
• Many inotropes decrease SVR
– Improves short term hemodynamic profile
– May not improve outcomes unless combined with coronary revascularization
• Ventricular Assist Devices (VADs)
– Consider for patients with very low cardiac output (< 1.2 L/min/m2) who have failed to respond to IABP and reperfusion
– Device and catheter inserted percutaneously into the left atrium
– Dobutamine
– Milrinone
Thiele H. N Engl J Med. 2012 Oct 4;367(14):1287‐96.
O'Connor CM. N Engl J Med. 2012 Oct 4;367(14):1349‐50.
Patient Case: SM
Patient Case: SM
The PA initiates SM on epinephrine at 0.04 mcg/kg/min and norepinephrine at 0.03 mcg/kg/min. An hour later, the nurse pulls a reading from the Swan‐
Ganz catheter.
Norepinephrine is initiated at 0.03 mcg/kg/min, but we still need to address the low CI.
Continuous Infusions
Epinephrine 0.04 mcg/kg/min
Norepinephrine 0.03 mcg/kg/min
121
Areas of Future Research
Summary
• Treat the patient not the number
• Fluids, fluids, and more fluids!
• Choice of vasopressor or inotrope:
• Do physiologically balanced crystalloids have better outcomes than normal saline?
• Can vasopressin be used as first line for septic shock?
– Swan‐Ganz: what values are abnormal?
– Pathophys: what is the cause of patients instability?
• Sepsis or low SVR: Norepinephrine
• Cardiogenic or low CO: consider side effect profile when choosing agent
– VANISH trial currently underway
• Further study of vasopressors in specific disease states
– Can patient tolerate an agent that will decrease SVR?
– Avoid dopamine
• Use the lowest possible dose to maintain perfusion
• Terbutaline or nitroglycerin ointment may be used to treat extravasation
Additional References
1.
2.
3.
Questions?
4.
5.
6.
7.
Hoffman EW. Basics of cardiovascular hemodynamic monitoring. Drug Intell Clin Pharm. 1982 Sep;16(9):657‐64.
Barnes AD, Lee SH. Shock. In: Koda‐Kimble MA, Young LY, Kradjan WA, editors. Applied Therapeutics: The Clinical Use of Drugs. Philadelphia: Lippincott Williams & Wilkins. 2005; p 22‐1‐22‐36.
MacLaren R, Rudis MI, Dasta JF. Use of Vasopressors and Inotropes in the Pharmacotherapy of Shock. In: Dipiro JT, Talbert JL, editors. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw Hill. 2008; p 417‐440.
Erstad BL. Hypovolemic Shock. In: Dipiro JT, Talbert JL, editors. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw Hill. 2008; p 441‐454.
Russell JA. Management of sepsis. N Engl J Med. 2006 Oct 19;355(16):1699‐713.
Hollenberg SM. Inotrope and vasopressor therapy of septic shock. Crit Care Clin. 2009 Oct;25(4):781‐802, ix.
Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock 2012. Crit Care Med. 2013 Feb;41(2):580‐637.
15. Raghunathan K, Shaw A, Nathanson B, etal. Association between the choice of IV crystalloid and in‐hospital mortality among critically ill adults with sepsis. Crit Care Med. 2014 Jul;42(7):1585‐91.
16. Overgaard CB, Dzavík V. Inotropes and vasopressors: review of physiology and clinical use in cardiovascular disease. Circulation. 2008 Sep 2;118(10):1047‐56.
17. Norepinephrine. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
18. De Backer D, Biston P, Devriendt J, etal. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010 Mar 4;362(9):779‐
89. 19. Epinephrine. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
20. Annane D, Vignon P, Renault A, etal. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet. 2007 Aug 25;370(9588):676‐84.
21. Myburgh JA, Higgins A, Jovanovska A, etal. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med. 2008 Dec;34(12):2226‐
34. Epub 2008 Jul 25.
8. Topalian S, Ginsberg F, Parrillo JE. Cardiogenic shock. Crit Care Med. 2008 Jan;36(1 Suppl):S66‐74.
9. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001 Aug 23;345(8):588‐95.
10. Myburgh JA, Finfer S, Bellomo R, etal. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012 Nov 15;367(20):1901‐11.
11. Finfer S, Bellomo R, Boyce N, etal. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004 May 27;350(22):2247‐
56.
12. Caironi P, Tognoni G, Masson S, etal. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014 Apr 10;370(15):1412‐21.
13. Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013 Sep
26;369(13):1243‐51.
14. Yunos NM, Bellomo R, Hegarty C, etal. Association between a chloride‐liberal vs
chloride‐restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012 Oct 17;308(15):1566‐72.
122
22. Levy B, Perez P, Perny J, etal. Comparison of norepinephrine‐dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock. A prospective, randomized pilot study. Crit Care Med. 2011 Mar;39(3):450‐5.
23. Vasopressin. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
24. Vasotrict(R) [package insert]. Spring Valley, NY: Par Pharmaceutical Companies Inc. 2014
25. Landry DW, Levin HR, Gallant EM, etal. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997 Mar 4;95(5):1122‐5.
26. Russell JA, Walley KR, Singer J, etal. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877‐87.
27. Gordon AC, Wang N, Walley KR, etal. The Cardiopulmonary Effects of Vasopressin Compared With Norepinephrine in Septic Shock. Chest. 2012 Apr 19. [Epub ahead of print] 28. Gordon AC, Russell JA, Walley KR, etal. The effects of vasopressin on acute kidney injury in septic shock. Intensive Care Med. 2010 Jan;36(1):83‐91. Epub 2009 Oct 20.
29. Patel BM, Chittock DR, Russell JA, etal. Beneficial effects of short‐term vasopressin infusion during severe septic shock. Anesthesiology. 2002 Mar;96(3):576‐82.
30. Torgersen C, Dünser MW, Wenzel V, etal. Comparing two different arginine vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open‐
label trial. Intensive Care Med. 2010 Jan;36(1):57‐65.
31. Phenylephrine. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
32. Dopamine. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
33. Bellomo R, Chapman M, Finfer S, etal. Low‐dose dopamine in patients with early renal dysfunction: a placebo‐controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. 2000 Dec 23‐
30;356(9248):2139‐43.
34. Midodrine. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
35. Le A, Patel S. Extravasation of Noncytotoxic Drugs: A Review of the Literature. Ann Pharmacother. 2014 Apr 8;48(7):870‐886.
36.
37.
38.
39.
40.
41.
42.
43.
44.
Reynolds PM, MacLaren R, Mueller SW, etal. Management of extravasation injuries: a focused evaluation of noncytotoxic medications. Pharmacotherapy. 2014 Jun;34(6):617‐32.
Stier PA, Bogner MP, Webster K, etal. Use of subcutaneous terbutaline to reverse peripheral ischemia. Am J Emerg Med. 1999 Jan;17(1):91‐4.
Denkler KA, Cohen BE. Reversal of dopamine extravasation injury with topical nitroglycerin ointment. Plast Reconstr Surg. 1989 Nov;84(5):811‐3.
Wong AF, McCulloch LM, Sola A. Treatment of peripheral tissue ischemia with topical
nitroglycerin ointment in neonates. J Pediatr. 1992 Dec;121(6):980‐3.
O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA Guideline for the Management of ST‐
Elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4):e78‐e140.
Dobutamine. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
Milrinone. In: DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
Thiele H, Zeymer U, Neumann FJ, etal. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med. 2012 Oct 4;367(14):1287‐96. doi: 10.1056/NEJMoa1208410. Epub 2012 Aug 26.
O'Connor CM, Rogers JG. Evidence for overturning the guidelines in cardiogenic shock. N Engl J Med. 2012 Oct 4;367(14):1349‐50. doi: 10.1056/NEJMe1209601. Epub 2012 Aug 26.
123
2015 Annual Meeting
Saturday, May 23
8:00—9:00 a.m.
Management of Invasive Fungal Infections: Applying Evidence-based Strategies
and Individualizing Antifungal Therapy
0204-0000-15-412-L01-P
This activity is planned and conducted by ASHP Advantage and
supported by an educational grant from Merck.
124
Maanaggem
ment of In
nvassive Funggal
Infec
I ction
ns: A
Applyyingg Evid
dencce‐
bassed Straategiies aand Indiividu
ualizzing A
Antiifunggal
Th
heraapy
LSHP Annuaal Meetin
ng 2015 –– New Orlleans, LA – May 23
3, 2015 Planned and cond
ducted by ASHP Advantag
ge and supported by an
educational grant fro
om Merck.
125
Activity Overview
As the 3rd most common cause of bloodstream infections in the intensive care unit, and the fourth most
common cause of nosocomial bloodstream infections, invasive candidiasis is common and deadly. While C.
albicans remains the most prevalent species in the USA, the prevalence of non-albicans Candida species has
increased since 2004, and C. parapsilosis and C. glabrata each comprise approximately 15% of all Candida
isolates.
The wider availability and use of newer agents over the past decade has resulted in additional choices of agents,
but also in the incidence of antifungal resistance, in particular for C. glabrata to azoles and (of recent concern) to
echinocandins. Faculty will discuss current antifungal therapies for the treatment of candidemia, focusing on
recent studies that affect the interpretation and use of treatment guidelines and the importance of using local
epidemiology and resistance patterns. Management principles for the identification, monitoring, and
management of antifungal adverse effects, drug interactions, and therapeutic drug monitoring will also be
highlighted.
Learning Objectives
At the conclusion of this knowledge-based educational activity, participants should be able to
•
•
•
•
Review rapid diagnostics and their roles for diagnosis and treatment of systemic Candida infections.
Discuss therapeutic drug monitoring for azole antifungals.
Recommend treatment options for patients with systemic candidiasis or candidemia infections.
Describe evolving resistance mechanisms and changing paradigms for treating systemic candidiasis or
candidemia infections.
Continuing Education Accreditation
The American Society of Health-System Pharmacists is accredited by the Accreditation Council for
Pharmacy Education as a provider of continuing pharmacy education. This activity provides 1.0
hour (0.1 CEU – no partial credit) of continuing pharmacy education credit (ACPE activity #02040000-15-412-L01-P).
Participants will process CPE credit online at http://elearning.ashp.org/my-activities, with the option of printing
a CE certificate. CPE credit will be reported directly to CPE Monitor. Per ACPE, CPE credit must be claimed no
later than 60 days from the date of the live activity or completion of a home study activity.
126
Management of Invasive Fungal Infections: Applying Evidence‐based
Strategies and Individualizing Antifungal Therapy Activity Faculty Kevin W. Garey, Pharm.D., M.S., FASHP Professor and Chair Department of Clinical Sciences and Administration University of Houston College of Pharmacy Houston, Texas Kevin W. Garey, Pharm.D., M.S., FASHP is Professor at the University of Houston College of Pharmacy and Chair of the Department of Clinical Sciences and Administration at the University of Houston College of Pharmacy in Houston, Texas. Dr. Garey is an Adjunct Professor at the University of Texas School of Public Health and a Clinical Specialist and Researcher at Baylor St. Luke’s Medical Center in Houston, Texas. He received a Bachelor of Science in Pharmacy degree from Dalhousie University in Halifax, Nova Scotia, Canada, a Doctor of Pharmacy from the State University of New York in Buffalo, New York, and Master of Science in Biometry from the University of Texas School of Public Health in Austin, Texas. He completed a pharmacy practice residency at Bassett Healthcare, Cooperstown, NY and infectious disease specialty residency and fellowship training at the University of Illinois at Chicago College of Pharmacy in Chicago, Illinois. Dr. Garey has numerous publications in infectious diseases topics and has presented extensively at national and international professional conferences. He has received numerous professional awards including the ASHP Drug Therapy Research Award, ASHP Best Practices Award in Health‐System Pharmacy, the Society of Infectious Diseases Pharmacists Impact Paper in Infectious Diseases Pharmacotherapy Award and the University of Houston Faculty Leadership award. He is a Fellow of ASHP. Dr. Garey's research interests involve clinical and translational research involving healthcare‐associated infections including post‐surgical infections, candidemia, and Clostridium difficile infection. 127
3
Disclosure Statement
In accordance with the Accreditation Council for Continuing Medical Education’s Standards for Commercial
Support and the Accreditation Council for Pharmacy Education’s Guidelines for Standards for Commercial
Support, ASHP Advantage requires that all individuals involved in the development of activity content disclose
their relevant financial relationships. A commercial interest is any entity producing, marketing, re-selling, or
distributing health care goods or services consumed by, or used on, patients. A person has a relevant financial
relationship if the individual or his or her spouse/partner has a financial relationship (e.g., employee, consultant,
research grant recipient, speakers bureau, or stockholder) in any amount occurring in the last 12 months with a
commercial interest whose products or services may be discussed in the educational activity content over which
the individual has control. The existence of these relationships is provided for the information of participants
and should not be assumed to have an adverse impact on presentations.
All faculty and planners for ASHP Advantage education activities are qualified and selected by ASHP Advantage
and required to disclose any relevant financial relationships with commercial interests. ASHP Advantage
identifies and resolves conflicts of interest prior to an individual’s participation in development of content for an
educational activity.
•
Peggy L. Carver, Pharm.D., FCCP, serves on the speakers bureau for Merck and Astellas, Inc.
•
Kevin W. Garey, Pharm.D., M.S., FASHP, has received research grants from Astellas, Inc. and T2
Biosystems.
•
All other planners report no financial relationships relevant to this activity.
128
Disclosures
• Peggy L. Carver, Pharm.D., FCCP, serves on the
speakers bureau for Merck and Astellas, Inc.
Management of Invasive Fungal Infections: Applying Evidence‐based Strategies and Individualizing Antifungal Therapy
• Kevin W. Garey, Pharm.D., M.S., FASHP, has received research grants from Astellas, Inc. and T2
Biosystems.
• All other planners report no financial relationships relevant to this activity.
Professor and Chair
Department of Clinical Sciences and Administration
University of Houston College of Pharmacy
Houston, Texas
Planned and conducted by ASHP Advantage
and supported by an educational grant from Merck
Systemic Candida Infections
Learning Objectives
• Review rapid diagnostics and their roles for diagnosis
and treatment of systemic Candida infections.
67 year old white male past admission acute pancreatitis
Vitals: 102.3F, 100/50, 101, 23
WBC: 13,000 Baseline Cr: 1.4
Current Cr: 1.8
• Recommend treatment options and describe evolving
resistance mechanisms and changing paradigms for
treating systemic candidiasis or candidemia infections.
Pharmacy
is Phabulous • Discuss indications for antifungal therapeutic drug
monitoring.
Central venous catheter associated for TPN
Also received antibiotics for pancreatitis
• Identify current therapeutic options for the diagnosis and
treatment of aspergillosis infections.
Central venous catheter
Send Blood samples
Start therapy (micafungin)
Diagnosis: Suspected systemic candidiasis!!! A delay in echinocandins also is associated with poor outcomes
A delay in the initiation of antifungals increases bad outcomes in patients with candidemia
Multicenter study of 169 patients with candidemia given caspofungin
Morrell M et al. Antimicrobial
Agents Chemother. 2005; 49:
3640-5.
Garey KW et al. Clin Infect
Dis. 2006; 43:25 31.
Hsu D. J Antimicrob Chemother. 2010; 65(8):1765‐70.
129
Blood cultures take a long time to identify Candida
BC drawn
Yeast
2.4 days
T2 Magnetic resonance
We would like to start antifungals here
Speciation
2.2 days
• I think ID/antimicrobial stewardship
pharmacists are going to become “react to
positive diagnostic test” pharmacists
Antifungal
Susceptibilities
Culture +
(time 0)
Implications for pharmacy practice
SPECIFIC Antifungal Rx initiated
EMPIRIC Antifungal Rx initiated
0.5 days
Rapid test : MALDI‐TOF MS or PNA‐FISH
… but we usually
start them here
….and many times, we wont get it right until here
But, when a stewardship pharmacist is involved, good things happen!
Systemic Candida Infections
67 year old white male‐ past admission acute pancreatitis
Vitals: 102.3F, 100/50, 101, 23
• PNA‐FISH and Candida
WBC: 13,000 Baseline Cr: 1.4
Current Cr: 1.8
– Pharmacist reacted to results
– $1729 saved per patient
– Forrest GN et al. J Clin Microb. 2006; 44:3381‐3.
Central venous catheter associated for TPN
Pharmacy
is Phabulous Also received antibiotics for pancreatitis
• MALDI‐TOF and (Gram‐negative)
– Pharmacist reacted to results
– Approximately $12k saved per patient
– Perez KK et al. Arch Pathol Lab Med. 2012; 137:
1247‐54.
Send Blood samples using a rapid diagnostic
Diagnosis: Systemic Candida infection!!! Which antifungal regimen would you choose to treat the patient?
How do we make our
decision about what
antifungal to use?
If you were choosing using general susceptibility to antifungals
Candida species a. Fluconazole 400mg IV once daily
b. Fluconazole 6 mg/kg IV once daily
c. An echinocandin (your choice) FDA
indicated fixed dose
FLUC
ECHINO
AMB
C. albicans
S
S
S
C. tropicalis
S
S
S
C. parapsilosis
S
S to R S
C. glabrata C. krusei d. An echinocandin (your choice) using a
mg/kg once daily dose
S = susceptible;
S‐DD to R S
S to I
R
S
S to I S‐DD = susceptible dose – dependent; R = resistant
FLUC = fluconazole; AMP B = amphotericin B; ECH = caspofungin, micafungin, anidulafungin Pappas PG et al. Clin Infect Dis. 2009; 48:503‐35
130
IDSA Guideline Recommendations:
Initial therapy with fluconazole vs. an echinocandin
Fluconazole
An Echinocandin
Less critically ill
Moderately severe to severe illness
IDSA guidelines recommendation on management of candidemia in non‐neutropenic patients Initial (empiric) therapy options
Fluconazole
No recent azole exposure
An Echinocandin
Caspofungin
Loading dose of 70 mg  50 mg daily
Loading dose of 800 mg (12 mg/kg)  400 mg (6 mg/kg) daily
Recent azole exposure Micafungin 100 mg daily
Anidulafungin
Loading dose: 200 mg  100 mg daily
Pappas PG et al. Clin Infect Dis. 2009; 48:503‐35.
Pappas PG et al. Clin Infect Dis. 2009; 48:503‐35.
How long to continue treatment for candidemia?
Fluconazole
• Human evidence suggests that the appropriate dose of
fluconazole is associated with:
– Better treatment outcomes
– Reduced mortality
– Decreased resistance
2 weeks*
* No obvious metastatic complications
• Dose: 6 mg/kg (C. glabrata: 12 mg/kg)
• Pharmacodynamics
When to start counting treatment days?
– Dose: MIC or AUC:MIC
– Animal models support an AUC/MIC breakpoint of 25‐50 After documented clearance of Candida species from bloodstream
• Thus: appropriate dosing should affect outcomes
Lewis RE. Mayo Clin Proc. 2011; 86: 805-17.
Andes D et al. Antimicrob Agents Chemother. 1999; 43:2116‐20.
Pappas PG et al. Clin Infect Dis. 2009; 48:503‐35
Inappropriate doses of fluconazole are associated with increased risk of antifungal resistance.
Patients (%) with pre‐exposure to fluconazole An inappropriate fluconazole dose increases hospital costs
Total hospital costs stratified by adequate fluconazole dose given at the onset of symptoms (Day 0) or later.
Initial dose (mg/kg) of prior fluconazole therapy 100%
8 (89%)
90%
80%
70%
60%
4 (44%)
50%
40%
30%
2 (22%)
20%
3 (33%)
1(11%)
10%
0%
Lower risk
≤2 mg/kg
Total hospital costs stratified by adequate fluconazole dose given at the
onset of symptoms (Day 0) or later.
Fluconazole-susceptible
Fluconazole-resistant
Garey KW et al. Int J Antimicrob Agents. 2007; 29:557-62.
Higher risk
3‐5 mg/kg
Fluconazole dose range (mg/kg)
Lower risk
≥6 mg/kg
A dose in the 3‐5 mg/kg range was associated with a subsequent increased risk of fluconazole resistant Candida
(p‐value=0.049)
Shah DN et al. Antimicrob Agents Chemother. 2012; 56:3239‐43.
131
Highlights of Recent Studies and European Candida Guidelines
Echinocandins inhibit glucan synthase
– For moderately or severely ill patients
mannoproteins
• Start with an echinocandin or amphotericin B if catheters cannot be removed • Inhibit β‐1,3‐glucan synthase enzyme
– Severity of illness and choice of antifungal predict response in patients with C. glabrata fungemia, but do not influence mortality
1,3
1,6
glucans
– Catalytic subunit PPL
(Fks1p/2p)
bilaye
r
– Encoded by 3 FKS related genes in Candida spp. (FKS1, FKS2, FKS3)
• When there is improvement, switch to fluconazole (if the pathogen is susceptible), and to PO therapy after 10 days of IV therapy • Treat for 2 weeks after blood cultures are negative
– New CLSI C. glabrata fluconazole susceptibility breakpoints are predictive of response when fluconazole is dosed appropriately.
– Where do pharmacists come in?
β -1,3 glucan
synthase
chitin
Ergosterol
Yeast
• Appropriate dosing!
Cornely OA et al. Clin Microbiol Infect. 2012; 18:19‐37. Andes DR et al. Clin Infect Dis. 2012;54:1110‐
22. Eschenauer GA et al. J Antimicrob Chemother. 2013;68(4):922‐6. Echinocandin resistance relatively uncommon globally
FKS mutations are associated with reduced echinocandin susceptibility AA
Fks1p
0
F625 – P663
Hot spot 1
1900
AA
Fks2p
0
D1340 – L3148
F658 – P667
Hot spot 1
Hot spot 2
• Susceptibility patterns of 3,107 Candida species from 34 countries
• 38% cross‐resistance to fluconazole
1900
D1374 – L1381
Hot spot 2
Rates of resistance (varies by region)
• Two regions (HS1 and HS2) of Fks1/2p are associated with echinocandin resistance
• Prominent mutations typically confer cross‐
resistance to all echinocandins All Candida species Up to 1.7%
Candida albicans
Up to 0.6%
Candida glabrata
Up to 3.8%
Pfaller MA et al. J Clin Microbiol. 2013; 51:390‐2.
Will echinocandin resistance make us change to a more individualized dosing strategy? Emergence of echinocandin resistance in C. glabrata
35
35
30
30
25
20
15
10
20
Shields et al. (2011)
(n = 39)
Prior echinocandin therapy
OR 10.65; 95% CI 2.51‐ 45.24
OR 19.65; 95% CI 7.19‐58.1
P=0.0001
Prior episode of candidemia
OR 18.59;
95% CI 1.56 – 221.69
P = < 0.05
‐‐‐
Prior echinocandin therapy
OR 9.17; 95% CI 1.9 – 44.46
P = < 0.05
P = 0.008
Presence of an FKS mutation
P = 0.033
P = 0.0391
OR 41.7; 95% CI 3.96‐
445.7
15
10
5
0
0
Echinocandin
Alexander et al.
(2013)
(n = 278)
Risk factors for FKS mutant C. glabrata 25
5
Fluconazole
Beyda et al. (2014)
(n = 78)
Texas Medical Center
% Resistant
% Resistant
Duke University Hospital
Risk factors for echinocandin treatment failure
Fluconazole
Caspofungin
Alexander BD et al. Clin Infect Dis. 2013; 56:1724‐32.
Beyda ND et al. Clin Infect Dis; 2014; 59:819‐25.
Alexander BD et al. Clin Infect Dis. 2013; 56:1724‐32.
Beyda ND et al. Clin Infect Dis; 2014; 59:819‐25. Shields RK et al. Antimicrob Agents Chemother. 2012;56:4862‐9.
132
CLASSIFICATION OF ASPERGILLOSIS
The Fungal World
FUNGI
YEASTS
Candida spp.
MOULDS
Cryptococcus
Trichosporon beigelii
Blastochizomyces capitus
Zygomycetae
Airway or nasal exposure to airborne Aspergillus
Dimorphic
Fungi
Invasive aspergillosis
Septate Fungi
Chronic aspergillosis Rhizopus
Aspergillus spp.
(>3 months)
Hyalohyphomycoses
Fusarium sp.
Pseudoallescheria boydii
Scedosporium prolificans
Paecilomyces spp
Mucor
Persistence without disease
Allergic
(colonization of the airways or nose/sinuses)
Absidia
• Acute (<1 month course)
• Subacute /chronic necrotizing (1‐3 months)
• Chronic cavitary pulmonary
• Aspergilloma of lung
• Chronic fibrosing pulmonary
• Chronic invasive sinusitis • Maxillary sinus aspergilloma
• Allergic bronchopulmonary (ABPA)
• Extrinsic allergic (broncho)alveolitis
• Asthma with fungal sensitization
• Allergic Aspergillus sinusitis
Timeframe of Fungal Infection post HSCT
Patient case – diagnosis of aspergillosis
Phase I
Pre-engraftment
(<30 days posttransplant)
• AR is a 42‐year‐old male, post‐HSCT for AML, complicated by grade II GVHD, who presents with cough, dyspnea with pulmonary nodules 3 weeks post‐transplant.
Phase II
Post-engraftment
(30-100 days posttransplant)
Neutropenia, mucositis, and acute graft‐versus‐
host disease
• Invasive pulmonary aspergillosis was diagnosed via:
– chest CT (nodules with halo) Phase III
Late post-engraftment
(>100 days posttransplant)
Impaired cellular Impaired cellular and immunity and acute and humoral immunity and chronic graft‐versus‐host chronic graft‐versus‐host disease
disease
All Candida spp.
– positive galactomannan antigen tests (levels 3.2, 1.9)
Aspergillus spp
– a needle biopsy which grew A. fumigatus.
Day 0
Image provided by Dr. Carver
Factors relating to Underlying Condition
Primary Host Factor
• Hematological malignancy
• Allogeneic hematopoietic stem cell transplantation
• Solid organ transplantation
• Solid tumor
• Other immune disorder
• Climate
• Construction work
• Place of residence
• Tobacco or cannabis use
• Contaminated food or spices
• Pets, potted plants, gardening
• Lack of HEPA filtration during hospitalization
Environmental Factors
Day 365 and beyond
Difficulties in the Diagnosis of Invasive Aspergillosis
Risk Factors for Invasive Aspergillosis
Innate Immune Status
Day 100
Day 15‐45
Tomblyn M et al. Biol Blood Marrow Transplant. 2009 Oct;15(10):1143‐238 Engraftment: absolute neutrophil count ≥500 cells/mm3
AML = acute myeloid leukemia; GVHD = graft‐versus‐host‐disease; HSCT=Hematopoietic Stem Cell Transplantation
Polymorphisms of:
• Toll‐like receptors
• C‐type lectins
• Mannose‐binding lectins
• plasminogen
• Others?
Aspergillus spp.
•
Clinical/patient
‒ nonspecific symptoms
• Neutropenia
• Progressive cancer
• Graft vs host disease
• Chemotherapy
• Corticosteroids
• Anti‐T‐cell antibodies
‒ tissue biopsies difficult to obtain
•
Microbiological
‒ Tissue cultures often unavailable
‒ Difficult to differentiate • Diabetes
• Iron overload
• Trauma, burns
• Renal impairment
• Metabolic acidosis
• Prior respiratory disease
colonization vs. infection
‒ Blood cultures rarely positive
Other Factors
30
Adapted from Herbrecht R et al. Ann N Y Acad Sci. 2012. 1272:23‐30.
133
The search for fungal biomarkers for invasive aspergillosis
Radiological Difficulties in the Diagnosis of Invasive Aspergillosis
CT Scan
• “Halo sign” –
–
–
–
Halo
very sensitive but non specific
perimeter of ground‐glass opacity
surrounding hemorrhagic nodular lesion
small vessel angioinvasion  thrombosis of small/medium sized vessels  ischemic
necrosis
seen EARLY in disease; lasts <5 days
• Galactomannan antigen
–
–
–
–
‒
(also Penicillium spp)
–
good negative predictive value, but low
positive predictive value
•
test performs less well in solid organ transplant patients
Cross‐reactivity with pip/tazo
‒
–
crescent of gas above a soft tissue sequestrum within a nodular or cavitary
lesion; due to tissue contraction
Air
not useful for early diagnosis
crescent
seen LATE in angioinvasive IA
correlates with recovery of neutrophils
–
–
Species specific
Simple, sensitive but potential for contamination
Novel methods under development ‒
monoclonal antibody JF5
Aspergillus nucleic acids
siderophore detection
MALDI‐TOF
‒
• β‐D‐glucan
‒
nonspecific for Candida
‘pan’ fungal except cryptococcus and zygomycetes
‒
Johnson G, et al. Biomark Med. 2014; 8:429‐51. Hornton CR. 2014. Exp Rev Clin Imm 10(6):771‐80. Images provided by Dr. Carver
http://www.medscape.org/viewarticle/444470_4.
Pinto PS. Radiology. 2004; 230: 109‐110.
PCR
Detects Aspergillus species
–
• “Air‐crescent” Sign
•
–
Patient case – initial therapy of aspergillosis
Activity of Common Systemic Antifungal Agents against non‐Candida Species
Fungus
• AR was initiated on voriconazole, but he experienced visual hallucinations, which responded to a dosage reduction, and then a severe rash.
• Therapy was changed to
Liposomal‐AmB (5 mg/kg/day
IV).
AmB

Aspergillus spp.
(not A. terreus)

Fusarium
occas R

Scedosporium
occas R
Flucon
Itra
Vori
Posa
Echino
X




X
X


(breakthrus)
occas R
X
X
+/‐


X
occas R
Zygomycetes

X
X
X

X
Cryptococcus





X
X = no in vitro activity;  = in vitro activity; R = resistance
AmB = amphotericin B; Flucon = fluconazole; Itra = itraconazole; Posa = posaconazole; Vori = voriconazole; Echino = echinocandins (caspofungin, micafungin, anidulafungin)
Image provided by Dr. Carver
First Line Therapy for Invasive Aspergillosis
IDSA
(USA)1
United Kingdom2
d‐AmB
D
D
L‐AmB
AI
AI
Antifungal agent
Voriconazole vs. d-AmB for Aspergillosis
ECIL
DGHO
(European
guidelines)3
German guidelines4
Australia5
D
EII
Alternative
BI
AII
Alternative
22% relative survival benefit P = 0.02
AMPHOTERICIN B
BII
ABCD
D
Voriconazole
80
% Surviving
ABLC
100
AZOLES
Itraconazole
Voriconazole
C
AI
AI
AI
AI
CII
AI
Recommended
Posaconazole
58%
AmB/OLAT*
40
20
ECHINOCANDINS
Caspofungin
Median d‐AmB duration = 10 days; (n=107)
Median voriconazole duration = 77 days
0
Micafungin
COMBINATION
Antifungal Therapy
71%
60
0
Not recommended
Discouraged
Discouraged
CIII
14
28
42
56
70
84
# Days of Therapy
‘No supportive evidence’
OLAT (other licensed antifungal therapy) utilized: Lipid AmB 44%; itraconazole 36%; other or combo 21% d‐AmB= deoxycholate AmB
1Walsh TJ et al. Clin Infect Dis 2008; 46:32‐60; 2Prentice AG et al. http://www.bcshguidelines.com/documents/fungal_infection_bcsh_2008.pdf accessed 10/24/14; 3Maertens J et al. Bone Marrow Transpl 2011;46:709‐18; 4Bohme A et al. Ann Hematol 2009;88:97‐110; 5Thursky KA et al. Intern Med J 2008;38;496‐520. AmB = amphotericin B; d‐AmB= deoxycholate AmB; L‐AmB = liposomal AmB; ABLC = AmB lipid complex; ABCD = AmB colloid dispersion
134
Herbrecht R, et al. N Eng J Med. 2002; 347(6):408‐15.
Herbrecht R, et al. Clin Infect Dis 2014. Epub 014/11/22.
What if the patient doesn’t respond to Voriconazole?
Mechanism of Action of Antifungals
• Causes of antifungal therapy failure
–
–
–
–
Echinocandins
affect β-1,3
cross-linking
Cell membrane and cell wall
Fungal cell
Host factors (severity of illness, immune suppression)
Primary or acquired drug resistance
Wrong diagnosis or mixed infection
Pharmacokinetic factors Mannoproteins
-(1,6)-glucan
-(1,3)-glucan
Cell
wall
Chitin
• complex pharmacokinetics of antifungal agents
• Drug‐drug or drug‐food interactions
• adherence
Cell Membrane
(Phospholipid bilayer)
• Treatment options ‐ salvage therapy of aspergillosis
-(1,3)-glucan synthase
Ergosterol
– CONTINUE with the same agent, or another agent in the same class with a broader spectrum
– CHANGE to a different antifungal class
– COMBINE antifungal drugs
Azoles inhibit
enzymes
involved in this
pathway
Nucci M. et al. Clin Infect Dis 2008;1426‐33.
AmB binds to
ergosterol
Ergosterol
Synthesis
Pathway
Squalene
Slide adapted from R. Lewis, Pharm.D http://www.doctorfungus.org/thedrugs/antif_pharm.php Accessed 10/7/14.
Combination Therapy for Invasive Aspergillosis
Should we use Combination Antifungal Therapy ?
The Case FOR Combination Therapy
• Mortality rates are HIGH
Study Design
Main outcomes
CASPOFUNGIN + L‐AmB
Aliff 2003
• Retrospective study in leukemics (N=30)
• Salvage therapy with L‐AmB + caspo
The Case AGAINST Kontoy‐
iannis
2003
• Retrospective, heme patients, (N=48)
• Salvage therapy of caspo addition after ≥7 d L‐AmB
• Only 18% response to combo therapy
Combination Therapy
Caillot 2007
• Prospective, open label in heme patients (N=30)
• L‐AmB 3 mg/kg/d + caspo vs L‐AmB 10 mg/kg/day
• “Combistrat” study. More favorable responses (partial or complete) in combo tx group
• Favorable response in 60% (18/30)
CASPOFUNGIN or ANIDULAFUNGIN + VORICONAZOLE
•
• Enables ↑ spectrum of ac vity
Lack of •
•
Marr 2004
• Vori (prior to 2001) vs vori + caspo (after 2001) after progression of
disease on ≥7 d AmB
• combo therapy pts had a significantly lower rate of
mortality vs vori monotherapy
•
correlation between in vitro
data, animal models, and clinical experience
• Salvage therapy with caspo + another ‘mold‐active’ agent in Maertens patients refractory to or intolerant of standard antifungal therapy 2006
(N=53)
•
solid clinical data
Singh 2006
• Prospective, randomized, MC, observational • Vori or caspo (N=40) 1o therapy vs historical control (N=47)
of L‐AmB therapy in SOT • No difference in 90 day survival overall, although in pts with renal failure or A. fumigatus, combo therapy was associated with  survival
Upton 2007
• Retrospective in HSCT (N=405); Vori + caspo vs caspo alone
• No difference in clinical outcomes of Vori + caspo as primary therapy vs vori monotherapy
Marr 2012
• Prospective, randomized, MC study in heme ± HSCT (N=277 )
• Vori alone vs vori + anidula; 1o endpoint = 6 wk survival
• trend toward  6 wk survival with combination of vori + anidula vs vori monotherapy.
• More rapid killing
•  chances of developing resistance
• No overlapping toxicities
Regimen
Possibility of antagonism
↑ risk of drug interactions and toxicities
• Success = 55% & 49% (at end of combo therapy & Day 84, respectively). • Day 84 survival = 55%.
Aliff. Cancer 2003;4:1025-32; Kontoyiannis. Cancer 2003;2:292-9. Caillot D. Cancer 2007; 110:2740. Marr et al. CID 2004;39:797-802.; Maertens et al. Cancer 2006;107:288897. Singh. Transplantation 2006; 81(3): 320-6; Upton. CID 2007;44:531. Marr K. Presented at: 22nd ECCMID, London, UK, 3/31/12-4/3/12.
MC = multicenter; SOT = Solid organ transplant; HSCT = hematopoietic stem cell transplant; heme= hematological malignancy; L-AmB = liposomal amphotericin B; Vori =
voriconazole; anidula = anidulafungin; caspo = caspofungin; mica=micafungin
Therapeutic drug monitoring (TDM) of antifungals ?
Drug Interactions with Azole Antifungals CYP enzymes
• When is TDM needed?
– An established relationship exists between
plasma drug concentrations and:
• efficacy
• toxicity
– Recommended for drugs with:
• narrow therapeutic index
• variable pharmacokinetics
• questionable compliance, absorption, or
drug‐drug interactions
P‐glycoprotein
Substrate Inhibitor
Substrate
Inhibitor
Fluconazole
3A4
3A4 (++)
2C9, 2C19 (++)
Yes
No
Itraconazole
3A4
3A4 (+++)
Yes
Yes
Voriconazole
3A4 2C9, 2C19 (for
N‐oxide metabolite)
3A4 (+)
2C9 (++)
2C19 (++)
No
No
3A4 (++)
Yes
Yes
Posaconazole
NOT a substrate of CYPs; metabolized via UGT pathway
UGT = UDP‐glucuronidation; CYP = cytochrome P450; CYP interactions are classified as +++ = strong; ++ = moderate; + = weak. Saad AH, et al. 2006. Pharmacotherapy 26(12):1730‐44.
135
Side Effects of Systemic Antifungal Agents
Adverse Effect
AmB
Flucon
Itra
Vori
X
X (possible with IV)
(possible with IV)
Posa
Echino
X
X
Nephrotoxicity

X
Abdominal Discomfort
X




X
 Hepatic Transaminases






Rash, photosensitivity
X




Infusion‐related Reactions / Histamine Release

X
X
X
X

CNS & Visual Disturbances
X
X
X

X
X
Cardiomyopathy (itra),  QT (azoles), ? echinos
X



(vori ‐
malignancy)


Plasma Concentration Monitoring of Antifungals
Serum concentration monitoring necessary?
Drug
Itraconazole
Voriconazole
Posaconazole
suspension
& tablets
Flucytosine
?
Target concentrations for
Treatment & Prophylaxis
Timing of sample
Trough after 7 days therapy
Yes, to ensure absorption & efficacy
Trough > 0.5 μg/mL Yes • Wide range of recs due to heterogeneous study designs.
• Trough after 5 days • Troughs >1‐2 µg/mL;
therapy? concs >2.05 µg/mL assoc with • Nonlinear metabolism,
improved outcome; 2‐5.5 μg/mL so time to SS is probably best target
unpredictable
• Concs >5.5 μg/mL assoc with  risk of visual & hepatic adverse events
• variable metabolism due to nonlinear PK & genetic variability in CYP2C19  unpredictable dose‐
exposure relationship
• low concs are assoc with poor outcome; high concs are assoc with adverse effects.
• Random level at SS
Maybe
• Outcomes (but not adverse events) correlate with higher plasma concs in prophylaxis & possibly treatment
Yes
• high concs are assoc with toxicity
• Treatment: not well studied concs >1.25 mg/L needed?
• Prophylaxis: ≥700 ng/mL ? Peak conc < 100 μg/mL (>7 days therapy).
• Long t1/2 ensures little fluctuation in peaks &
troughs at SS.
• 2 hours post‐dose peak
Adapted from: Dodds‐Ashley ES et al. Clin Infect Dis. 2006;43 suppl 1:S28‐39. ; Smith J et al. Antimicrob Agents Chemother. 2006; 50:1570‐2. ; Jang SH et al. Clin Pharmacol Ther. 2010; 88:115‐9. ; Hussaini T et al. Pharmacotherapy 2011:31(2)214‐25. NA = not applicable or not known; concs = concentrations; SS=steady state
Adapted from Lewis RE. Mayo Clin Proc. 2011;86(8):805‐817 Conclusions
Long‐term adverse effects of antifungals
• Pharmacists reacting to rapid diagnostic tests for systemic candidiasis could significantly improve patient care
• Treatment of candidemia
• Long‐term use of antifungals is common
– Prophylaxis
– Treatment of aspergillosis
– Fluconazole:
• ≥6 mg/kg (800 mg for all?)
• Improved benefit (treatment success, mortality, and resistance)
– Echinocandins:
• Voriconazole
• Fixed doses are great with low MICs
• Did this fixed dosing strategy encourage resistance?
• Individualized dosing strategy needs further study
– Alopecia
– Phototoxicity
• Although aspergillosis is most often treated with voriconazole, amphotericin B, and echinocandins are often utilized in therapy, in particular as salvage therapy or as part of combination therapy
• Adverse effects and drug interactions remain problematic with antifungals
• The role of therapeutic drug monitoring of antifungals remains controversial; however, voriconazole (and perhaps posaconazole) should
be monitored
• skin cancer
• photosensitivity
– Periostitis/Fluoride toxicity
136
Management of Invasive Fungal Infections: Applying Evidence-based
Strategies and Individualizing Antifungal Therapy
Self-assessment Questions
1. When do IDSA Guidelines recommend initial therapy with fluconazole?
a. When the patient is severely ill
b. When the patient has recent azole exposure
c. When the patient only has IV access
d. When the patient is less critically ill with no recent azole exposure
2. Long term therapy with antifungal agents:
a. is more common in patients who are treated for aspergillosis
b. is always well tolerated, if therapeutic drug monitoring (TDM) is employed
c. is associated with the same toxicities as observed with short term therapy
d. is rare, since most fungal infections require only short term (< 2 week) therapy
3. Long term therapy with voriconazole has been associated with:
a. nephrotoxicity
b. periostitis
c. fluoride deficiency
d. hirsutism
Answers
1. d
2. a
3. b
137
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Date of
Activity
5/23/15
Activity Title
Enrollment
Code
Management of Invasive Fungal Infections: Applying Evidencebased Strategies and Individualizing Antifungal Therapy
NEED HELP? Contact [email protected].
138
14
Credit
Hours
1.0
2015 Annual Meeting
Saturday, May 23
9:00—11:00 a.m.
Emerging Technologies to Decrease Opioid Abuse: An Update for Pharmacists/
Technicians
Board of Advisors / Directors, American Society of Pain Educators,
Montclair, NJ
Consultant / Core team member, Chronic Pain Team, Group Health
Seattle, Washington
Consultant, Home Health and Hospice Services, Group Health
Seattle, Washington
Director and Owner, Palliative Care Strategies
Everett, WA
0179-0000-15-009-L01-P / 0179-0000-15-009-L01-T
Knowledge based activity
 Describe how the role for the use of opioids in acute,






 Describe how the role for the use of opioids in acute,
chronic and cancer pain has changed in the past 20
years.
Differentiate addiction, physical dependency, tolerance, 
pseudoaddiction, and hyperalgesia.
Identify typical characteristics of patients who would be

identified as "high risk" , "moderate risk" and "low risk"
for opioid misuse and what is the current standard best
practice model for properly monitoring these patients

when they are receiving opioid therapy.
State the best practice model for using opioids in a
patient with a past and/or current history of abuse or
diversion of opioids.
Describe the key features of the REMS recommendations
of the FDA for opioids.
Describe the FDA current guidelines regarding the
current and future labeling of opioids products in the
category of those with “abuse-deterrent technology”.
List examples of opioids products that have “abusedeterrent” technology and how these products could be
utilized to improve patient care and community safety.
chronic and cancer pain has changed in the past 20
years.
Recognize the best practice model for using opioids in a
patient with a past and/or current history of abuse or
diversion of opioids.
Describe how the FDA defines opioids that contain
“abuse-deterrent technology”.
List examples of opioids products that have “abusedeterrent” technology.
139
Speaker has disclosed that he has
no relevant financial relationships.
Emerging Technologies to Decrease
Opioid Abuse
Objectives
 Describe how the role for the use of opioids in chronic noncancer pain has changed in the past 20 years.
 Managing Risk
Maximizing Benefit
 Differentiate addiction, physical dependency, tolerance,
pseudoaddiction, and hyperalgesia.
 Identify typical characteristics of patients who would be
identified as "high risk" , "moderate risk" and "low risk" for
opioid misuse and what is the current standard best practice
model for properly monitoring these patients when they are
receiving opioid therapy.
Certified Pain Educator
Board Certified Oncology Pharmacist
Pain Management / Palliative Care Pharmacist Specialist
Hospice Consultant
Chronic non-cancer Pain Team
LTC Elderly Pain Consultant
Private pain management consultant
Pain Patient: Case example
Objectives (continued)
 Describe the FDA current guidelines regarding the current and
 Patient History: 38-year-old female; 65”; 173 lbs
 Vital Signs: within normal limits
 Chronic case of “pain all over”; poor sleep; daytime drowsiness;
future labeling of opioids products in the category of those with
“abuse-deterrent technology”.
fatigue; pain of shoulder, lower back, buttocks, knee and hip;
myalgia; progressive weight gain; peripheral edema; memory
issues
 Give examples of opioids products that have “abuse-deterrent”
technology and how these products could be utilized to
improve patient care and community safety.
 Medical History: Fibromyalgia, migraine w/aura, IBS, TMJ, GERD
 Social History: ~3 cigarettes/day on/off; social drinker; SRDU–
marijuana 1-2x/week
 Married, mother of 2 children (16-yo twins)
 Vocation: real estate sales
 Avocation: cycling
TMJ, temporomandibular joint; FMS, fibromyalgia syndrome; GERD, gastroesophageal reflux disease; SRDU, social-recreational drug user
•
Meet the Patient and Her Medications
Clinical Considerations to Think About…
When asked to rate her pain, the patient indicates 10/10 on
the pain scale.
 What concerns do you have regarding the use of opioids for this
patient?
 Clinical
 Abuse/misuse/diversion risk by the patient? By teenagers in the
Prescriptions in home:
sumatriptan 50mg PO (2x/month)
home?
topiramate 100mg QHS
metoclopramide (PRN, 2x/mo)
omeprazole 20mg QD
dicyclomine 20mg Q6H
methadone 20mg Q8H
cyclobenzaprine 10mg Q8H
pregabalin 150 mg Q12
oxycodone 5mg Q6H PRN
tramadol 50mg 2 tabs Q6H PRN
trazodone 100mg QHS
carisoprodol 350mg PRN
 Does the cannabinoid use by the patient concern you?
 What would be the benefits/risks of using opioids with ADT for this
patient?
 What type of follow-up would you want for this patient?
 Counseling tips for this patient?
140
Using Medication for Pain:
“An outdated model of care”
“New Model of Care”
 Acetaminophen / ibuprofen or hydrocodone-combination for
 Medications are not the only option for pain
everyone.
management.
 React (over-react) to pain – only prescribe medications PRN







or prescribe (in the name of compassion) way more than
needed
 “Everyone gets addicted” or “No one gets addicted”
 “My patients would never misuse their medications”
 “What is urine testing?”
Heat / cold
Physical therapy
TENS
Acupuncture
Massage
Distraction
Relaxation
 If the patient continues to complain, “Vote them off the
island!”
 There does not exist any one medication which will solve all
 For some patients medications relieve most / all of the pain,
pain conditions.
 What are the patient’s expectations for pain medications?
for other patients medications may only relieve part of the
pain.
 Pain is unique to each person
 Reaction to medication is unique to each person
 Side effects may be worse than the reduction in pain
 “Feel better?”
 Improvement in their ability to function?
 Improve their sleep?
 Not have to suffer?
Pain – Treatment Options…
 Manage your risk by managing your patient
 Non-pharmacological (heat, cold, distraction, massage, TENs,
acupuncture, spinal cord stimulation)
 Patient agreements
 Urine testing
 Risk stratification
 Physical therapy – strengthening, rehabilitation
 Behavioral – relaxation, stress reduction
 Incorporate tools
 Simple analgesics
 Functional improvement assessment
 Abuse deterrent technology (ADT)
 Acetaminophen
 Salicylates
 NSAIDs
 Non-selective versus selective
 Oral versus topical
 Pharmacist is your friend
 Opioids often make better “cabooses than engines”
 Multimodality approaches
141
…Pain – Treatment Options
…Pain – Treatment Options
 Opioids
 Adjuvants
 PRN administration of IM / IV / oral short-acting
 Patient-controlled analgesia
 Regular scheduled administration of long-acting (controlled-









release / sustained release) opioids
 Unique routes (transdermal, transmucosal, spinal opioids)
 Local anesthetics




Local instillation / infiltration
Spinal (epidural / intrathecal)
Topical
Nerve blocks
Antidepressants
Anticonvulsants
Antiarrhythmics / local anesthetics
Alpha-2-adrenergic agents
NMDA antagonists
Topical products
Muscle relaxants
Sleeping agents
Miscellaneous (cannabinoids, antihistamines, adenosine,
antipsychotics, psychostimulants, anxiolytics)
Opioids as a
“Friend” of pain management
Opioids:
Friend or Foe of Pain
Management??
 No risk of GI bleeds, renal toxicity, hepatotoxicity
 Strongest of analgesics
 Quick onset
 No ceiling effect with many of the agents
 Ability to provide analgesia in a variety of pain syndromes
American Academy of Pain Medicine and American Pain Society. The use of opioids for the treatment
of chronic pain. Consensus statement from the American Academy of Pain Medicine and the
American Pain Society. Clin J Pain. 1997;13:6-8.
Passik SD, Weinreb HJ. Managing chronic nonmalignant pain: overcoming obstacles to the use of
opioids. Adv Ther. 2000;17:70-83.
Opioids as a
“Foe” of pain management
The Opioid Pendulum
 Constipation
 Decreased functioning
 Risk of dependency, addiction
 Lack of anti-inflammatory effect
Avoidance
Even dying people at
risk of addiction
 Tolerance, neuroadaptation, hyperalgesia
 Potential of misuse, abuse and diversion
Chang G, Chen L and Mao J. Opioid tolerance and hyperalgesia. Med Clin N Am 2007;91:199-211.
Angst MS and Clark JD. Opioid-induced hyperalgesia. A qualitative systematic review. Anesthesiology
2006;104:570-587.
Chou R et al. J Pain 2009;10:113-130
FDA. Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
04/2013.FDA.
Extended-Release (ER) and Long-Acting (LA) Opioid Analgesics Risk Evaluation and Mitigation
Strategy (REMS). 04/3013.
142
Widespread Use
Opiophobia must go
Balance
Risk stratification and
principles of addiction
medicine applied to opioid
prescribing
regardless of the pain
problem at hand
Ethical Principles of Pain
Management
The Four “A’s” of Pain Treatment Outcomes
 Analgesia (pain relief)
 Balancing act
 “Prevent harm”, “Remove harm”, “Do good”
 “Provide compassionate care”
 “Do no harm”
 “Patient rights”
 Activities of daily living (physical and psychosocial
functioning)
 Adverse effects (side effects)
 Aberrant drug-taking concerning opioid use
(addiction-related outcomes)
Passik SD, Weinreb HJ. Adv Ther. 2000;17:70-80.
Pain Relievers Obtained for Nonmedical Use
Factors That Argue Against Abuse
 Lower amounts of opioids
 Advanced age
 Cancer pain
 Perioperative pain
 No history of alcohol or substance
abuse
*Source of drugs for the most recent nonmedical use of pain relievers reported by persons aged 12 or
older in the United States 2010.
Chou R, et al. J Pain. 2009;10:113-30.
Gourlay DL, et al. Pain Med. 2009;10(S2):S115-23.
SAMHSA. Results From the 2010 National Survey on Drug Use and Health. HHS Publication No. (SMA) 11-4658, 2011.
More Predictive
Less Predictive
 Previous drug abuse
 Aggressive complaining
 Alcoholism
 Drug hoarding during reduced
 Forging
 Stealing meds
 Unsanctioned dose escalation
 Recurrent lost Rx
Goals for medication therapy
1.
2.
3.
4.
time of need
 Requesting specific meds
 Unapproved uses
Improve patient functionality
Provide analgesia (comfort)
Minimize side effects
Eliminate misuse, abuse, diversion
 Sharing with relatives
 Younger age
 High dose
 Pain syndrome controversial
Trescot AM, Boswell MV, Atluri SL et al. Opioid guidelines in
the management of chronic noncancer pain.
Pain Physician 20069:1-40.
Portenoy RK. J Pain Symptom Manage 1996;11:203-217.
Chou R, et al. J Pain. 2009;10:113-30.
143
Considerations for Implementing
Chronic Opioid Therapy (> 90 days)
Responsible and Ethical Prescribing of
Opioids
 Pick the right patient







 Initiate on the basis of an explicit decision and
 Outcomes






Reliability
History
Intensity
Syndrome
Duration of treatment
Severity
agreement between prescriber and patient
Office measurements
 Gain informed consent – benefit and risks
Pain diaries
 Screen for potential comorbidities and risk
ADL functioning
Diversion prevention
factors
Pain agreement adherence
 Depression, anxiety, current and past substance abuse
Drug tests & pill counts
 Failure of other physical, behavioral, and non-
Molecule risks
opioid Rx
Webster LR, Webster RM: Predicting aberrant behaviors in opioid-treated patients: Preliminary validation of
the Opioid Risk Tool. Pain Med 6:432-442, 2005
Chou R, et al. J Pain. 2009;10:113-30.
Trescot AM et al. Pain Physician. 2006;9:1-40.
Agency Medical Directors Group. Interagency Guideline on Opioid Dosing for Chronic Pain. 2010 Update.
Available at: http://www.agencymeddirectors.wa.gov
Chronic Pain – Pharmacological
Interventions: “Ideal Model of Care”
Multimodal Drug Therapy
Descending Modulation
-Opioids
-Antidepressants (e.g. tricyclic and SNRI)
-Alpha-2 agonists (e.g. clonidine)
-Tapentadol and tramadol
 Interdisciplinary approach.
 Medications not to be considered as the sole strategy.
 Focus on functional improvement, not just pain reduction.
Central Sensitization
-Neuraxial local anesthetics
-Alpha-2 agonists (e.g. clonidine)
-NMDA-receptor antagonists (e.g. methadone)
-Anticonvulsants (e.g. gabapentin, pregabalin,
topiramate)
-Antidepressants (e.g. tricyclic and SNRI)
-Tapentadol and tramadol
-Opioids
-Acetaminophen
 Role of medications should be to complement, not supplant nonpharmacological approaches, physical therapy, life style changes, behavioral
approaches, etc.
 Have a risk management strategy in place.





Do not merely follow a “traditional approach”
When possible, one prescriber, one pharmacy for medications
Have a consistent documentation system
Consider role of patient pain diaries, medication agreements / contracts.
Peripheral Sensitization
-Topical local anesthetics, opioids, capsaicin, and
tricyclic antidepressants
-Non-steroidal anti-inflammatory drugs
Consistent urine testing
Federation of State Medical Boards. Model Policy on the Use of Opioid Analgesics for the Treatment of Chronic Pain. 2013.
Adapted from Gottschalk A, Smith DS. Am Fam Phys. 2001;63:1979-1986.
Differentiating Types of Pain
Nociceptive Pain
Somatic Pain
Location
Localized
Generalized
Radiating or specific
Patient Description
Pinprick, stabbing, or
sharp
Ache, pressure, or sharp
Burning, prickling,
tingling, electric shocklike, or lancinating
Mechanism of Pain
A-delta fiber activity
Located in the periphery
C Fiber activity
Involved deeper
innervation
Dermatomal (periphery),
or non-dermatomal
(central)
•Periosteum, joints, muscles
•Sickle cell
•Superficial laceration
•Superficial burns
•Intramuscular injections,
venous access
•Otitis media
•Stomatitis
•Extensive abrasion
•Colic pain
•Appendicitis
•Kidney stone
•Chronic pancreatitis
•IBS
•Angina
•Menstrual cramps
•Trigeminal neuralgia
•Avulsion neuralgia
•Posttraumatic neuralgia
•Peripheral neuropathy
(diabetes, HIV)
•Limb amputation
•Herpetic neuralgia
Clinical Examples
Somatic Pain
Neuropathic Pain
Visceral Pain
 Medication therapy overview
APAP/ NSAID
based on symptoms
Institute for Clinical Systems Improvement (ICSI). Assessment and Management of Acute Pain.
Sixth Edition, March 2008. www.icsi.org.
144
+
Opioid
Visceral Pain
Neuropathic Pain
Anticholinergic + Opioid / NSAID
Adjuvant
+
Opioid / NSAID
“Let the adjuvant be the engine and
the opioid the caboose”
Pain Patients vs.
Addicts
Round 1
Pain Patients = Addict???
Pain Patients
Addicts
Able to control use of
medications
Out of control with any
medications
Medications improve the Medications cause
quality of the patient’s life decrease in the quality of
life
Will want to decrease
medication if side effects
are present
Continues or increases
dose even with side
effects
Schnoll SH, Finch J. J Law Med Ethics. 1994;22:252-6.
Pain Patients vs.
Addicts
Physical dependence vs. addiction
Round 2
Pain Patients
Addicts
Continued concern about
the cause of the pain
Unaware or in denial of
medical problems related
to the pain
Follows agreement for
the use of meds
Does not follow the
agreement, escalates
dosage
Frequently has meds left
over from the previous
visit
Has no medication left
over, loses meds or
scripts, and always has a
“story”
Physical dependence is a physiological
phenomenon defined by the development of
an abstinence syndrome following abrupt
discontinuation of therapy, substantial dose
reduction, or administration of an antagonist
drug.
American Society of Addiction Medicine. Public Policy Statement on definitions related to the use of
opioids in pain treatment. J Addictive Dis. 1998;17:129-133.
Schnoll SH, Finch J. J Law Med Ethics. 1994;22:252-6.
145
Addiction vs. Pseudo Addiction
Physical dependence vs. addiction
Physical dependence is an expected occurrence in
all individuals in the presence of continuous use
of opioids for therapeutic or non-therapeutic
purposes. It does not, in and of itself imply
addiction.
Addiction
Pseudo-Addiction
Compulsive need for and use of
a habit-forming substance
characterized by tolerance and
physiological symptoms upon
withdrawal
A drug-seeking behavior that
simulates true addiction
occurring in patients who are
receiving inadequate pain
medication
Broadly: persistent compulsive
use of a substance known by the
user to be harmful
American Society of Addiction Medicine. Public Policy Statement on definitions related to the use of
opioids in pain treatment. J Addictive Dis. 1998;17:129-133.
Pappagallo M. Pseudotolerance. J Pharm Care Pain Symptom Control. 1998;6:95-98
Addiction Does Not Reside Solely
in Drugs
Addiction: 5Cs
 Addiction is not merely a disorder of drug

Chronic

Compulsive use

Control—impaired

Craving

Continued use despite harm
use
 Addiction also involves the following realms





Hemby SE. Curr Psychiatry Rep. 1999;1:159-65.
Prescott CA, Kendler KS. Am J Psychiatry. 1999;156:34-40.
Enoch MA, Goldman D. Curr Psychiatry Rep. 2001;3:144-51.
Tsuang MT, et al. Arch Gen Psychiatry. 1998;55:967-72.
Miller WR. Addiction. 1998;93:979-90.
Prescott CA, Kendler KS. Am J Psychiatry. 1999;156:34-40.
Enoch MA, Goldman D. Curr Psychiatry Rep. 2001;3:144-51.
Tsuang MT, et al. Arch Gen Psychiatry. 1998;55:967-72.
Miller WR. Addiction. 1998;93:979-90.
Addiction:
….A Multi-factorial Disease State
Psychology
Environment
Biology
Innate
Acquired
*
Universal Precautions
Availability
& Milieu
Drug
Genetic/familial
Psychiatric
Environment
Social
Spiritual
 Determine patient’s risk for opioid therapy or their outcome
status regarding abuse
 Every patient on long-term opioid treatment should be
*Manifestation
of the disease of
addiction
monitored for abuse/addiction
 Patient treatment agreement, education
 Secure storage of medications
 Structured initial and follow-up assessments
 Urine toxicology, prescription monitoring data
Reinforcement
Figure courtesy of JD Haddox, DDS, MD.
McLellan, et al. JAMA. 2000;284:1689-95.
Kendler KS, et al. Arch Gen Psychiatry. 2000;57:261-9.
Tsuang MT et al. Arch Gen Psychiatry. 1998;55:967-72.
Gourlay DL et al. Pain Medicine 2005;6:107-112
146
Risk Screening Tools
Opioid Risk Tool (ORT)
 Administration
 Opioid Risk Tool (ORT) – risk of opioid addiction
 On initial visit
 Prior to opioid therapy
 CAGE-AID – alcohol or drug problems
 PHQ-9 – depression severity
 Scoring
 Urine testing and pill counts
 0-3: low risk (6%)
 4-7: moderate risk (28%)
 >8: high risk (>90%)
 Function and pain assessment
Webster LR, Webster RM. AAPM 2005;6:432-442.
Brown RL, Rounds LA. Wisc Med J 1995;94:135-140.
Couwenbergh C, Gaag RJVD, Koeter et al. Substand Use and MIsuse 2009;44:823-834.
Leonardson GR, Kemper E, Ness FK et al. Psychological Reports 2005;97:161-166.
Kroenke K, Spitzer R, Williams W. JGIM 2001;16:601-616.
Webster LR, Webster RM. Pain Med 2005;6:432-442.
Tools for Assessing Function & Pain
Risk assessment for Opioid Use
 SF36 Health Survey
 High risk –need high intensity monitoring
 http://www.rand.org/health/surveys_tools/mos/mos_core_36item.html





 Brief Pain Inventory
 http://www.ohsu.edu/ahec/pain/paininventory.pdf
 Quality of Life Scale
 http://www.uic.edu/orgs/qli/questionaires/ questionnairehome.htm
Taking > 120mg MED (morphine oral equivalent mg per day)
Taking methadone
Current alcohol and/or drug abuse
25 years old and younger
Repeated problems following opioid management tx plan
 Frequent early refill requests
 Escalating dose without consultation with physician
 Getting opioids from multiple prescribers
 Oswestry Disability Index
 http://www.workcover.com/public/download.aspx?id=794&str=disability
index oswestry
Adapted from: Agency Medical Directors Group. Interagency Guideline on Opioid Dosing for Chronic Pain. 2010
Update. Available at: http://www.agencymeddirectors.wa.gov
Patient treatment agreements…
Risk assessment for Opioid Use
 Acknowledgement that previous treatment strategies have been
inadequate.
 Medium risk – need moderate intensity monitoring
 Extensive written explanations of the side effects and risks of opioid
therapy.
 Taking between 40mg - 120mg MED (morphine oral
equivalent mg per day)
 Personal or family history of alcohol and/or drug abuse or
mental health issues
 Terms for routine, random substance testing
 Outlining conditions in which therapy will be conducted (refills, how often,
etc.)
 Consequences for violating agreement
 Low risk – low intensity monitoring
 Taking < 40mg MED
 No personal or family history of alcohol and/or drug abuse or
 Procedures for discontinuing opioids should it become necessary.
 Emphasis on the importance of improved functionality in order for opioid
mental health issues
therapy to continue.
 Restrictions regarding single prescriber, single pharmacy
Adapted from: Agency Medical Directors Group. Interagency Guideline on Opioid Dosing for Chronic Pain. 2010 Update.
Trescot AM et al. Pain Physician. 2006;9:1-40.
147
UDS – Red Flag Results
Tapering or discontinuing opioids
 Negative for opioid(s) prescribed
 Positive for amphetamine , methamphetamine, cocaine,
benzodiazepines
 Positive for other opioids not prescribed
 Positive for alcohol
Indication for tapering
Taper method
• Urine drug screen is consistent with substance abuse concerns
• Behavior suggests that patient may be misusing or diverting1
Over 3-7 days or 15% / day2
• Medication side effects indicate risks greater than benefit 3
• Co-morbidities increase risk of consumption
• Morphine equivalent exceeds recommended threshold
10% per week
• Function and pain not improved
• Long-term opioid prescription with tolerance
• Co-morbidities increase risk of consumption
10% every 2-4 weeks
1. Behaviors may include: stealing/borrowing drugs, injecting oral/topical opioids, aggressive
demands for opioids
2. Opioid withdrawal is unpleasant for the patient but is not dangerous
3. Side effects of opioids may include: depression, sleeping problems, worsening pain, sexual
problems, fatigue, constipation, falling/breaking bones, itching, nausea or vomiting, breathing
problems
Commercially Available Oral / SL / Nasal Opioids
Combination
Teaching About Medication Storage and Sharing
Hydrocodone / APAP:
 Sharing meds seen as safe by “self-treaters”
(includes generic and branded Vicodin,
Loratab, Zydone)
5/325; 7.5/325;
 Educate patients about medication storage
Hydrocodone / Ibuprofen:
(Vicoprofen)
5/200; 7.5/200
 “Safe” or “lock box”
Kadian specific: 10;20;30;40;50;60;80;100;200
Avinza specific: 30; 45; 60;75; 90; 120
Embeda (morphine+naltrexone): 20/0.8; 30/1.2;
50/2; 60/2.4; 80/3.2; 100/4
Oxycodone (generic)
Oxycodone-LA
5; 10, 15; 30 IR
(includes generic and Percocet, Roxicet)
2.5/325; 5/325; 7.5/325; 10/325;
schedule programmed by the MD
elixirs: 2mg/ml, 4mg/ml,20mg/ml
“Long acting” (LA/ER)
Morphine-LA 15; 30; 60; 100; 200;
Tramadol:(generic and Ultram) 50
Tapentadol: (Nucynta) 50, 75, 100
elixirs: 1mg/ml, 20mg/ml
Oxycodone / APAP:
 New devices being developed -- patient have access and on a
Immediate Release
Morphine 10; 15; 30
Hydromorphone(generic,/Dilaudid)
tablets: 2; 4; 8 IR
elixir: 1mg/ml
OxyContin specific: 10, 15, 20, 30, 40, 60, 80
Targiniq (oxycodone+naloxone) 10/5; 20/10; 40/20
Oxymorphone-LA
5; 7.5; 10; 15; 20; 30; 40
Oxycodone / Ibuprofen: 5/400
Oxymorphone 5; 10
Fentanyl-TTS 12; 25; 50; 75;100(mcg/hr)
Codeine/APAP
Codeine 15; 30; 60
Hydrocodone ER
15/300;30/300;60/300
Hysingla specific: 20, 30, 40, 60, 80, 100, 120
Zohydro specific: 10, 15, 20, 30, 40, 50
Fentanyl tabs (buccal/ OTFC)
Hydromorphone ER
8, 12, 16
Actiq, Fentora: 0.2;0.3;0.4 0.6;0.8;1.2; 1.6
Fentanyl SL
Methadone
5; 10; elixir 1mg/ml
Spray (Subsys): 0.1; 0.2; 0.4; 0.6; 0.8
Film (Onsolis): 0.2; 0.4; 0.6; 0.8; 1.2
Fentanyl nasal (Lazanda) 0.1, 0.4
LA/ER Oral Opioid Formulations
Name
Dosing Interval
Dosage form
Morphine
MS Contin/generic
Avinza
Embeda
Kadian
Q 8 or 12 H
Q 24 H
Q 12 or 24 H
Q 12 or 24 H
Tablet
Capsule
Capsule
Capsule
No
No
Yes
No
Q 12 H
Tablet
Q 12 H
Tablet
Yes
Yes
Q 12 H
Q 12 H
Tablet
Tablet
Yes
No
Q 24 H
Q 12 H
Tablet
Capsule
Yes
Yes with new formulation
Targiniq
Oxymorphone
Opana
Generic
Hydrocodone
Hysingla
Zohydro
Hydromorphone
Exalgo
Tapentadol
Nucynta
Q 24 h
Tablet
Yes
Q 24 H
Tablet
Yes
50, 100, 150, 200, 250
Three Significant Risks of Using
Opioids for Chronic Pain
Tamper resistant
 Deterioration of functioning / increasing pain
 Misuse, abuse, diversion
 Inadvertent over-dosage
Oxycodone
OxyContin
Tapentadol ER
148
Hyperalgesia
 Thought to involved NMDA receptor activation 
sensitization of pronociceptive pathways
Hyperalgesia
 Characterized by patients who once responded to an
Fact or fiction?
opioid and in spite of being on a stable doses for a
period of time now have increased pain sensitivity
Angst MS and Clark JD. Opioid-induced hyperalgesia. A qualitative systematic review. Anesthesiology 2006;104:570587.
Differentiation of Opioid-induced
Hyperalgesia (OIH)
Opioid-induced Hyperalgesia (OIH)
 Two forms of OIH can be distinguished
 Need to distinguish from
 All can result in either:
Increased sensitivity to pain; aggravation of preexisting pain; or, expression of novel pain symptoms.





 OIH1: Opioid maintenance therapy
 Involves up-regulation of pain facilitating neuronal pathways at multiple levels
of the central and peripheral nervous system
 Stimulation of excitatory amino acid neurotransmitter system.
 OIH2: Very high and escalating doses of opioids
 Usually implicated with high doses of morphine or hydromorphone
 Severe allodynia, myoclonus noted
 Thought to be due to metabolites inhibiting glycineric inhibition at spinal cord
tolerance
progression of painful disease process
increased activity
increased stress
clinical exacerbation of preexisting pain
 Typically produces diffuse pain, less defined in quality and often
extending to other areas
 OIH can mimic opioid withdrawal
level inducing a strychnine-like excitatory intoxication.
 OIH often worsened with increasing dosage
2006;104:570-587.
Davis MP, Shaiova LA, Angst. When opioids cause pain. J Clin Oncol 2007;25:4497-4498.
Lee M, et al. Pain Physician 2011;14:145-161.
Misuse, abuse and diversion
Prevention Strategies for Opioid-Induced
Hyperalgesia
 Misuse
 Using opioid for purposes other than intended
 Use of adjuvant therapies for “opioid sparing” effect
 Anticonvulsants
 Antidepressants
 Depression, sleep, anxiety, constipation pain
 Abuse
 Opioid rotation
 Manipulating the opioid delivery system, or using the opioid at a higher
than prescribed dose to attempt to obtain a faster onset, or greater
euphoria
 To take advantage of “incomplete cross tolerance”
 To avoid toxic metabolites
 FDA definition: “Intentional, non-therapeutic use of a drug product or
substance, even once, to achieve a desirable psychological or
physiological effect”
 Combination of opioid and low-dose mu receptor antagonist (e.g.
buprenorphine and naltrexone)
 Blockade of the NMDA receptor (e.g., ketamine)
 Diversion
 Selling/giving/buying a portion of a prescription to/from another person
 Stealing medication from a friend/relative/stranger
Silverman SM. Pain Physician. 2009;12(3):679-684.
149
Methods of abuse
Abuse Deterrent Technology (ADT)
FDA Guidance for Industry
 Crush/grind/grate
 Goals
 Mastication
 ADT intended to make manipulation more difficult or to make
 Intravenous injection
abuse of manipulated product less attractive or rewarding
 Nasal insufflation
 Caveats
 Inhalation by vaporization
 “FDA approved technologies have not yet proven successful at
deterring the most common form of abuse – swallowing a number
of intact tablets or capsules to achieve a feeling of euphoria”
 “A product with ADT does not mean that there is no risk of abuse.
It means rather that the risk of abuse is lower than it would be
without those properties”
 Ethanol co-ingestion
 Multiple oral dose administration
 Heating/microwaving
 Freezing
 Solvent extraction
FDA. Guidance for Industry: Abuse Deterrent Opioids – Evaluation and Labeling. April 2015.
Abuse-Deterrent Technologies (ADT)
Abuse-Deterrent Technologies (ADT)
(continued)
 Aversion
 Physical/chemical barriers
 Substances added to product to produce an unpleasant effect if
 Prevent chewing, crushing, cutting, grating, grinding
 Resist extraction of opioid with common solvents
 These barriers can limit drug release or change the physical form
manipulated or if a higher dose is used than directed
 E.g. nasal irritants
 Delivery system
of the drug rendering it less amenable to abuse
 Drug-release designs can offer resistance to abuse
 Agonist/antagonist combinations
 E.g. depot injections, SQ implants
 Antagonist to interfere with, reduce or defeat the euphoria
 New molecular entities or prodrugs
associated with abuse.
 Design so there is a need for enzymatic activation, different
 Antagonist can be sequestered and released only on
receptor binding profiles, slower penetration into the CNS
manipulation of the drug.
FDA Labeling for ADT(continued)
FDA Labeling for ADT
 Types of studies:
 Need scientifically rigorous studies to evaluate
 In vitro manipulation/extraction studies
 Positive controls, comparator drugs, outcome measures,
 Test the ability of product to be crushed, cut, grated, etc with common household items
statistical analysis
(spoons, cutters, coffee grinders) and solvents (vinegar, alcohol, water, isopropanol,
acetone)
 Will ADT be expected to have meaningful impact on the abuse
 If two ingredients in product (e.g. agonist-antagonist) can agonist be extracted without
antagonist contamination?
of that product
 E.g. short-acting opioids with nasal deterrents. Usual route of
 Vaporization (smoking)
 Nasal particle size
 Ability to liquefy and inject product (solvent, melting)
abuse is ORAL not NASAL with short-acting opioids
 Pharmacokinetic studies
 Effects of food/alcohol
 Compare oral to nasal, injectable
 Clinical abuse potential studies
 Drug-experienced, recreational drug user
 Pre-marketing trials to assess potential ADT under controlled settings
150
FDA Categories of Abuse
Deterrent Labeling
FDA Labeling for ADT(continued)
 Types of studies:
 Category I:
 Post-marketing studies
 In vitro physical and chemical tablet manipulation studies
 To determine whether the marketing of a product with ADT results in
demonstrate that the product resists crushing, breaking and
dissolution using a variety of tools and solvents and retains some
of the extended-release properties despite manipulation.
 In vitro data demonstrates product cannot be crushed and
dissolved or extracted in a small volume of solution suitable for
injection.
 These products would be labeled: “In vitro data demonstrate that the
meaningful reductions in abuse, misuse and related adverse clinical
outcomes including addiction, overdose and death.
 Comments:
 FDA will expect manufacturers to compare their formulations
against approved ADT versions of the same opioid.
product has physical and chemical properties that are expected to
deter intravenous abuse. However the abuse of this product is still
possible by the oral and nasal routes
 FDA is concerned that, with time, abusers may adapt to ADT and
discover methods to defeat them.
Deterrent Labeling
Deterrent Labeling
 Category I and II:
 Category II and III:
 In vitro data demonstrates from study of the oral and nasal routes
 Pharmacokinetic and clinical abuse potential studies demonstrate
demonstrated that no changes occurred in the extended-release
properties of the opioid after crushing or dissolution in a variety of
solvents
 These products would be labeled: “In vitro data demonstrate that the
the release of an antagonist following crushing or intravenous
abuse of the oral product (in a combination agonist-antagonist
product) and that the presence of the antagonist resulted in less
drug liking compared to a similar amount of the opioid alone when
given by oral or intranasal routes.
 These products would be labeled, “Pharmacokinetic studies, oral and
product has physical and chemical properties that are expected to
deter oral, nasal and intravenous abuse. However, abuse of the
product is still possible by the oral route.
intranasal studies demonstrate that the product has properties
expected to deter abuse via the oral, intranasal and intravenous
routes. However, abuse by these routes is still possible.
Current ER Opioids with ADT
(in order of date of FDA approval)
Mythology of ADT Technology
Opioid Product
Description of technology
Embeda®
Addition of sequestered naltrexone – designed to release antagonist if
crushed, and then snorted, or crushed, dissolved and then injected
intravenously
 All ADT technology is the same
OxyContin®
Resistec polymer matrix – designed to be plastic-like, hard to break,
becomes gel in water, thus difficult to use in a syringe
 ADT technology is fail-safe
Opana®
INTAC polyethylene oxide matrix – designed to render tablet highly
resistant to crushing; when exposed to water forms a gel leading to
difficulty drawing into a syringe.
 ADT technology has been proven to decrease addiction,
Nucynta®
Polyethylene oxide matrix – designed to render tablet highly resistant to
crushing or extraction of active drug
Exalgo®
OROS technology - osmotically active bilayer core enclosed in a
semipermeable tablet shell membrane – designed to minimize crushing
and active drug extraction
Targiniq®
Addition of naloxone – designed to block the euphoric effect if its crushed
and then snorted, or crushed, dissolved and then injected intravenously.
Hysingla®
Resistec polymer matrix – designed to be plastic-like, hard to break,
becomes gel in water, thus difficult to use in a syringe
Zohydro®
BeadTek formulation – designed to make it hard to crush and snort.
 Prevents abuse/misuse/diversion
abuse, over-dosages, misuse, diversion, etc.
 ADT technology alone will ensure that my patients will not
misuse, abuse or divert their opioids
 ADT technology ensures the best pharmacokinetics of the
opioid delivery system.
151
Precautions / wrong assumptions
regarding ADT Opioids
Precautions / wrong assumptions
regarding ADT Opioids (continued)
 ADT do not prevent the most common form of abuse – taking
 Generic oxymorphone (Opana) does not have tamper resistant
extra tablets/capsules
properties.
 Some of the new formulations with ADT are contraindicated in
 Still need to account for FDA requirement that patients be
mechanical bowel obstruction
opioid tolerant prior to prescribing some of the higher dosage
strengths.
 Some of the new formulations must be taken ONE tablet at a
 All of the ADT products can still be abused and misused
time and not be wet or licked prior to swallowing
 Abusers may turn to other opioids:
 Reviewing post-marketing studies, the FDA concluded, “the
data do not yet demonstrate a reduction in OxyContin abuse
following the replacement of OxyContin with reformulated
OxyContin in the marketplace”.
 Short-acting
 Transdermal fentanyl
 Buprenorphine
Potential reasons for Inadvertent Overdosages with ER Opioids
Tolerance
 “Needing increased doses to maintain level of pain
control”
 Patient error
 Has not proven to be a limitation to short- or
 Misread dose or dosing instructions
 Chew, split, break or crush ER formulation for ease of swallowing
 Food / alcohol interactions
long-term opioid use.
 Rapid escalation of drug doses in cancer pain
usually due to disease progression.
 Patient not opioid tolerant
 Studies suggest that use of long-acting oral opioids
 Wrong conversions
as maintenance therapy for primarily nociceptive
pain does not lead to uncontrolled dose escalation.
 In appropriate use of Fentanyl products
 Methadone
Savage S, Covington EC, Heit HA et al. (2001). Definitions related to the use of opiates for the treatment of pain: a
consensus document from the American Academy of Pain Medicine, the American Pain Society, and the American Society
of Addiction Medicine. American Society of Addiction Medicine. http://www.asam.or/pain/definitions2.pdf.
American Society of Addiction Medicine. Public Policy Statement on definitions related to the use of opioids in pain
treatment. J Addictive Dis. 1998;17:129-133.
Tolerance
Tolerance
To which effects does opioid tolerance occur?
 Innate tolerance
 Genetically determined, seen with first dose
 Analgesic effects?
 Acquired tolerance
 Pharmacokinetic (desensitization of receptors)
 Pharmacodynamic (reduced concentration of drug
 Dizziness?
 Euphoria / dysphoria feelings?
 Respiratory depression?
at receptors)
 Learned (reinforcement of an effect of a drug)
 Sedation?
 Constipation?
 Nausea?
2006;104:570-587.
152
FDA Tolerance definition for ER Opioids
Opioid Tolerance - LA / ER Opioids
Product
 FDA Indications: moderate to severe pain in opioid tolerant
Morphine
• MS Contin / generic
• Avinza
• Kadian
• Embeda
patients who require continuous around-the-clock opioid
analgesia for an extended period of time
 Opioid tolerant definitions: (taking at least a week)





Oxycodone oral 30 mg / 24 hours
Fentanyl 25 mcg / hr patch
Hydromorphone 8 mg oral / 24 hours
Oxymorphone oral 25 mg / 24 hours
FDA. Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics.
04/2013.FDA.
Extended-Release (ER) and Long-Acting (LA) Opioid Analgesics Risk Evaluation and Mitigation
Strategy (REMS). 04/3013.
Approximate Equianalgesic Dose
Morphine (reference)
30 mg oral
10 mg intravenous / SQ
Codeine
200 mg oral
Fentanyl transdermal
12.5 mcg/hr transdermal
Hydrocodone
30 mg oral
Hydromorphone
7.5 mg oral
1.5 mg intravenous / SQ
Methadone
Chronic 4 mg – 7.5 mg*
Oxycodone
20 mg oral
Oxymorphone
10 mg oral
Tapentadol
100 mg oral
Tramadol
N/A
100 and 200 mg size
90, 120 mg size
100, 130, 150 and 200 mg sizes
100 mg / 4 mg size
• Targiniq
• 60 and 80 mg size, or any single dose > 40 mg or total daily
dose > 80 mg
• Any single dose > 40/20 or total daily dose > 80/40 mg
Hydrocodone
• Hysingla
• Zohydro
• Any single dose > 80 mg
• 50 mg size, or any single dose > 40, or any daily dose > 80
Exalgo (hydromorphone)
All strengths 8, 12, 16 mg
Duragesic (fentanyl TDS)
All dosage strengths (12, 25, 50, 75, 100 mcg/hr)
Nucynta (tapentadol)
No FDA limitations
Opana (oxymorphone)
No FDA limitations
Checklist for Appropriate Use of
Transdermal Fentanyl
Opioid Equivalent Doses
 Patient should not be cachectic or edematous or sweaty.
**(remember fentanyl is lipophilic, doesn’t pass easily through aqueous media)
AND
 Patient should not be running fevers or putting a heat source (pads, water
beds, etc) directly on or near the transdermal patch
**(remember heat dramatically speeds up transdermal delivery of drug)
AND
 Patient’s pain should be relatively stable.
**(remember fentanyl has a lag time of 16-24 hrs to absorb)
AND
 Patient has pain described as “moderate” or “severe” and is not opioid naive.
**(remember even the lowest size patch is “worth” > 30 mg oral morphine per day)
AND
 Patient cannot tolerate oral therapies
* Conversion highly variable based on dose, drug interactions, unique patient variables
**(remember sustained-release oral morphine provides greater consistency in serum opioid levels)
Short-Acting Fentanyl Products
Fentanyl Products
 Indication: management of breakthrough pain in cancer patients 18
 Actiq® (and generic equivalents)
 “Lollipop” formulation – 200, 400, 600, 800, 1200, 1600 mcg
years of age and older who are already receiving and who are tolerant
to opioid therapy for their underlying persistent cancer pain
 Opioid tolerant definitions: (receiving for one week or longer)





•
•
•
•
Oxycodone
• OxyContin
Morphine oral 60 mg / 24 hours
Opioid
Product sizes and dosages at which patient needs to be
opioid tolerant prior to being prescribed the ER opioid
 Fentora®
 Buccal tablet – 100, 200, 300, 400, 600, 800 mcg
Morphine oral 60 mg / 24 hours
Oxycodone oral 30 mg / 24 hours
 Abstral®
 Sublingual tablet – 100, 200, 300, 400, 600, 800 mcg
Fentanyl 25 mcg / hr patch
Hydromorphone 8 mg oral / 24 hours
Oxymorphone oral 25 mg / 24 hours
 Onsolis®
 Buccal soluble film – 200, 400, 600, 800, 1200 mcg
 Contraindications include:
 Acute pain, post-op pain, dental pain, migraines
 Subsys®
 Sublingual spray – 100, 200, 400, 600, 800, 1200, 1600 mcg
 May be dispensed only to patients enrolled in the transmucosal
immediate release fentanyl (TIRF) REMS Access program @
www.TIRFREMSaccess.com
 Lazanda®
 Nasal spray – 100, 400 mcg
153
What makes the use of methadone more
complex than other opioids?
Fentanyl Products
 Do NOT interchange products without first starting over at the
 Methadone has unique pharmacokinetics leading to variations
in serum levels, the amount of free drug available at receptor
and drug accumulation.
LOWEST dose available of the new product
 Differences exist in pharmacokinetics of TIRF medications
 TIRF medications are NOT equivalent to any other fentanyl product,
 Long, and variable half-life: mean 40 hours (range: 5 - 130 hours)
 Good, and variable bioavailability: mean 75% (range: 36 – 100%)
 Highly bound to plasma proteins: mean free fraction 13%
including another TIRF medication, on a mcg for mcg basis.
(4-fold interindividual variation)
 Limit use of TIRF medications to 4 or fewer doses per day.
 Methadone has numerous drug interactions.
 Unique and potentially dangerous side effects
 Titration and conversion to- and from- other opioids does not
follow “textbook” standards
Eap CB, Buclin T and Baumann P. Clin Pharmacokinet 2002;41:1153-1193.
TIRF = transmucosal immediate release fentanyl
Drug interactions with methadone…
Methadone and Torsades
 Methadone, by itself, in low to moderate doses (< 100
 Methadone is metabolized mainly through the CYT P450 3A4 and
mg/day), most likely has little risk to cause torsades.
2D6 isoenzymes
 By itself, at higher doses (> 100 mg/day) or at low- to
 Common inhibitors of 3A4 and 2D6
moderate doses in conjunction with other drugs associated
with QT prolongation, methadone can cause Torsades.
( METH serum levels   opioid effects,  sedation,  risk resp. depression)

3A4: amitriptyline, ciprofloxacin, fluconazole, sertraline
 Drugs that prolong QT and/or induce Torsades
 2D6: fluoxetine, paroxetine, sertraline
 Azithromycin, chlorpromazine, cisapride, clarithromycin, dolasetron,
erythromycin, haloperidol, levofloxacin, lithium, methadone,
ondansetron, quetiapine, risperidone, tizanidine, venlafaxine
 Common inducers of 3A4
( METH serum levels   opioid effects,  risk withdrawal reaction)
 Amprenavir, efavirenz, nelfinavir, nevirapine, phenobarbital, phenytoin,
rifampin, ritonavir, spironolactone
Krantz MJ, Lewkowlez L, Hays H et al. Ann Intern Med. 2002;137:501-504
Piguet V et al. J Clin Psychopharm. 2994;24:446-8.
Eap CB, Buclin T and Baumann P. Clin Pharmacokinet 2002;41:1153-1193.
Methadone conversion
recommendations
TDD Oral Morphine
EPERC Conversion
(morphine : methadone)*
% of morphine dose
(FDA)
< 100 mg
3:1
20 - 30%
101 – 300 mg
5:1
10 - 20%
301 – 600 mg
10 : 1
8 – 12%
601 – 800 mg
12 : 1
5 – 10%
801 – 1000 mg
15 : 1
5 – 10%
> 1000 mg
20 : 1
< 5%
Friedman method
< 1000mg
per day
AND
< 65 yo
< 1000mg
per day
BUT
> 65 yo
> 1000mg
per day
BUT
< 2000mg
per day
> 2000mg
per day
10 : 1
20 : 1
20 : 1
Call
pharmacist
*Gazelle G and Fine P End-of-life Physician Education Resource Center, July 2006
Friedman LL, Rodgers PE Clinics in Family Practice 2004;6:371-393
154
Back to our patient, now what do you
think…
Pain –“Ideal Model of Care”
 Have a risk management strategy in place for chronic pain
 What concerns do you have regarding the use of opioids for this
patients on maintenance opioid therapy
patient?
 Clinical
 Abuse/misuse/diversion risk by the patient? By teenagers in the
 Do not merely follow a “traditional approach”
 One prescriber, one pharmacy for medications
 Have patient and prescriber sign opioid agreement
 Do not combine opioids with sedative-hypnotics, benzodiazepines or
home?
 Does the cannabinoid use by the patient concern you?
barbiturates unless benefits outweigh risks
 Routinely assess function, pain state and aberrant behaviors
 Have a consistent documentation system and urine testing
 Consider role of patient pain diaries
 Use ADT technology IN ADDITION TO all of the above
 Proactively manage side effects, especially CONSTIPATION
 What would be the benefits/risks of using opioids with ADT for this
patient?
 What type of follow-up would you want for this patient?
 Counseling tips for this patient?
Balancing Medication Use in
Patients


Pain control

Comfort level
Non-pharmacological strategies




Improving overall
function
Minimizing side
effects
Medical / legal guidelines for opioid use
Ethical issues
155
2015 Annual Meeting
Saturday, May 23
11:00 a.m.—12:00 p.m.
Director - Pharmacy Technician Program
New Orleans, LA
0179-0000-15-007-L04-P / 0179-0000-15-007-L04-T
 Identify USP Chapter <797> Risk Levels
Describe Primary and Secondary Engineering
Controls
 Explain quality assurance and identify
products and methods of ensuring proper
aseptic technique
 Identify best practice standards for
Pharmacists in USP Chapter <797> compliance
 Identify gaps in USP Chapter <797>
compliance
 Identify USP Chapter <797> Risk Levels
Controls
 Explain quality assurance and identify
products and methods of ensuring proper
aseptic technique
 Identify best practice standards for Pharmacy
Technicians in USP Chapter <797> compliance
156
Learning Objectives:
Pharmacist
Sterile Compounding:
USP Chapter <797>
Pharmacy Technician Program Director – Delgado Community College
ACPE Certified Trainer: Sterile Compounding and Aseptic Technique
Identify USP Chapter
<797> Risk Levels


Describe Primary and
Secondary Engineering
Controls
Identify USP Chapter
<797> Risk Levels


Explain quality assurance
and identify products and
methods of ensuring
proper aseptic technique
Describe Primary and
Secondary Engineering
Controls

Explain quality
assurance and identify
products and methods of
ensuring proper aseptic
technique

Identify best practice
standards for Pharmacy
Technicians in USP
Chapter <797>
Compliance

Identify best practice
standards for Pharmacists
in USP Chapter <797>
Compliance

Identify gaps in USP <797>
compliance
Compounded Sterile Products
(CSPs)
USP General Chapter <797>
The objective of this chapter is to describe conditions
and practices to prevent harm, including death, to
patients that could result from

Any Compounded:
 Drug
(1)
Microbial contamination (nonsterility),
 Biologic
(2)
Excessive bacterial endotoxins,
 Nutrient
(3)
Variability in the intended strength of correct
ingredients that exceeds either monograph limits for
official articles
 Diagnostic
(4)
Unintended chemical and physical contaminants, and
(5)
Ingredients of inappropriate quality in compounded
sterile preparations (CSPs).
 Radiopharmaceutical
3
Source: 2015 USP Compounding Compendium
Chapter <979> Standards:
Who and Where?

Technicians
 Physicians
Everywhere CSPs are prepared
 Hospitals
 Clinics
 Anywhere

Aqueous bronchial or nasal inhalations
Irrigation for wounds and body cavities

Ophthalmic preparations
Level
Medium-Risk Level
High-Risk Level
 Nurses
 Physician
Injections

Low-Risk
 Pharmacists


Risk Levels
Anyone who prepares CSPs
 Pharmacy
Pharmacy Technician

Practice
CSPs are stored
157
Low-Risk Level CSP

ISO Class 5 or better air quality

Only sterile ingredients, products,
components, and devices


Low-Risk Level CSP

Involves only transfer, measuring, and
mixing not more than three
commercially manufactured sterile
products

Not more than two entries into any one
sterile container or package

Single-volume transfers with a sterile
syringe and needle
48 hours at controlled room temperature

14 days refrigerated

45 days in a solid frozen state (-25o to -10o)
12-Hour or Less BUD

PEC not located in a ISO Class 7 or better area

PEC MUST be ISO Class 5

Windows and doors must be sealed if connected to outdoors
or high traffic

Procedures for PPE must be followed; Sinks must not be
located in immediate area of PEC device

Follow specifications for Cleaning and Disinfecting the Sterile
Compounding Areas, Personnel Training and Competency
Evaluation of Garbing, Aseptic Work Practices and
Cleaning/Disinfecting Procedure, and Viable and Nonviable
Environmental Sampling Testing must be followed.
Meets requirements of Low-Risk and has
one or more of the following conditions:
 Multiple
individual or small doses are
combined to prepare a CSP that will
administered in multiple doses
 Ampuls
– contents passed through a
sterile filter
 Bottles,

Medium-Risk Level CSP
Examples of Low-Risk CSPs

Storage cannot exceed:
Bags
 Complex
aseptic manipulations other
than a singe-volume transfer
 Vials
 Requires
 Simple
aseptic measuring and transferring –
not more than 3 manufactured sterile
products
unusually long compounding
duration
 Admixtures
 Nutritional
solutions
Medium-Risk Level CSP

At risk for contamination
Nonsterile ingredients
 Exposed to air quality worse than ISO
Class 5 for more than 1 hour
 Compounding personnel are improperly
garbed and gloved
 Nonsterile water containing preparations
are stored for more than 6 hours before
being sterilized
 Unopened bulk ingredients: Chemical
purity and content strength is assumed,
not verified
 30
9

hours at controlled room temperature

days refrigerated
 45

HIgh-Risk Level CSP
days in a solid frozen state (-25o to -10o)
Examples of Medium-Risk CSP

TPN

Filling reservoirs of injection and infusion
devices with more than three sterile drug
products

Transfer of volumes from multiple ampuls or
vials into one or more final sterile containers
158
High-Risk Level CSP
Additional High-Risk CSP
Requirments

All nonsterile devices rinsed with sterle,
pyrogen-free water

If product will be subjected to terminal
sterilization – prefilter with 1.2 micron
filter or smaller


3

Sterilization by filtration shall be
completed with a 0. or 0.22 micron filter;
entire process must be completed in an
ISO Class 5 or better environment
days in a solid frozen state (-25o to -10o)
Examples of High-Risk CSP

Dissolving nonsterile bulk drug and nutrient
powders to make a solution that will be
terminally sterilized

Exposing sterile ingredients/components to
room air quality worse than ISO Class 5 for
more than 1 hour

Measuring and mixing sterile ingredients in
nonsterile devices
Primary Engineering Controls (PECs)

days refrigerated
 45

 24 hours at controlled room temperature

ISO Class 5
 LAFW
Secondary Engineering Controls

Area/Environment where PEC is located

Controlled temperature

Well lit

Clean room / Buffer area

Anteroom

Characteristics
 BSC
 CAI

 CACI

Located within a restricted access ISO
Class 7 buffer area

Quality Assurance

Air quality

Disinfection processes

PPE

Review of orders and packages

Inspection of CSPs for absence of particulate
matter and leaks

Inspection of label for accuracy and
completeness

Media-fill testing

Gloved finger-tip sampling

Surface sampling

Bacterial Endotoxin testing

Temperature monitoring of all storage
environments
ISO Class 8 or better

Impervious

Free from cracks and crevices

Smooth

Non-Shedding

Resistant to damage from disinfecting agents
Quality Assurance
Testing and evaluation

ISO Class 7 or better

159
Characteristics of a QA Program:

Formal and Written policy

Descriptive oh specific activities for
monitoring and evaluation and how results
will be reported and evaluated

Thresholds for evaluations and follow-up

Effectively addresses risk management
Chapter <797> QA
Requirements
Media Fill Tests

Routine disinfection and air quality testing

Visual confirmation of properly donned PPE

Review orders and packages for correct
identity and amounts

Visual inspection of CSPs and labels

Media fill test to verify aseptic process
Best Practice
Completed annually

Completed without interruption

Appropriate risk level environments under
conditions that simulate the most
challenging or stressful conditions
Best Practice: Training

USP Chapter <797>

LABP regulations

ASHP gap analysis tool

Review /Revise P&P to match current
standards


TRAINING, Validation, and Documentation

Training course involving written exams, technique
demonstration, process validation, and media-fill
testing

Training and evaluation must occur before making CSPs
for patient administration

Recertified/Validated annually

Maintain records of training hours, testing and
validations

Pharmacists


Pharmacy Technicians

Gap Analysis


Identifies areas of compliance

Identifies areas of non-compliance
Are you here?
Recommended minimum 40 hour course in sterile
compounding and aseptic technique
Identify Gaps
Why is Gap analysis important?
USP <797>
Partial
Compliance
Recommended minimum 20 hour course in sterile
compounding an aseptic technique
USP <797>
Compliant

Standards in USP Chapter <797>

Training

Lack of formal Sterile compounding
training

Trainer not fully knowledgeable in USP
<797>

Lack of specialty expertise
Or, are you here?
160
Resources
Bridge the Gap

Resources






2015 USP Compounding Compendium
Gap Analysis Survey Compounding Sterile
Preparations USP <797>; International
Journal of Pharmaceutical Compounding
ASHP
ACPE
LABP

Buchanan, E. Clyde, M.S. FASHP and Cassano, Angela T.,
Pharm.D., BCPS (2007). The ASHP Discussion Guide on USP
Chapter <797> for Compounding Sterile Preparations.

Douglas, Kate, Kastango, Eric S., MBA, RPh, FASHP, and Cantor,
Peter (2014). The 2014 USP Chapter <797> Compliance Survey.
Pharmacy Purchasing & Products,Vol 11 No. 10: 6
http://www.pppmag.com/article/1589/October_2014_Cleanro
oms_Compounding/The_2014_USP_Chapter_797_Compliance_S
urvey/

Kastango, Eric S., MBA, RPh, FASHP (2009). The Top 10 Gaps in
USP Chapter <797> Compliance. Pharmacy Purchasing &
Products,Vol 6 No. 10:
http://www.pppmag.com/article/617/October_2009_Cleanroo
ms_Compounding/The_Top_10_Gaps_in_USP_Chapter_797_Co
mpliance/

McCarney,Lisa, BAAS, CPhT, PhTR (2012). Sterile Compounding
and Aseptic Techniques; St. Paul, MN: Paradigm Publishing Inc.

Ochoa, Pamella S., and Vega, Jose’ A. (2015). Concepts in
Sterile Preparations and Aseptic Technique. Burlington, MA:
Jones & Bartlett Learning.

The United States Pharmacopeial Convention (2015). 2015 USP
Compounding Compendium; Update Feb 2015: <797> 43-87
Create a Culture of Excellence




Patient safety is ALWAYS #1
Follow Best Practices
Uses errors as opportunities for learning
Do the right thing
161
2015 Annual Meeting
Saturday, May 23
12:00—1:00 p.m.
Trends in Pharmacy Law & Regulation
Jeffery Evans, PharmD
Assistant Professor
University of Louisiana at Monroe
Monroe, LA
William Kirchain, PharmD, CDE
Associate Professor of Clinical Sciences
Xavier University of Louisiana College of Pharmacy
New Orleans, LA
0179-0000-15-012-L03-P / 0179-0000-15-012-L03-T
Pharmacists Objectives:
 Outline the elements of the Changes in
current Pharmacy Law or Health Policy that
are either functioning or "in place” and a part
of the current health care environment
 Translate to patients what issues, challenges
and benefits may be available to them under
the Changes in current Pharmacy Law or
Health Policy
 List possible practice opportunities for
pharmacist to exploit to their patient’s benefit
brought about by the changes in current
Pharmacy Law or Health Policy
 Create initial business plans to expand into
collaborative care practices.
 Outline the elements of the Changes in
current Pharmacy Law or Health Policy that
are either functioning or "in place” and a part
of the current health care environment
 Translate to patients what issues, challenges
and benefits may be available to them under
the Changes in current Pharmacy Law or
Health Policy
 List possible practice opportunities for
pharmacist to exploit to their patient’s benefit
brought about by the changes in current
Pharmacy Law or Health Policy
 Create initial business plans to expand into
collaborative care practices.
Speakers have disclosed that they have no relevant financial
relationships.
162

Medical Marijuana (HB 6, HB
117)

William R. Kirchain, PharmD, CDE
Xavier University of Louisiana, College of Pharmacy
Jeffrey D. Evans, PharmD, BCPS
University of Louisiana Monroe, School of Pharmacy
Physician…
1. Neurologist, oncologist, or ophthalmologist
with valid DEA #.
2. With a LA # to prescribe cannabis sativa.
3. Doctrines of patient relationship and
therapeutic choice are satisfied.
Pharmacists…
1. BOP issued cannabis sativa dispensing permit.
2. Doctrine of corresponding responsibility is
satisfied.
3. FDCA related issues are satisfied.
Creates Therapeutic
Marijuana Utilization Review
Board.
 Creates “Grower” license.
 Creates regulatory fund.


163
Puts legalized marijuana on
ballot for this fall.
Exempts NP’s with MSN, DNP from
Collaborative Practice Agreement… if
in a medically underserved area or
an area comprising at least 1
medically underserved population;
as designated by the HRSA or DHH
Suspends Louisiana Board of
Pharmacy rule providing that
computer generated electronic
signatures on prescriptions are
invalid.
(Buford)
Status:
Status:




adds to the LA
Health Care Consumers‘ Right to
Know law:
(1) Healthcare quality information published by
DHH that allows comparison of information
across providers.
(2) Data related to payments for services
published by DHH in a format from which the
user can generate reports.
Prohibits the dispensing of an interchangeable
biological product if the prescription requires
the named product and requires notification to
the prescriber when an interchangeable
biological product is dispensed.
Status
Status:
Changes the abilities of Physician Assistants in
the State of Louisiana
For LTC residents; prohibits limits on # of Rxs per
day including…
(1) DHH
(2) DHH contractors
(3) Managed or Coordinated Care Organizations
(4)
Status
Establishes a formula for reimbursement
Status:
164
Authorizes Rxs of opioid antagonists (naloxone)
without individual assessment as long as…
Establishes…
Closed Pharmacy Formulary Oversight Panel
Excludes coverage of…
Narcotics, Compounded, Investigational Drugs
Establishes…
Maximum Nonemergent Out-of-Pocket = $750.00
(1) The person receiving the opioid antagonist has
completed training (by DHH) for the safe
administration during a drug overdose.
(2) The opioid antagonist is approved by the FDA
for intranasal administration.
Status:
Status:
Protocol to Provide Naloxone
Pharmacist obtains CPE: Opiate Overdose
to provide to either Potential Recipient/Patient…
i.
Determine – Hx Opiate Use (overdose risk)
ii.
Determine - Appropriate product (SQ /Nasal)
iii. Provide instruction: Prevention – Treatment
iv. Referral to Addiction Treatment Providers
v.
FAQ Sheet on Naloxone/Opiate Overdose
What are your
legislative priorities
for Louisiana?
1.



Grassley [R-IA]
Brown [D-OH]
Capito [R-WV]
Casey [D-PA]
Cochran [R-MS]
Gardner [R-CO]
S–314: Provider Status
HR–592: Provider Status
S–776: Reduces MTM chronic disease
threshold to 1 from the current 2 or more.
165
Gillibrand [D-NY]
Heinrich [D-NM]
Kirk [R-IL]
Schumer [D-NY]
Wicker [R-MS]
Running count = 75 (34 D, 41 R)
Including…
Byrne (AL)
Harper (MS)
Palazzo (MS)
O’Rouke (TX)
What are your
legislative priorities for
the United States?
Palazzo (TX)
 dot-pharmacy domain
 Drug Quality/Security
 Continuing competency
 Prescription Abuse
Potentially Legitimate
VIPP or Vet-VIP Certifiied
Illegitimate
Internet Drug Outlet Identification Program. Progress report for state and federal
regulators. National Association of Boards of Pharmacy. October 2014
What are your regulatory
priorities for the Board of
Pharmacy?
D.E.A.
Initiatives
166
& Related
State (Year)
Required for Initial Rx…
Exempted for…
Penalties
OH (2011)
CII – CV > 12 weeks; then
Annually upon Renewal
If patient suspected of
abusing/diverting drugs
Hydrocodone then Q3M
Hospice Patients
Disciplinary Action
Emergency Rx
Post-surgery Rx
Hospitals & LTC facilities
Cancer & Hospice patients
Single dose Rx for a procedure
Hospice patients,
Post-surgery - NR or ≤ 7 days
Hospitals, Residential Care
ED (≤5 d supply)
Hospice patients,
When it is not practicable to
access PMP in a timely manner
If PMP query will adversely
affect the patient
Disciplinary Action
KY (2012)
Additional Hydrocodone same patient
TN (2013)
Any CS Rx with refills
Opioids & Benzos > 7 days
Annually upon Renewal
NY(2013)
Initial Rx for C II-IV
12-42.5-402… (7) the board shall develop criteria for indicators of
misuse, abuse, and diversion and based on those criteria,
provide unsolicited reports
of dispensed controlled
substances to… pharmacies for
Disciplinary Action
purposes of education to prevent and reduce occurrences of controlled
substance misuse, abuse, and diversion.
$2000 fine
+ 1 year Prision
+ Disciplinary Action
Haffajee RL, et a. Mandatory use of prescription drug monitoring programs. JAMA.
doi:10. 1001/jama.2014.18514. http://jama.jamanet work.com/ accessed: on
A.C.A.
Witters D. Arkansas, Kentucky see most improvement in uninsured rates. Gallup Healthways
Well Being Index. http://www. gallup. com/ poll/1 81664/arkansas-kentucky-improvementuninsured-rates.aspx. accessed 24 Feb 2015.
Catastrophic
BRONZE
SILVER
Gold
Platinum
USA
210
256
314
369
441
17.2%
Louisian
a
209
274
359
411
454
4.6%
11.4%
Alabama
169
191
249
238
229
255
303
243
279
326
369
315
319
375
419
353
334
n/a
487
384
171
200
258
377
438
2013
2014
Louisiana
21.7%
Massachusetts
4.9%
22.5%
Arkansas
Arkansas
Florida
Mississipp
i
Tennessee
Witters D. Arkansas, Kentucky see most improvement in uninsured rates. Gallup
Healthways Well Being Index. http://www. gallup. com/ poll/1 81664/arkansas-kentuckyimprovement-uninsured-rates.aspx. accessed 24 Feb 2015.
Gabel JR, Whitmore H, Stromberg S, et al. Analysis finds no nationwide increase in health insurance marketplace premiums. The Commonwealth Fund. http://www.commonweal thfund.org/publications/blog/2014/dec/zero‐inflation‐nationwide‐for‐marketplace‐
premiums. 22 December 2014. accessed 22 January 2015.
167
Catastrophic
BRONZE
SILVER
Gold
Platinum
$ 6,574
$ 5,203
$2,965
$1,215
$ 552
Louisian $ 6,435
a
$4,848
$2,642
$1,071
$ 449
USA
Alabama
$ 6,560 $ 5,712 $ 3,142 $ 1,368
$ 602
Arkansas
$ 6,600 $ 5,636 $ 2,458 $ 1,227
n/a
Florida
$ 6,600 $ 5,680 $ 4,048 $ 1,152
$ 710
Mississipp $ 6,600
$ 5,147 $ 3,000 $ 1,209
$ 472
i
Gabel JR,
Whitmore H,
Stromberg S,
Tennessee
$ 6,600
$ et al. Analysis finds no nationwide increase in health 4,823 $ 3,011 $ 2,313
$1,000
insurance marketplace premiums. The Commonwealth Fund. http://www.commonweal thfund.org/publications/blog/2014/dec/zero‐inflation‐nationwide‐for‐marketplace‐prem
iums. 22 December 2014. accessed 22 January 2015.
Altman D. Why low growth in health care costs still sting. Washington Post –
Washington Wire. http://blogs.wsj.com/washwire/2015/04/08/why-low-growthin-health-costs-still-stings. April 2015.
For the budget period 2010-2019
$
800
700
$
600
500
$
400
300
200
100
Social Safety & Support Systems
Environment & Culture
Maslow’s Hammer
… "if all you have is a hammer,
everything looks like a nail."
(déformation professionnelle )
0
2010 Estimate
2015 Estimate
Congressional Budget Office. Congress of the United States. Updated budget
projections 2015-2025. March 2015. http://www.cbo.gov/sites/default/
files/cbofiles/attachments/ 49973-Udated_Budget_Projections.pdf. accessed March
2015.
By the end of 2016…
30% tied to Quality/Value-based
Outcomes
By the end of 2018
50% tied to Quality/Value-based
Outcomes
C.M.S.
… Hospital Value Based Purchasing and
Better, smarter, healthier: in historic announcement, HHS sets clear goals and
timeline for shifting Medicare reimbursements from volume to value. Centers for
Hospital Readmissions Reduction Programs
Medicare & Medicaid Services. Dept Health & Human Services. Washington,
DC. http://www.hhs.
168
Payments  1 % for fiscal year 2014 -
 Data Blocking
 Interoperability Barriers…
2015.
Base on 3 categories of HAC…
1.
2.
3.
inconsistent technical standards
divergent privacy, security policies
inefficient culture of data exchange
Central-line associated infections (sepsis)
Catheter-associated urinary tract infections,
Serious Complications, (8 types of injuries)
Report to Congress. Subcommittee on Labor, Health and Human Services,
Education And Related Agencies, Committee on Appropriations, on health
information blocking April 2015. The Office of the National Coordinator for Health
Information Technology (ONC) Department of Health and Human Services.
http://www.healthit.gov/sites/default/files
Rau J. 721 hospitals penalized for patient safety.
http://kaiserhealthnews.org/news/721-hospitals-penalized-for-patient-safety/
lh
b
 Prescribers must be enrolled to
Under Part B
 Allows Equip/Supplies @ Home
Under Part D
 Facilitates IV Medication @
Home
issue a valid Medicare Rx
 Enrollment deadline is June 1, 2015
 Manufacturers are required
to post the most up to date ePI on FDA.gov
 Pharmacists must access the
e-PI through FDA.gov
F.D.A.
169
In LA the patient MUST be…
a
danger to self or others OR
 unable to provide for basic
needs AND unable to
survive safely or guard
against serious harm.
Treatment Advocacy Center. Eliminating barriers to the treatment of mental
illness. http://www.treatmentadvocacycenter.org/legal-resources/louisiana.
… involuntary treatment is valid
under “Donaldson” only if it is
determined that such treatment is
in the patient's best interest and
that the patient lacks the capacity
to decide to seek such treatment.
SCOTUS. O’Connor v. Donaldson
1975
…“there is no constitutional basis to
civilly commit a person if she is not
dangerous to others and is capable of
surviving safely in freedom.”
Rudnick A. Depression and competence to refuse psychiatric treatment, J Med Ethics
2002;28:151-155
Elements of competent decisions…
No legal basis for “punishment”
 Little legal basis outside of
psych

Coherence of preferences
Expression … of thoughts
… of understanding
… of reasoning
… of appreciation
Rudnick A. Depression and competence to refuse psychiatric treatment, J Med Ethics
2002;28:151-155
170
Because of increasing concerns that AVMA
has received from members…
1) Veterinary pharmacology education is
encouraged;
2) Pharmacists are reminded consult the
veterinarian if there are questions about
patient care and/or use of over the counter
drugs;
3) Veterinarians are reminded to deliver
clear prescriptions in line with state rules,
to help avoid medication errors.
Must bear Veterinary Legend
Labeled with Animal’s Species
Labeled with the Animal’s/Client’s
Name
Should not be filled with drugs
approved/labeled for human use.
 Disruptive engagement
Reflections
 Personalized experiences
 Value-driven practice
171

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