TAVR Effective in Older, High-Risk Patients

Transcription

Cardiology News
w w w. e c a r d i o l o g y n e w s . c o m
VO L . 9 , N O. 5
percutaneous
coronary
intervention is on
the rise in the
United States, and
the RIVAL trial shows why. 6
Triglyceride levels are highly
responsive to changes in diet and
lifestyle; expert groups distill the
evidence and recommend limiting
added sugars to 10% of calories
consumed. 7
The outcomes
of endovascular
mitral valve
repair with the
MitraClip persisted
for 2 years in
EVEREST II. 13
Specialized, nurse-led, guidelinedriven atrial fibrillation clinics
outperformed usual care in a
Dutch study. 20
For patients with suspected
STEMI,
taking an
ambulance
to the
hospital
sped all aspects of care on the
way to the cath lab, compared
with taking any other means. 30
Implementing
Health Reform:
Dr. Gary Wiltz
explains how the
ACA provisions for
community health
centers will affect
primary care in underserved
areas. 35
A new program from Health and
Human Services, Partnership for
Patients, aims to cut
readmissions and preventable
injuries. 36
probably be seen
‘asThisonewillof the
biggest steps
in cardiovascular medicine
... in our lifetime.
’
B Y P AT R I C E W E N D L I N G
FROM THE ANNUAL MEETING OF THE
AMERICAN COLLEGE OF CARDIOLOGY
NEW ORLEANS – Transcatheter aor-
tic valve replacement was associated
with the same survival rates at 1 year as
was conventional surgery in older, highrisk patients with severe, symptomatic
aortic stenosis in the PARTNER trial.
All-cause mortality at 30 days favored
transcatheter aortic valve replacement
(TAVR) at 3.4%, compared with 6.5% for
open surgery, and was similar at 1 year,
with rates of 24% and 27%, respectively.
The difference at 1 year reached the trial’s prespecified noninferiority margin
with a P value of .001.
“We already learned from the previous cohort that TAVR is the standard of
care for patients who can’t tolerate
surgery. So this [finding] opens up a
new set of patients who may very well
benefit as much with TAVR as with the
gold standard surgery,” coprincipal investigator Dr. Craig B. Smith said at the
meeting.
The stroke rate with transcatheter aortic valve replacement in the industry-
N ASEEM M ILLER /E LSEVIER G LOBAL M EDICAL N EWS
Using radial
access for
TAVR Effective in Older,
High-Risk Patients
This finding opens up a new set of patients who may “benefit as much with TAVR
as with the gold standard surgery,” said Dr. Craig B. Smith of the PARTNER trial.
sponsored PARTNER (Placement of
Aortic Transcatheter Valve) trial, however, was twice the rate observed with
surgery.
Stroke plus transient ischemic attack
(TIA) rates were significantly more frequent with TAVR than with surgery at
STICH Supports Surgery for
Heart Failure With Ischemia
NEW ORLEANS – Although the addi-
tion of coronary bypass surgery to aggressive medical care failed to significantly reduce the primary end point of
all-cause death in patients with coronary
artery disease and heart failure in the
Surgical Treatment for Ischemic Heart
Failure trial, several experts characterized
the trial as a success.
STICH investigator Dr. Eric Velazquez
said the data support coronary artery dis-
CARDIOLOGY NEWS
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W H AT ’ S N E W S
M AY 2 0 1 1
T he Leading Inde p endent Ne wspaper for the Cardiologist
ease assessment in all patients presenting
with heart failure.
“We have known for decades that, in
patients with left ventricular dysfunction and ischemia, left ventricular dysfunction is the major cause of mortality.
And you have now proven the concept,”
Dr. Bernard Gersch said. “This is an incredible trial. It’s a stunning achievement, and very difficult to do.”
After 6 years of follow-up among 1,202
randomized patients, there was a nonsignificant reduction in Kaplan Meier
all-cause mortality rates with coronary
artery bypass grafting plus medical ther-
both 30 days (5.5% vs. 2.4%) and 1 year
(8.3% vs. 4.3%). When only major
strokes were compared, the difference
was not significant between TAVR and
surgery at 30 days (3.8% vs. 2.1%) or 1
year (5.1% vs. 2.4%), said Dr. Smith,
See TAVR page 14
As-treated analysis showed a
reduction in all-cause death
risk of 30% with CABG.
apy, from 46% to 41%, Dr. Velazquez reported at the meeting.
After adjustment of this outcome for
prespecified baseline variables, the hazard ratio was 0.82 and P value .039.
Among key secondary outcomes,
however, bypass surgery significantly reduced Kaplan-Meier cardiovascular mortality event rates, from 39% to 32%, and
crude cardiovascular mortality rates,
from 33% to 28%.
Both Kaplan-Meier event rates and
crude rates of death or cardiovascular
hospitalization were significantly reSee STICH page 8
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NEWS
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M AY 2 0 1 1 • C A R D I O L O G Y N E W S
HEART OF THE MATTER
Coronary Revascularization
In Ischemic Heart Disease
Cardiology News
President, IMNG Alan J. Imhoff
Editor in Chief Mary Jo M. Dales
Executive Director, Operations Jim Chicca
Executive Editors Denise Fulton, Kathy Scarbeck
Director, Production/Manufacturing Yvonne
Evans Struss
Production Manager Judi Sheffer
Production Specialists Maria Aquino, Anthony
Draper, Rebecca Slebodnik
Managing Editor Catherine Hackett
oronary revascularization using by- random assignment or because they were
pass grafting with arterial or venous crossed over to surgery (620) were comconduits has been with us since pared with those patients who remained
1968 when Dr. Rene Favaloro performed on medical therapy (592), the effects of
the first saphenous venous graft for the surgery were even more impressive, with
treatment of angina pectoris ( J. Thorac. a 30% decrease in all-cause mortality (P
Cardiovasc. Surg. 1969;58:178-85). Al- less than .001). The patients included in
though it is clear that coronary artery by- STICH were severely symptomatic, alpass grafting (CABG) has been effective in most all with significant angina and 37%
decreasing symptomatic angina, with few in NYHA HF class III/IV with a mean
exceptions there has been little
ejection fraction of 27%.
to support its benefit in proSurgery carried an early uplonging life. One of those exfront mortality risk of approxceptions was identified in a subimately 4%, which took about
group of the initial Coronary
2 years to overcome.
Artery Surgery Study carried
One interesting additional
out in the 1980s and sponsored
aspect of STICH was the viaby the National Heart, Lung,
bility study carried out in a
and Blood Institute (N. Engl. J.
subset of 601 patients using eiMed. 1985;312:1665-71). Of the
ther dobutamine echocardio780 patients with chronic stable
grams or SPECT stress testSIDNEY
angina randomized to mediing. Although patients who
cine only or CABG, there was G O L D S T E I N , M . D . demonstrated viability had a
a significant decrease in both
better outcome, viability did
angina and mortality in a subgroup of 160 not define those patients who would benpatients with ejection fractions below 50%, efit by CABG (N. Engl. J. Med.
primarily in patients with triple-vessel dis- 2011;364:1617-25).
ease.
The “backstory” of the STICH trial was
Since that report in 1985, there have the failure of the U.S. cardiothoracic
been no clinical mortality trials examining surgery centers to participate in it in a sigthe clinical benefit of CABG surgery in pa- nificant way. A total of 26 countries were
tients with ischemic heart failure. A ran- required to achieve the 2,136 patients endomized trial to evaluate the benefit of rolled in the total STICH trial, and only
surgical ventricular reconstruction plus 307 patients (14%) were American. The
CABG, compared with CABG alone, failed failure of the academic and large clinical
to observe any benefit (N. Engl. J. Med. centers to grasp the importance of this tri2009:360;1705-17).
al, and their reluctance to participate, was
The suggestion that CABG could im- unfortunate.
prove ventricular function is based on the
The results of STICH indicate that the
observations by Dr. Shahbudin Rahim- addition of CABG to patients already retoola in the 1980s in studies showing im- ceiving optimal medical therapy provides
proved function in patients before and af- a significant mortality and morbidity benter CABG (Am. Heart J. 1989;117:211-21). efit. Unfortunately, viability studies do not
He proposed the concept that areas of “hi- provide helpful information in regard to
bernating myocardium” exist in the is- the optimal selection of patients for CABG
chemic ventricle that can be revived by in ischemic heart failure. That decision aprestoring its blood supply by CABG. But pears to depend upon the availability of acto a large degree, patients with ischemic ceptable target vessels. But the data do
heart failure have not been a prime target support CABG, performed with an acfor CABG, and attempts to show clinical ceptable risk in experienced hands, as probenefit in symptomatic improvement in viding long-term benefits for heart failure
heart failure has not been explored.
patients.
The recent report of the Surgical TreatRevascularization provides an addiment for Ischemic Heart Failure (STICH) tional mode of therapy for the treatment
trial has provided important information of patients with symptomatic ischemic
supporting the mortality and morbidity heart failure, which could become a pobenefit of revascularization in patients tential therapeutic target for percutaneous
with symptomatic ischemic heart failure intervention in patients with the appro(N. Engl. J. Med. 2011;364:1607-16). This priate anatomy.
■
study, also supported by NHLBI, was carried out in 26 countries throughout the DR. GOLDSTEIN, medical editor of
world. In the 1,212 patients randomized CARDIOLOGY NEWS, is professor of
to standard medical therapy alone, com- medicine at Wayne State University and
pared with medical therapy plus CABG, division head emeritus of cardiovascular
there was no significant benefit observed medicine at Henry Ford Hospital, both in
in the CABG patients in all-cause mortal- Detroit. He is chair of the data safety
ity, but there was a 19% decrease in car- monitoring committee for the STICH trial,
diovascular mortality (P = .05) over a 3- sponsored by NHLBI and Abbott
year mean follow-up, and a 26% decrease Laboratories. Dr. Goldstein also serves on
in all-cause mortality and cardiovascular such committees for other National Institutes
hospitalization (P less than .001). When of Health trials and for several
patients who received CABG either by pharmaceutical companies.
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4
NEWS
VITALS
VADs ‘Reasonable’ as Bridge to Retransplantation
Major Finding: Among patients retransplanted at least a
year after an initial transplantation, median survival was 7
years and did not differ between those bridged with a VAD
and those who did not receive any mechanical circulatory
support.
Data Source: A retrospective review of 1,535 patients who
underwent cardiac retransplantation during 1982-2009.
Disclosures: Dr. Morales disclosed having relationships
with Berlin Heart Inc., Syncardia Systems Inc., and CircuLite Inc. as an investigator and/or consultant.
BY SUSAN LONDON
FROM THE ANNUAL MEETING
OF THE INTERNATIONAL
SOCIETY FOR HEART AND
LUNG TRANSPLANTATION
SAN DIEGO – Ventricular as-
sist devices appear to be a “reasonable strategy” for supporting certain patients who have
failing cardiac grafts and are
waiting for a new heart, concludes a retrospective review of
more than 1,500 patients who
had a second transplant.
In the group who had retransplantation at least 1 year after their first transplantation,
median survival was about 7
years. There was no difference
between patients bridged with a
ventricular assist device (VAD)
and those who did not have
bridging with any type of mechanical circulatory support, according to results reported at
the meeting.
But survival was poor for
those who were bridged after
any interval with extracorporeal membrane oxygenation
(ECMO) and for those who underwent retransplantation be-
NEWS
M AY 2 0 1 1 • W W W. E C A R D I O L O G Y N E W S . C O M
cause they had primary graft failure or
a hyperacute rejection, regardless of
whether they were mechanically supported.
“The use of ECMO to bridge any patient to retransplantation does not appear judicious, nor does the use of mechanical circulatory support to bridge
patients with primary graft failure or hyperacute rejection to retransplantation,”
said coinvestigator Dr. David L.S.
Morales of the departments of surgery
and pediatrics at the Texas Children’s
Hospital in Houston.
“However, the use of VADs to bridge
patients to transplant after a year could
be a reasonable strategy,” he said.
Although mechanical circulatory support is widely accepted for bridging patients to initial heart transplantation, its
use for bridging to retransplantation has
not been well studied. The investigators
therefore took a closer look at this issue,
analyzing data from the United Network
for Organ Sharing (UNOS) database for
1,535 patients who underwent cardiac retransplantation during 1982-2009.
Results showed that just 8% of the patients were bridged to retransplantation,
with a VAD in about two-thirds of cas-
es and ECMO in the other third. The
mean age was 41 years in the former and
35 years in the latter, with children
(younger than age 18) comprising 15%
and 35%, respectively.
The patients bridged to retransplantation were significantly more likely than
were their nonbridged counterparts to
have primary graft failure or hyperacute
rejection (54% vs. 11%) and significantly less likely to have chronic rejection
(16% vs. 63%).
And the bridged patients by and large
underwent retransplantation early, with
64% in the VAD group and 76% in the
5
ECMO group retransplanted within 3
months of their primary transplantation, compared with just 12% of their
nonbridged peers.
“Regardless of mechanical circulatory
support, patients retransplanted for primary graft failure or hyperacute rejection do not do well,” Dr. Morales commented. Specifically, in patients with
these indications for retransplantation,
the 1-year mortality rate was 83%, with
essentially no difference according to
whether they received bridging or the
type received.
In the entire study population, median overall survival after retransplantation
was 6.1 years in nonbridged patients,
significantly longer than the 1.5 years in
VAD-bridged patients and the 30 days in
ECMO-bridged patients.
But when analyses were restricted to
patients who underwent retransplantation at least 1 year after primary transplantation, median survival was similar
in nonbridged and VAD-bridged patients,
at 7.0 and 6.9 years. Compared with
those groups, however, survival was sig‘The use of ECMO
to bridge any
patient to
retransplantation
does not appear
judicious.’
DR. MORALES
nificantly shorter – just 6 months – in the
ECMO group.
“Patients bridged to retransplant with
ECMO have poor outcomes regardless of
timing or indication,” Dr. Morales concluded of the findings. “And all patients
retransplanted for hyperacute rejection
or primary graft failure do poorly, regardless of mechanical circulatory support,” he said. “However, patients who
are bridged with a VAD to retransplant
that is done a year post–primary transplant do have similar outcomes as compared to retransplant patients without
mechanical circulatory support.”
As for study limitations, “it is very important to note that we do not know the
number of patients placed on mechanical circulatory support as a bridge to
transplant who died while on support,”
he pointed out.
Despite the more favorable findings
for VAD bridging, his pediatric patients
needing retransplantation in adolescence
often have chronic vasculopathy in their
graft, Dr. Morales said. “They are a very,
very difficult group to support with mechanical support with LVADs because we
have to continue the immunosuppression,” and the patients often die from infections as a result.
“It’s one of the reasons I’m interested in the total artificial heart, because
the ability to take the heart out completely and stop immunosuppression, I
think, will help bridge those patients,”
he commented. “The total artificial
heart has lasted in patients for quite a
long period of time, and I think eventually will start to be used maybe as a
bridge to destination, as it was originally
intended.”
■
6
NEWS
RIVAL Results Support Radial PCI Access TG/HDL
NEW ORLEANS – With broader use of
radial-artery access for percutaneous
coronary interventions already gaining
momentum in the United States, results
from the largest study by far to compare
radial- and femoral-artery approaches
may give a boost to the radial camp.
Although results from the Radial vs.
Femoral Access for Coronary Intervention (RIVAL) trial showed primary end
point equivalence for the two arterial access strategies in a 7,000-patient randomized trial, radial access may have
won by not losing.
“The similar efficacy helps the radial
approach, because there was a persistent
uncertainty whether it really was as good
as femoral, Dr. Sanjit S. Jolly, lead investigator of the trial, said at the meeting.
Also, the study’s
findings “in highvolume centers and
in patients with STelevation MIs will
produce more momentum for a
shift,” he predicted.
Interventional
cardiologists in
some countries
have embraced radial-artery access for
placing coronary catheters into patients.
Dr. Jolly, a cardiologist at McMaster University in Hamilton, Ontario, cited rates
exceeding 90% in France and 95% in
Canada. But just last year, U.S. cardiologists used radial access for a mere 4% of
their coronary catheterizations, based on
data collected by the National Cardiovascular Data Registry, said Dr. Edward J. McNulty, an interventional cardiologist at
Kaiser Permanente San Francisco.
The U.S. numbers have a long way to go
before they start to resemble what is now
routine in many other places, but some
clues at the meeting suggest they began
trending up even before Dr. Jolly delivered
the RIVAL results. For example, in a separate talk, Dr. Akshay Khandelwal, director of outpatient cardiovascular services at
Henry Ford Hospital, Detroit, recounted
his personal experience introducing radial access into his practice starting about 18
months ago. By March, roughly 75% of
his procedures used radial access.
“At Columbia [University’s Center for
Interventional Vascular Therapy] the frequency of radial access has increased,”
agreed Dr. Martin B. Leon, who directs
the center in New York. “It was in single
digits in 2010, but now it’s more than
20%,” he said.
Part of this shift is driven by physicians
who believe they might achieve better results, with less bleeding and access site
complications, and part comes from patient demand because most patients find
the radial approach more comfortable.
“Patients like it, and I think that will
drive the option,” Dr. McNulty said. Another important factor is cost.
“There is a recent trend in the U.S. to do
VITALS
BY MITCHEL L. ZOLER
Major Finding: Patients with acute coronary syndrome undergoing PCI had
similar rates of death, MI, stroke, or major bleeds not related to coronary
artery bypass surgery during the 30 days following their intervention.
Data Source: The Radial vs Femoral Access for Coronary Intervention (RIVAL)
trial, which enrolled 7,021 patients at 158 centers in 32 countries.
Disclosures: Dr. Jolly has received consultant fees or honoraria from
Boehringer-Ingelheim, GlaxoSmithKline, and Sanofi-Aventis, and research
grants from Merck. Dr. McNulty said he had no disclosures. Dr. Leon said he
has been an unpaid consultant to Abbott, Boston Scientific, and Medtronic.
Dr. Stone said that he has been a consultant to numerous pharmaceutical and
device companies, including Lilly, BMS/Sanofi, Medtronic, AstraZeneca, Vascular Solutions, Gilead, The Medicines Company, Abbott Vascular, Boston Scientific, Ortho-McNeil, Edwards, and Merck; interests in Micardia, Biostar I and
II, FlowCardia, Embrella, Caliber, Medfocus I and II, Accelerator, and Access
Closure; and received research funds from InfraReDx, TherOx, Atrium, and Volcano. Dr. Khandelwal said he had no disclosures.
more outpatient angioplasty in low-risk
and stable patients,” Dr. Leon said, and radial access makes same-day discharge feasible much more often than does femoral
access. “If that trend continues ... you can
imagine that the radial approach will
The findings in
be attractive.”
high-volume
Until RIVAL,
centers and in
studies of radial
ST-elevation MI
and femoral entry
patients will add
had been too small
more momentum
for a definitive
for a shift.
comparison. “Our
hypothesis was a
DR. JOLLY
paradigm shift”
that radial would result in a significantly
reduced rate of a primary outcome of
death, MI, stroke, and bleeding not related to coronary bypass during the 30 days
following PCI in patients with acute coronary syndrome. (Dr. Jolly admitted that in
his own practice he performs about 80%
of his cases via the wrist.)
The study enrolled 7,021 patients at 158 sites in
32 countries, piggybacked onto an
acute coronary
syndrome trial that
tested clopidogrel
and aspirin (CURRENT–OASIS 7).
The patient’s average age was 62 years, nearly three-quarters were men, and 45% had unstable
angina, with the remaining patients split
evenly between STEMI and non-STEMI.
The combined end point occurred in
roughly 4% of patients in both groups.
The rate of major bleeds not linked with
bypass also occurred at roughly similar
rates, just under 1%, in both the radial and
femoral groups, an unexpected failure
for the radial approach. “We expected to
see a large decrease in major bleeds” in
the radial access patients, Dr. Jolly said.
Concurrently with his report, the results were published online (Lancet 2011
[doi:10.1016/S0140-6736(11)60404-2]).
The only prespecified end point where
radial access outperformed femoral access was in the secondary measure of
major vascular access site complications:
large hematomas, pseudoaneurysms requiring closure, arteriovenous fistula,
and other vascular surgery related to
the access site. In the radial group, this
occurred in 1.4% of patients and in 3.7%
of those in the femoral group, for a significant 63% relative risk reduction.
These complications “don’t cause
deaths,” Jolly admitted, “but they are
important to patients. They can cause
significant discomfort.”
But others minimized the importance
of access site complications.
“Access site hematomas don’t impact
mortality. Large bleeds are associated with
mortality. Gastrointestinal bleeds, genitourinary bleeds, and intracranial bleeds
really impact mortality,” commented Dr.
Gregg W. Stone, professor of medicine
and director of cardiovascular research
and education at Columbia. (He noted
that he performs 99% of his coronary interventions via the thigh.)
Aside from the basic findings, perhaps
the most notable results focused on the
importance of operator and center experience. One prespecified subgroup
analysis split the
The RIVAL results participating cenare unlikely to
ters into tertiles
change practice.
based on their anWhat may change nual volume of rapractice,
dial-access procehowever, is
dures. The highest
patient comfort.
tertile
centers
showed a signifiDR. STONE
cant reduction in
the study’s primary end point when using radial access.
Also, focusing on outcomes in STEMI
patients showed that, in this subgroup,
radial access led to a significant reduction
in the primary end point, an effect that
Dr. Jolly speculated related to individual
operator experience. Only the most experienced operators were comfortable
treating these patients radially, he said.
The subgroup findings convinced
some cardiologists that RIVAL, in sum,
scored a triumph for radial access. “At the
least, radial access reduced bleeding, and
at best it improved the hard outcomes of
death and MI” at the high-volume centers, noted Dr. Khandelwal in an interview. “Perhaps our goal should be to emulate the operators in the top tertile.”
But Dr. Stone had the take of a
femoral-artery enthusiast. “I don’t think
in and of itself these data will change
practice. What might change practice,”
he conceded, “is patient comfort.” ■
Ratio Predicts
10-Year Events
B Y C A R O L I N E H E LW I C K
NEW ORLEANS – In the 10-year
follow-up of a study in patients with
stable coronary artery disease, the ratio of triglycerides to high-density
lipoproteins was highly predictive of
major adverse cardiovascular events.
Dr. Raul D. Santos of the Heart Institute at the University of Sao Paulo
Medical School Hospital in Brazil reported the analysis, which was part of
the Medical, Angioplasty, or Surgery
Study (MASS-II). That study compared the long-term effects of medical
treatment, angioplasty, or surgical
strategies in patients with stable angina symptoms of multivessel CAD and
preserved ventricular function, determining that surgery was the optimal
approach in this patient subset ( J. Am.
Coll. Cardiol. 2004;43:1743-51)
“After 10 years of follow-up of stable CAD patients in MASS-II, the
TG[triglyceride]/HDL ratio was the
only lipid parameter independently
associated” with major adverse cardiovascular events (MACE), he said.
The study randomly assigned 611
patients to coronary artery bypass
grafting, percutaneous coronary intervention, or medical therapy. Lipidmodifying therapies were equally instituted in all study patient groups.
Levels of total, HDL, non-HDL, and
LDL cholesterol, as well as
LDL/HDL and TG/HDL ratios,
were divided into distribution quartiles. Mean levels of lipids were 150
mg/dL for TG, 37 mg/dL for HDL
cholesterol, and 140 mg/dL for LDL
cholesterol.
In the MASS-II patients followed for
an average of 11.4 years (range 9-15
years), MACE were observed in 42% of
the PCI arm, 59% of the medical therapy arm, and 33% of the CABG arm.
After adjustment for confounders,
the investigators found the following
factors to be independently associated with MACE: age greater than 65
years, randomization to CABG versus
medical therapy, systemic arterial hypertension, and TG/HDL ratio determined at 6 months.
For the TG/HDL ratio, the hazard
ratio for the occurrence of MACE,
comparing the highest and lowest
quartiles of the ratios, was significant at 1.57. No association was
found between MACE and other
plasma lipids.
In patients with a TG/HDL ratio
above 6, only about 45% of patients
were free of MACE at 10 years, compared with more than 70% for those
with a TG/HDL ratio of less than 3.
Dr. Santos has served on the speakers bureaus of Novartis, Merck, Biolab, and Bristol-Myers Squibb.
■
NEWS
7
AHA Targets High Triglycerides in Statement
BY JENNIE SMITH
FROM CIRCULATION
riglyceride levels, which play a
large role in both atherosclerotic
risk and metabolic health, are
highly responsive to decreases in dietary
sugar intake and saturated and trans fat
intake, along with
increases
in
omega-3 acid intake and exercise,
according to a scientific statement
from the American
Heart Association.
“What’s new is
that we point out
that triglycerides
might be considered a marker for metabolic health,” said Dr. Neil J. Stone of
Northwestern University, Chicago, vice
chair of the statement’s writing group, in
an interview. “If you have a country
where you’re seeing more obesity and
more diabetes, it becomes important for
people to start asking themselves ‘are
there signs that I should be doing something different?’ and this is one,” he said.
T
The scientific advisory, citing some
528 sources, was not presented as a clinical guideline so much as a distillation of
30 years worth of evidence on the complex relationship among lifestyle factors,
triglycerides, and cardiovascular and
metabolic health (Circulation 2011
[doi:10.1161/CIR. 0b013e3182 160726]).
However, the
‘What’s
statement’s aunew is ...
thors, led by Dr.
triglycerides
Michael Miller, dimight be
rector of the Cenconsidered a
ter for Preventive
marker for
Cardiology at the
metabolic health.’ University
of
Maryland, BaltiDR. STONE
more, included a
number of recommendations on diagnosing and treating
hypertriglyceridemia, focusing on dietary
and lifestyle changes.
The statement emphasizes the “increasingly crucial role” of triglycerides in
the evaluation and management of cardiovascular disease, and the importance
of diet – including consumption of sugars common in beverages – in contributing to unhealthy triglyceride levels.
E DITORIAL A DVISORY B OARD
SIDNEY GOLDSTEIN, M.D., Wayne State
ILEANA L. PIÑA, M.D., Case Western
University, Detroit
Reserve University, Cleveland
OTELIO RANDALL, M.D., Howard University,
Washington
RITA F. REDBERG, M.D., University of
California, San Francisco
HOWARD (HANK) ROSMAN, M.D., St. John
Hospital and Medical Center, Detroit
THOMAS J. RYAN, M.D., Boston University
HANI N. SABBAH, PH.D., Henry Ford
Hospital, Detroit
LESLIE ANNE SAXON, M.D., University of
Southern California, Los Angeles
DAVID H. SPODICK, M.D., University of
Massachusetts, Worcester
RICHARD M. STEINGART, M.D., Memorial
Sloan Kettering Cancer Center, New York
PAUL D. THOMPSON, M.D., Hartford
(Conn.) Hospital
CHRISTOPHER J. WHITE, M.D., Oschner
Clinic Foundation, New Orleans
ROBERTA WILLIAMS, M.D., University of
Southern California, Los Angeles
MEDICAL EDITOR
ERIC R. BATES, M.D., University of
Michigan, Ann Arbor
GEORGE BELLER, M.D., University of
Virginia, Charlottesville
ROBERT M. CALIFF, M.D., Duke University,
Durham, N.C.
PRAKASH C. DEEDWANIA, M.D., University
of California, San Francisco, Fresno
JOHN FLACK, M.D., Wayne State
University, Detroit
ANTONIO M. GOTTO JR., M.D., Cornell
University, New York
DAVID L. HAYES, M.D., Mayo Clinic,
Rochester, Minn.
DAVID R. HOLMES JR., M.D., Mayo Clinic,
Rochester, Minn.
BARRY M. MASSIE, M.D., University of
California, San Francisco
CHRISTOPHER M. O’CONNOR, M.D., Duke
University, Durham, N.C.
GEORGE J. PHILIPPIDES, M.D., Boston
University
Want Daily
Medical News
and Commentary?
Follow us on
Twitter.com/MedicalNewsNet
Reductions of 50% or more are achievable without the use of medication – indeed medication is not a widely accepted
strategy for reducing triglycerides except
among people with extremely high values
of greater than 500 mg/dL. “The subject
of medication and triglycerides is still
lacking crucial clinical trial evidence,” Dr.
Miller and colleagues wrote in their analysis, noting that certain medications, including hormonal treatments, can also
contribute to elevated triglycerides.
About a third of American adults have
elevated triglyceride levels, which are defined as fasting triglyceride of 150 mg/dL
or higher. The authors recommended
that optimal fasting triglyceride levels
now be defined as 100 mg/dL – and that
clinicians screen initially for nonfasting
triglyceride, defining normal at below
200 mg/dL. People with higher nonfasting levels may then be further screened
for fasting triglyceride.
The new dietary recommendations include restricting added dietary sugar to
5%-10% of calories consumed. In support of this, the authors cited a study of
6,113 U.S. adults showing that the lowest triglyceride levels were observed
when added sugar represented less than
10% of total energy, and that higher
triglyceride levels corresponded with
added sugar accounting for a greater
proportion of energy intake ( JAMA
2010;303:1490-7).
The authors singled out fructose, a type
of dietary sugar increasingly common in
processed foods and soft drinks, as particularly problematic. Fructose in excess of
100 g/day, and possibly in excess of 50
g/day, has been associated with raised
triglyceride levels. A typical can of cola or
lemon-lime soda contains more than 20
grams of fructose, the authors noted.
Dr. Miller and his colleagues advocated weight loss of 5%-10% of body
weight, which is associated with a 20%
reduction in triglycerides, and regular
aerobic exercise, to reduce triglyceride
levels closer to optimal.
They also promoted increasing dietary
fiber, keeping saturated fat below 7% of
calories, eliminating trans fat from the
diet, and increasing omega-3 polyunsaturated fatty acid consumption in the
form of marine fish, though the authors
said more research was needed to determine whether supplementing with fishoil capsules provided equivalent benefits.
Complete abstinence from alcohol was
also recommended for people with very
high triglycerides.
“Overall, optimization of nutritionrelated practices can result in a marked
triglyceride-lowering effect that ranges
between 20% and 50%,” they concluded.
Funding for the scientific advisory
statement was provided by the American
Heart Association. Dr. Miller declared no
conflicts of interest affecting the drafting
of the statement. However, Dr. Stone
and the report’s third author, Dr. Christie
Ballantyne of Baylor College of Medicine in Houston, disclosed support from
pharmaceutical industry sources. Other
coauthors and some reviewers disclosed
additional support from pharmaceutical
and agricultural firms.
■
Advice Healthful, but Evidence Weak
VIEW ON THE NEWS
The advisory recommends restricting added
dietary sugar to 5%-10% of calories consumed.
t is interesting that the AHA statement recommends intensive dietary and weight loss
strategies to achieve an
optimal fasting triglyceride level below 100
mg/dL. While epidemiological studies have
shown triglycerides to be
an independent risk factor
for cardiovascular disease,
most of the residual risk
associated with hypertriglyceridemia tends to disappear after controlling for HDL cholesterol.
Current National Cholesterol Education Program guidelines do not
identify triglycerides as a specific
target for therapy, except when levels are extremely elevated (above
500 mg/dL), due to increased risk
for pancreatitis. Drugs that reduce
triglycerides may also affect other
lipoprotein concentrations, and clinical trial evidence demonstrating
that triglyceride reduction decreases
cardiovascular risk is lacking. For
example, an analysis of the VA-HIT
trial showed that coronary event reduction was due to increases in
HDL cholesterol achieved with the
study drug; although triglycerides
I
were also reduced, they were not associated with a decrease in coronary events ( JAMA
2001;285:1585-91).
Thus, while the AHA
statement’s stringent dietary and lifestyle recommendations should have
healthful effects, the evidence linking the expected decrease in triglycerides to cardiovascular
benefit is weak.
Perhaps the high prevalence of
hypertriglyceridemia in patients
with the metabolic syndrome accounts for the intensity of the recommended lifestyle measures, in
which case I applaud this attempt to
address rising rates of overweight
and obesity.
ANTONIO M. GOTTO JR., M.D., is the
Stephen and Suzanne Weiss Dean and
Professor of Medicine at Weill Cornell
Medical College, New York. He is a
consultant for AstraZeneca, KOWA,
and Merck; sits on the Board of
Directors for Aegerion Pharmaceuticals
and Arisaph Pharmaceuticals; and is a
member of advisory boards for DuPont
and Vatera Capital.
NEWS
Assess All HF Patients for CAD
STICH from page 1
duced with bypass, from 68% to 58%.
The secondary outcomes remained significant after adjustment.
As anticipated, CABG was associated
with an early risk of death that took 2
years to abate, observed Dr. Velazquez,
director of the cardiac diagnostic unit
and echocardiography laboratories at
Duke University Medical Center in
Durham, N.C.
In all, 17% of the 602 patients randomly assigned to
medical therapy
alone crossed over
to receive bypass
surgery before the
end of follow-up,
and 9% of the 610
patients assigned
to CABG received
medical treatment
only.
When the data were analyzed on an
as-treated basis from the resulting 592
medical therapy and 620 CABG patients,
the addition of bypass surgery significantly reduced deaths from any cause by
22%, from 49% to 38% for a significant
risk reduction of 30%, Dr. Velazquez
said.
The researchers then performed a perprotocol analysis of the 537 medical
therapy patients who did not cross over
to CABG during the first year of followup and the 555 CABG patients who actually underwent the procedure. Once
again, the primary outcome of all-cause
mortality was significantly reduced, this
time from 48% to 37%, giving a risk reduction of 24%.
Current guidelines do not support
evaluation of coronary artery disease in
patients with heart failure who present
without chest pain, resulting in a lost
opportunity for clinicians and leaving
the exact number of patients for whom
the results of STICH would apply unclear, Dr. Velazquez commented in an
interview.
“The guidelines need to recognize that
coronary artery disease presents in many
ways in our patients and that evaluation
of coronary artery disease is important
not only for consideration of bypass
surgery, but also to
optimize medical
With these
therapy and CAD
results, ‘patients
medication,” he
should be
said.
informed of the
Despite
the
short-term risk for
medical adherence
a potential longand operative reterm benefit.’
sults achieved in
the trial, STICHDR. VELAZQUEZ
like patients remain at substantial risk with a 5-year
mortality rate of 40% with medication
only.
“Decision making for CABG is complex,” Dr. Velazquez said. “It should be
individualized and now with the results
of the STICH trial, patients should be informed of the short-term risk for a potential long-term benefit.”
Future analyses of the mechanisms of
benefit associated with bypass surgery
will prove important in determining
whether the benefit is from an improvement in diastolic dysfunction or perhaps
a reduction in sudden cardiac death or recurrent infarction, added Dr. Gersch,
professor of medicine at the Mayo Clinic, Rochester, Minn.
Dr. Steven Bolling said he agreed that
STICH is a landmark trial and called the
difference in outcomes between the in-
tention-to-treat and actual treatment
analyses “interesting.” Yet, “if the biological effect that our patients feel is really what [guides the] treatment they receive, then under that analysis, of
course, as a surgeon, you must conclude that patients with left-ventricular
dysfunction should receive coronary
artery bypass,” added Dr. Bolling, professor of surgery and director of the mitral valve clinic at the University of
Michigan, Ann Arbor.
Patients in STICH were randomized
at 99 medical centers in 22 countries and
had a left ventricular ejection fraction of
35% or less and coronary artery disease
suitable for CABG. The median time to
CABG was 10 days.
In all, 91% of patients received at least
one arterial conduit, 86% received at
least one venous conduit, and 88% received a total of at least two grafts. The
median hospital stay was 9 days (range
7-13).
Only 5 of the 1,202 patients were not
evaluable with a median follow-up of 40
months. The overall duration of followup was 56 months.
The STICH results were published online concurrently with Dr. Velazquez’s
presentation (N. Engl. J. Med. 2011
[10.1056/NEJMa1100356]).
The STICH Extension study will test
the durability of the current results at 10
years.
STICH was supported by grants from
the National Heart, Lung, and Blood Institute (90%) and Abbott Laboratories
(2%).
Dr. Velazquez reported receiving consulting fees from Novartis, Gilead, and
Boehringer-Ingelheim Pharmaceuticals.
Two of his coauthors reported similar relationships with Medtronic, St. Jude
Medical, Biotronik, CardioMEMS, and
Novartis.
Dr. Gersch has financial relationships
Myocardial Viability Failed to Predict Outcomes in STICH
yocardial viability failed to predict a significant survival benefit
from coronary bypass surgery in patients with coronary artery disease
and left ventricular dysfunction in the
STICH Viability
substudy.
The data are
surprising and
call into question the longstanding practice of assessing
myocardial viability as a means
to predict clinical benefit from CABG.
The substudy included 610 of the
1,212 patients in the STICH trial who
underwent baseline myocardial viability testing using SPECT or dobutamine
echocardiography, or both, and were
randomly assigned to aggressive medical therapy with or without CABG.
At a median follow-up of 5 years,
51% of patients without viable myocardium and 37% with viable myocardium died. The presence of viable
M
myocardium significantly reduced the
risk of all-cause mortality by 36%, but
the survival advantage lost statistical
significance in a multivariable analysis
that included other prognostic variables, Dr. Robert
Bonow reported
at the meeting.
‘Myocardial
The secondary
viability ... should
outcome of carnot be the
deciding factor in diovascular morselecting the best tality was also
significantly lowtherapy.’
er in patients
with myocardial
DR. BONOW
viability compared with those without, at 29% and
43%, respectively, but once again, the
association lost significance in multivariable analysis.
Notably, the secondary end point of
death plus cardiovascular hospitalization retained significance in multivariable analysis in favor of patients with
myocardial viability, occurring in 63%
of patients with viable myocardium
and 82% of those without.
There was no significant interaction,
however, between myocardial viability
status and medical versus surgical
treatment with respect to mortality,
whether assessed according to treatment assigned or to the treatment actually received, said Dr. Bonow, professor of cardiology at Northwestern
University in Chicago. Five-year allcause mortality rates among the 114
patients without myocardial viability
were 56% with medical therapy and
42% with CABG. Among the 487 patients with myocardial viability the
rates were 35% vs. 31%, respectively.
“The lack of interaction between
myocardial viability and benefit from
CABG in this study indicates that assessment of myocardial viability, independent of other relevant variables,
should not be the deciding factor in selecting the best therapy for patients
with ischemic left ventricular function,” he said.
STICH Viability was supported by
grants from the NHLBI and Abbott
Laboratories. Dr. Bonow had no relevant disclosures.
–Patrice Wendling
with several device and pharmaceutical
companies, including Boston Scientific,
Merck, Ortho-McNeil, and Abbott Laboratories. Dr. Bolling disclosed that has
received remuneration from Edwards
Lifesciences.
■
To view a video
interview with Dr.
Velazquez, scan this
QR code or visit
www.youtube.com/
watch?v=IKu_
tgHgEbA.
Value of CABG
Confirmed
VIEW ON THE NEWS
8
ndoubtedly, the impact of
CABG on survival in the
STICH trial was underestimated
by the performance of statistical
analysis on an intent-to-treat basis. There was a 17% crossover
rate from the medical arm to the
surgical revascularization arm,
which reduced the importance
of surgery in these patients. Patients with low ejection fraction
and chronic angina do benefit
from CABG (Ann. Thorac. Surg.
2007;83:2029-35). Despite the frequent presence of multiple comorbidities, we have reported
90% perioperative survival in
this patient population (Cardiol.
Clin. 1995 Feb;13:35-42).
Our experience echoes the
secondary end point of the
STICH trial – that patients have
reduced long-term mortality
and need for future hospitalizations after undergoing CABG
for ischemic heart failure.
Aggressive medical optimization has significantly improved
long-term mortality, but the underlying disease process of ischemia is largely unaltered.
Likewise, just which patients
with ischemic left ventricular
heart failure who have the most
to gain from CABG has yet to be
defined. An interesting, yet
counterintuitive, finding of the
STICH trial was that assessment
of myocardial viability with respect to treatment groups
showed no significant impact on
mortality. In general, patients
with viable myocardium fared
better both in the medical and
medical plus CABG group,
which could be an effect of underlying heart function rather
than any therapeutic effects of
either arm. Despite its shortcomings, the STICH trial confirms the value of CABG in ischemic cardiomyopathy.
U
DR. AHMET KILIC and DR.
IRVING L. KRON are with the
division of thoracic and
cardiovascular surgery at the
University of Virginia,
Charlottesville.
Stroke in non-valvular AF
N DED
RA N 2
AT ME NES
G
I
BI OM EL
DA REC UID
W FG
O A
N IN
PRADAXA 150 MG TWICE DAILY—REDUCES THE RISK
OF STROKE IN NON-VALVULAR ATRIAL FIBRILLATION (AF)1
RISK REDUCED
Image is a patient portrayal.
Indications and Usage
PRADAXA (dabigatran etexilate mesylate) capsules is indicated
to reduce the risk of stroke and systemic embolism in patients with
non-valvular atrial fibrillation.
IMPORTANT SAFETY INFORMATION
ABOUT PRADAXA
CONTRAINDICATIONS
PRADAXA is contraindicated in patients with active pathological
bleeding and patients with a known serious hypersensitivity reaction
(e.g., anaphylactic reaction or anaphylactic shock) to PRADAXA.
WARNINGS AND PRECAUTIONS
Risk of Bleeding
PRADAXA increases the risk of bleeding and can cause
significant and, sometimes, fatal bleeding.
Risk factors for bleeding include:
—Medications that increase the risk of bleeding in general (e.g.,
anti-platelet agents, heparin, fibrinolytic therapy, and chronic
use of NSAIDs)
—Labor and delivery
Promptly evaluate any signs or symptoms of blood loss, such as
a drop in hemoglobin and/or hematocrit or hypotension.
Discontinue PRADAXA in patients with active pathological bleeding.
Please see additional Important Safety Information about
PRADAXA and brief summary of full Prescribing Information on
the following pages.
P R A DA X A 1 5 0 M G T W I C E DA I LY
In non-valvular atrial fibrillation
Significant risk reduction of stroke vs warfarin1
Effects of PRADAXA compared to warfarin were more apparent in patients with lower levels of INR control.
Statistically significant reduction in stroke/systemic embolism
• Efficacy of PRADAXA was generally consistent across major subgroups*
Patients With Events
250
200
202
134
150
P-value for superiority=0.0001
Hazard Ratio: 0.65
95% CI (0.52, 0.81)
100
CI=confidence interval.
50
N=18,113
0
warfarin
N=6022
PRADAXA
150 mg
N=6076
IMPORTANT SAFETY INFORMATION ABOUT PRADAXA (continued from previous page)
Temporary Discontinuation of PRADAXA
Discontinuing PRADAXA for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke.
Lapses in therapy should be avoided, and if PRADAXA must be temporarily discontinued for any reason, therapy should be
restarted as soon as possible.
Effect of P-gp Inducers and Inhibitors on PRADAXA Exposure
The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces dabigatran exposure and should generally be
avoided. P-gp inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin, do not require dose adjustments.
These results should not be extrapolated to other P-gp inhibitors.
ADVERSE REACTIONS
In the pivotal trial comparing PRADAXA to warfarin, the most frequent adverse reactions leading to discontinuation of PRADAXA
were bleeding and gastrointestinal (GI) events. PRADAXA 150 mg resulted in a higher rate of major GI bleeds and any GI bleeds
compared to warfarin. In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA than with warfarin.
Patients on PRADAXA 150 mg had an increased incidence of GI adverse reactions. These were commonly dyspepsia (including
abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including
GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and GI ulcer). Drug
hypersensitivity reactions were reported in <0.1% of patients receiving PRADAXA.
Other Measures Evaluated
The risk of myocardial infarction was numerically greater in patients who received PRADAXA 150 mg than in those who
received warfarin.
*Major subgroups were prespecified and included age (<65, ≥65 and <75, ≥75), previous stroke/systemic embolism/TIA (no or
yes), heart failure (no or yes), diabetes (no or yes), hypertension (no or yes), warfarin use at entry (naïve or experienced).
References: 1. Pradaxa [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2011. 2. Wann LS, Curtis AB, Ellenbogen KA, et al, writing on behalf of
the 2006 ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation Writing Committee. 2011 ACCF/AHA/HRS focused update on the management of patients with
atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol.
2011;57:1330 –1337. 3. Data on file. Boehringer Ingelheim Pharmaceuticals, Inc.
PRADAXA® is a registered trademark of Boehringer Ingelheim Pharma GmbH and Co. KG and used under license.
COPYRIGHT © 2011 BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.
Lower total bleed rate vs warfarin1
Higher rate of major gastrointestinal (GI) bleeds (1.6% vs 1.1%)†‡
Fewer intracranial hemorrhages (0.3% vs 0.8%)†§
Hazard Ratio: 0.91
95% CI (0.85, 0.96)
2166
Bleeding Events (per 100 Patient-Years)
2000
18.4%
1993
warfarin (N=6022)
16.6%
PRADAXA 150 mg (N=6076)
1600
1200
800
Hazard Ratio: 0.80
95% CI (0.66, 0.98)
Hazard Ratio: 1.50
95% CI (1.2,1.9)
400
218
1.9%
179
125
1.5%
1.1%
186
1.6%
0
Total Bleeds
Life-Threatening
Bleeds†||
Major GI Bleeds†‡1,3
Hazard Ratio: 0.41
95% CI (0.28, 0.60)
90
0.8%
38
0.3%
Intracranial
Hemorrhage†§
• PRADAXA can cause serious and, sometimes, fatal bleeding
• Number of total GI bleeds was 681 vs 452 for warfarin (6.1% vs 4.0% for warfarin)1,3
• Number of major bleeds was 399 vs 421 for warfarin†‡
(3.3% vs 3.6% for warfarin, Hazard Ratio: 0.93, 95% CI [0.81, 1.07])
• Trend toward a higher incidence of major bleeding on PRADAXA for patients ≥75 years of age
(Hazard ratio: 1.2, 95% Cl [1.0 to 1.4])
—Risk of stroke and bleeding increase with age, but risk-benefit profile is favorable in all age groups
†
Patients contributed multiple events and events were counted in multiple categories.
‡
Major bleeds fulfilled 1 or more of the following criteria: bleeding associated with a reduction in hemoglobin of at least
2 grams per deciliter or leading to a transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or
organ (intraocular, intracranial, intraspinal, or intramuscular with compartment syndrome, retroperitoneal bleeding,
intra-articular bleeding, or pericardial bleeding).
§
Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.
||
A life-threatening bleed met 1 or more of the following criteria: fatal,
symptomatic intracranial bleed, reduction in hemoglobin of at least
5 grams per deciliter, transfusion of at least 4 units of blood, associated
with hypotension requiring the use of intravenous inotropic agents, or
necessitating surgical intervention.
Please see brief summary of full Prescribing Information for PRADAXA
on following page. For more information, visit www.PRADAXAPRO.com.
ALL RIGHTS RESERVED.
[03/11]
PX91306PROF
Significant Risk Reduction of Stroke
12
NEWS
Novel Drug Fails to Shrink Infarct Size Post MI
NEW ORLEANS – The investigational
drug delcasertib failed to reduce myocardial infarct size or improve clinical outcomes when given during percutaneous
coronary intervention for acute MI in the
phase IIb PROTECTION AMI trial.
Delcasertib is a highly selective in-
hibitor of delta protein kinase C, which
has been implicated in mitochondrial injury during ischemic reperfusion injury
and apoptosis or necrosis. Based on a previous study showing delcasertib reduced
biomarkers of infarct size, “we had expected a 20% reduction in infarct size,
and we did not observe that across all
dosages,” lead author Dr. A. Michael
Lincoff said at the meeting.
Dr. Sanjay Kaul of Cedars Sinai Med-
PRADAXA® (dabigatran etexilate mesylate) capsules for oral use
(Table 2, Cont’d.)
BRIEF SUMMARY OF PRESCRIBING INFORMATION
Please see package insert for full Prescribing Information.
INDICATIONS AND USAGE
PRADAXA is indicated to reduce the risk of stroke and systemic embolism in patients
with non-valvular atrial fibrillation.
CONTRAINDICATIONS
PRADAXA is contraindicated in patients with:
s Active pathological bleeding [see Warnings and Precautions and Adverse Reactions].
s History of a serious hypersensitivity reaction to PRADAXA (e.g., anaphylactic
reaction or anaphylactic shock) [see Adverse Reactions].
Risk of Bleeding: PRADAXA increases the risk of bleeding and can cause significant
and, sometimes, fatal bleeding. Risk factors for bleeding include the use of drugs that
increase the risk of bleeding in general (e.g., anti-platelet agents, heparin, fibrinolytic
therapy, and chronic use of NSAIDs) and labor and delivery. Promptly evaluate any
signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or
hypotension). Discontinue PRADAXA in patients with active pathological bleeding.
In the RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study, a
life-threatening bleed (bleeding that met one or more of the following criteria: fatal,
symptomatic intracranial, reduction in hemoglobin of at least 5 grams per deciliter,
transfusion of at least 4 units of blood, associated with hypotension requiring the use
of intravenous inotropic agents, or necessitating surgical intervention) occurred at an
annualized rate of 1.5% and 1.8% for PRADAXA 150 mg and warfarin, respectively
[see Adverse Reactions]. Temporary Discontinuation of PRADAXA: Discontinuing
anticoagulants, including PRADAXA, for active bleeding, elective surgery, or invasive
procedures places patients at an increased risk of stroke. Lapses in therapy should
be avoided, and if anticoagulation with PRADAXA must be temporarily discontinued
for any reason, therapy should be restarted as soon as possible. Effect of P-gp Inducers and Inhibitors on Dabigatran Exposure: The concomitant use of PRADAXA
with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibitors ketoconazole, verapamil, amiodarone, quinidine,
and clarithromycin do not require dose adjustments. These results should not be
extrapolated to other P-gp inhibitors.
ADVERSE REACTIONS
Clinical Trials Experience: The RE-LY study provided safety information on the use
of two doses of PRADAXA and warfarin. The numbers of patients and their exposures
are described in Table 1. Limited information is presented on the 110 mg dosing arm
because this dose is not approved.
Table 1 Summary of Treatment Exposure in RE-LY
Total number treated
Exposure
> 12 months
> 24 months
Mean exposure (months)
Total patient-years
PRADAXA
110 mg twice
daily
5983
PRADAXA
150 mg twice
daily
6059
4936
2387
20.5
10,242
4939
2405
20.3
10,261
Warfarin
5998
5193
2470
21.3
10,659
Because clinical studies are conducted under widely varying conditions and over
varying lengths of time, adverse reaction rates observed in the clinical studies
of a drug cannot be directly compared to rates in the clinical studies of another
drug and may not reflect the rates observed in practice. Drug Discontinuation in
RE-LY: The rates of adverse reactions leading to treatment discontinuation were 21%
for PRADAXA 150 mg and 16% for warfarin. The most frequent adverse reactions
leading to discontinuation of PRADAXA were bleeding and gastrointestinal events
(i.e., dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and
diarrhea). Bleeding [see Warnings and Precautions]: Table 2 shows the number of
patients experiencing serious bleeding during the treatment period in the RE-LY
study, with the bleeding rate per 100 patient-years (%). Major bleeds fulfilled one or
more of the following criteria: bleeding associated with a reduction in hemoglobin
of at least 2 grams per deciliter or leading to a transfusion of at least 2 units of
blood, or symptomatic bleeding in a critical area or organ (intraocular, intracranial,
intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding,
intra-articular bleeding or pericardial bleeding). A life-threatening bleed met one
or more of the following criteria: fatal, symptomatic intracranial bleed, reduction in
hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood,
associated with hypotension requiring the use of intravenous inotropic agents, or
necessitating surgical intervention. Intracranial hemorrhage included intracerebral
(hemorrhagic stroke), subarachnoid, and subdural bleeds.
Table 2 Bleeding Events* (per 100 Patient-Years)
Randomized patients
Patient-years
Intracranial
hemorrhage
PRADAXA
150 mg twice daily
N (%)
6076
12,033
38 (0.3)
Warfarin
N (%)
Hazard Ratio
(95% CI**)
Life-threatening
bleed
Major bleed
Any bleed
0.41 (0.28, 0.60)
PRADAXA
150 mg twice daily
N (%)
179 (1.5)
Warfarin
N (%)
Hazard Ratio
(95% CI**)
218 (1.9)
0.80 (0.66, 0.98)
399 (3.3)
1993 (16.6)
421 (3.6)
2166 (18.4)
0.93 (0.81, 1.07)
0.91 (0.85, 0.96)
*Patients contributed multiple events and events were counted in multiple categories.
**Confidence interval
The risk of major bleeds was similar with PRADAXA 150 mg and warfarin across
major subgroups defined by baseline characteristics, with the exception of age, where
there was a trend towards a higher incidence of major bleeding on PRADAXA (hazard
ratio 1.2, 95% CI: 1.0 to 1.4) for patients *75 years of age. There was a higher rate of
major gastrointestinal bleeds in patients receiving PRADAXA 150 mg than in patients
receiving warfarin (1.6% vs. 1.1%, respectively, with a hazard ratio vs. warfarin of 1.5,
95% CI, 1.2 to 1.9), and a higher rate of any gastrointestinal bleeds (6.1% vs. 4.0%, respectively). Gastrointestinal Adverse Reactions: Patients on PRADAXA 150 mg had an
increased incidence of gastrointestinal adverse reactions (35% vs. 24% on warfarin).
These were commonly dyspepsia (including abdominal pain upper, abdominal pain,
abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms
(including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic
gastritis, hemorrhagic erosive gastritis, and gastrointestinal ulcer). Hypersensitivity Reactions: In the RE-LY study, drug hypersensitivity (including urticaria, rash,
and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were
reported in <0.1% of patients receiving PRADAXA. The risk of myocardial infarction
was numerically greater in patients who received PRADAXA (1.5% for 150 mg dose)
than in those who received warfarin (1.1%).
DRUG INTERACTIONS
The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces
exposure to dabigatran and should generally be avoided. P-gp inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin do not require dose
adjustments. These results should not be extrapolated to other P-gp inhibitors.
USE IN SPECIFIC POPULATIONS
Pregnancy: Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Dabigatran has been shown to decrease the number of
implantations when male and female rats were treated at a dosage of 70 mg/kg
(about 2.6 to 3.0 times the human exposure at maximum recommended human
dose [MRHD] of 300 mg/day based on area under the curve [AUC] comparisons)
prior to mating and up to implantation (gestation Day 6). Treatment of pregnant rats
after implantation with dabigatran at the same dose increased the number of dead
offspring and caused excess vaginal/uterine bleeding close to parturition. Although
dabigatran increased the incidence of delayed or irregular ossification of fetal skull
bones and vertebrae in the rat, it did not induce major malformations in rats or rabbits. Labor and Delivery: Safety and effectiveness of PRADAXA during labor and
delivery have not been studied in clinical trials. Consider the risks of bleeding and
of stroke in using PRADAXA in this setting [see Warnings and Precautions]. Death of
offspring and mother rats during labor in association with uterine bleeding occurred
during treatment of pregnant rats from implantation (gestation Day 7) to weaning
(lactation Day 21) with dabigatran at a dose of 70 mg/kg (about 2.6 times the human
exposure at MRHD of 300 mg/day based on AUC comparisons). Nursing Mothers:
It is not known whether dabigatran is excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when PRADAXA is administered to a nursing woman. Pediatric Use: Safety and effectiveness of PRADAXA in
pediatric patients has not been established. Geriatric Use: Of the total number of
patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The
risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups [see Warnings and Precautions and Adverse Reactions]. Renal
Impairment: No dose adjustment of PRADAXA is recommended in patients with mild
or moderate renal impairment. Reduce the dose of PRADAXA in patients with severe
renal impairment (CrCl 15-30 mL/min). Dosing recommendations for patients with
CrCl <15 mL/min or on dialysis cannot be provided.
OVERDOSAGE
Accidental overdose may lead to hemorrhagic complications. There is no antidote
to dabigatran etexilate or dabigatran. In the event of hemorrhagic complications,
initiate appropriate clinical support, discontinue treatment with PRADAXA, and investigate the source of bleeding. Dabigatran is primarily excreted in the urine; therefore,
maintain adequate diuresis. Dabigatran can be dialyzed (protein binding is low), with
the removal of about 60% of drug over 2 to 3 hours; however, data supporting this
approach are limited. Consider surgical hemostasis or the transfusion of fresh frozen
plasma or red blood cells. There is some experimental evidence to support the role
of activated prothrombin complex concentrates (e.g., FEIBA), or recombinant Factor
VIIa, or concentrates of coagulation factors II, IX or X; however, their usefulness in
clinical settings has not been established. Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet
drugs have been used. Measurement of aPTT or ECT may help guide therapy.
©Copyright 2011 Boehringer Ingelheim Pharmaceuticals, Inc.
ALL RIGHTS RESERVED
Revised: March 2011
6022
11,794
90 (0.8)
ical Center, Los Angeles, commented that
delcasertib joins a long list of treatments
targeting reperfusion injury in which the
promise of cardioprotection seen in experimental models has not translated into
clinical trial evidence. Unfortunately, another one bites the dust,” he said.
Dr. Kaul said there are critical differences between animal models and humans – most notably that the timing of
ischemia in humans is uncertain – and he
PX-BS (3-11)
PX91425PROF
asked whether the treatment was given
too late, the dose was incorrect, and the
intravenous route of administration was
appropriate.
Dr. Lincoff replied that the lack of virtually any side effects associated with delcasertib, previously known as KAI-9803,
allowed them to use very high doses that
were shown to provide blood and tissue
levels similar to those seen with intracoronary administration. Animal studies
were comparing intravenous with intracoronary administration showed the
same effect, even when delcasertib was
administered after the ischemia had started. Typically, the drug was on board 17
minutes before PCI began.
Based on the results, Bristol-Myers
Squibb has decided not to continue development of delcasertib, although study
cosponsor KAI Pharmaceuticals has continued interest in evaluating the drug for
other indications, said Dr. Lincoff, director
of the Cleveland Clinic Coordinating Center for Clinical Research.
The phase IIb PROTECTION AMI
analysis included 1,176 patients with
acute ST-elevation MI, cardiac ischemia
for at least 30 minutes, arriving for PCI
within 6 hours of symptom onset and
randomly assigned them to placebo or
delcasertib IV infusion at 50 mg per
hour, 150 mg/hour or 450 mg/hour immediately before PCI.
Among 911 evaluable anterior STEMI
patients, there was no significant difference in the primary end point of infarct
size as assessed by creatine kinase-MB
area under the curve (AUC) between
the placebo arm (6,471 ng-hr/mL) and
delcasertib at the 50-mg dose (5,917 nghr/mL), the 150-mg dose (5,650 nghr/mL), or 450-mg dose (6,204 nghr/mL), Dr. Lincoff said.
ST-segment recovery AUC on 24-hour
ECG monitoring was also similar at
8,377 microvolt per minute, 7,707 microV/min., 7,779 microV/min. and
8,188 microV/min., respectively.
At 3-month follow-up, 8.6% of placebotreated patients had a left ventricular ejection fraction of 30% or more compared
with 5.1% treated with 50 mg delcasertib, 7.3% with 150 mg, and 9.0% with 450
mg. Outcomes were also similar among
156 patients with inferior STEMI.
Recognizing that some patients may
have arrived at the PCI lab and received
delcasertib after reperfusion injury occurred, the researchers evaluated a
prospectively defined subgroup of anterior MI patients based on pre-PCI TIMI
(Thrombolysis in Myocardial Infarction)
scores. Among these patients, there was
a soft trend toward improved CK-MB
AUC with delcasertib in patients with occluded TIMI flow (score 0/1), suggesting
there may be some biological activity
with the agent, Dr. Lincoff said.
PROTECTION AMI was supported
by Bristol-Myers Squibb and KAI Pharmaceuticals. Dr. Lincoff reported receiving research funding and travel reimbursement
from
KAI
and
Bristol-Myers Squibb, and serving as an
advisor to BMS.
■
Pages 12a—12dG
INTERVENTIONAL CARDIOLOGY
13
Although percutaneous repair is safer than surgery,
it does not reduce mitral regurgitation as completely.
NEW ORLEANS – T he durability and
safety of treating mitral regurgitation
with a percutaneous device as compared with that of surgical repair or replacement persisted at 2 years, according to an updated analysis of the
EVEREST II trial results presented at
the meeting.
“Our fundamental finding is that outcomes are very stable between 1 and 2
years of follow-up,” Dr. Ted Feldman,
principal investigator, announced at a
press briefing.
“The KaplanMeier curves for
mortality and reoperation remain
literally and completely flat through
that time period,
and clinical outcomes
are
durable,” he said.
On the basis of data from the first year
of the study, percutaneous repair with
the MitraClip was safer than surgery,
but surgery yielded more complete reduction in mitral regurgitation (N. Engl.
J. Med. 2011;364:1395-1406).
The 2-year results, presented at the
meeting, show that both approaches reduced mitral regurgitation, and meaningful clinical benefits persisted, said Dr.
Feldman, who is director of the cardiac
catheterization laboratory at the
NorthShore University HealthSystem in
Evanston, Ill.
Clinical outcome measures at 2 years’
follow-up showed that mitral regurgitation grade and left ventricular volumes
remained stable between 1 and 2 years
in both groups. The intergroup comparison showed a more favorable reduction in mitral regurgitation and a
greater reduction in left ventricular diastolic volume with surgery at 1 and 2
years, and no difference in systolic volume reduction.
Also, New York Heart Association
(NYHA) functional class was stable between years 1 and 2.
“Interestingly, the intergroup comparison showed a more favorable NYHA
class outcome at both years with the
clip,” Dr. Feldman reported.
The safety profile continued to be favorable, as well. “We saw no percutaneous device embolization; no device
fracture, erosion, or migration; and no
additional occurrence of single leaflet device attachment,” he reported.
“Stability is the major message in the
examination of 2-year outcomes,” Dr.
Feldman said.
“The randomized trial represents our
very early experience with the device.
Our procedural rate was 86% in the trial but in the postrandomization registry
is in the 96% range. We are certainly going to get better at doing this.”
At a panel convened to comment on
the study results, Dr. Gregg W. Stone,
professor of medicine at New York Presbyterian Hospital and Columbia University, New York, said that the follow-up
analysis of EVEREST II is “very well
done” and has, “for the most part, shown
stability and fairly comparable mortality,
though 22% of patients still need surgery
if they take the route of the percutaneous option.”
Dr. Steven F. Bolling, professor of
surgery at the University of Michigan,
Ann Arbor, maintained that while
EVEREST II “suffers a little from
‘Stability is the
major message in awkward analyses,” the results
the examination
are
promising,
of 2-year
pending the right
outcomes’ of
patient selection
percutaneous
and longer followrepair.
up.
Patients at high
DR. FELDMAN
surgical risk and
those with cardiomyopathy-associated
MR would be the appropriate subset for
further study in order to refine the optimal use of the device, said Dr. Bolling.
EVEREST II (Endovascular Valve
Edge-to-Edge Repair Study) is a
prospective, multicenter, randomized
controlled phase II trial comparing the
safety and efficacy of the MitraClip System with mitral valve surgery in the
treatment of mitral regurgitation. The
study enrolled 279 patients with 3+ or
4+ mitral regurgitation who were either
symptomatic or were asymptomatic
with a baseline left ejection fraction of
60%; 27% had functional mitral regurgitation and 73% had degenerative mitral regurgitation. Approximately half of
the patients had NYHA functional class
III or IV heart failure.
The patients were randomized 2:1 to
receive the MitraClip device (n = 184) or
mitral valve (MV) repair or replacement
(n = 95). More than 90% of the study
cohort was available for the 2-year
analysis.
Outcomes through 1 year (primary
safety and efficacy end points) were recently reported (N. Engl. J. Med. 2011;
364:1395-406), showing increased safety with the MitraClip device compared
to surgery, but greater reduction in mitral regurgitation with surgery. At 30
days, major adverse events occurred in
15% of the percutaneous arm versus
48% of the surgical arm. Left ventricular function improved in both groups,
as did NYHA functional class and quality of life at 1 year.
At the meeting, Dr. Feldman presented two analyses of the 2-year data. The
first was an intention-to-treat analysis, in
which any mitral valve surgery following
percutaneous repair was considered an
end-point event.
VITALS
EVEREST II: 2-Year Data Show MitraClip Safety
Major Finding: At 2 years, the composite primary efficacy end point of freedom from death, MV surgery for valve dysfunction (for device patients) or reoperation (for surgery patients), and MR greater than 2+ at 12 months was
met by 52% of the percutaneous group and by 66% of the surgery group.
Data Source: A prospective, multi-center, randomized controlled phase II trial
of 279 patients with 3+ or 4+ mitral regurgitation.
Disclosures: Dr. Feldman reported consulting fees, honoraria, and research
grants from Abbott Vascular. Dr. Stone reported consulting fees and honoraria
from Abbott Vascular and numerous other pharmaceutical and device companies. Dr. Bolling reported no relevant disclosures.
The second analysis was a comparison 6.2% of the percutaneous group and
of treatment strategies, in which MV 3.6% of the surgery group had MV
surgery following unsuccessful in-hospi- surgery or reoperation.
tal percutaneous repair was not considThere was no difference in the Kaered an end point event. In the latter plan-Meier mortality plot for the inanalysis, subsequent surgery within 90 tention-to-treat analysis at any time
days of the percutaneous procedure was point, he stressed. At 1 year, 95% of the
still considered a “success” for the Mitra- patients in each arm were alive; at 2
Clip.
years, 91% of the surgery arm and 90%
The composite primary efficacy end of the percutaneous arm were still
point was freedom from death, MV alive.
surgery for valve dysfunction (for device
The Kaplan-Meier plot for freedom
patients) or reoperation (for surgery pa- from MV surgery/reoperation, however,
tients), and mifavored the surtral regurgitagical arm: 96%
Patients at high surgical risk
tion greater than
versus 78% at 2
and those with cardiomyopathy2+ at 12 months.
years.
In the intenThe “need for
associated MR would be the
tion-to-treat
surgery in paappropriate subset for further
analysis, the pritients in the clip
mary composite
group was alstudy in order to refine the
end point was
most entirely in
optimal use of the device.
met at 2 years by
the first several
52% of the permonths after
cutaneous group and by 66% of the therapy, and after 6 months the curves
surgery group; in the 1-year analysis, overlapped at 1 and 2 years,” he obthese figures were 55% and 73%, reserved.
spectively.
“Importantly, 78% of device patients
More patients receiving the clip later are free from MV surgery at 2 years,”
had MV surgery (22%), compared with noted Dr. Feldman.
the few patients in the surgery arm who
When these early failures were exrequired reoperation (3.6%). There was cluded, there were no differences in the
no significant difference in mortality or need for MV surgery or for reoperation.
recurrent mitral regurgitation.
At the press conference, Dr. Feldman
In the second analysis, there was no explained that the two analyses “answer
statistical difference in the effectiveness different questions.”
end point between the two arms of the
“The intention-to-treat analysis gives
study.
the patient the odds of success with the
“When subsequent surgery within 90 clip at the end of the year,” he exdays on device patients is considered a plained. “It tells them that 78% will be
success, we see similarly stable results at free of the need for surgery at 2 years,
1 and 2 years,” he noted.
and 97% will have NYHA functional
In this analysis, the primary end point class I or II.”
was met at 2 years by 63% of the percuThe second analysis answers the questaneous group and by 66% of the tion, “What if I am in the 20% needing
surgery group.
surgery?” That analysis counts the comWhen the subsequent need for MV bined strategy of the clip, with surgery
surgery is removed as an end-point event, as needed.
■
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14
PARTNER Results
chief of cardiothoracic surgery at New York–Presbyterian Hospital/Columbia University Medical Center
in New York City.
Notably, patients who underwent conventional
surgery were significantly more likely than TAVR patients to experience major bleeding at 30 days (19.5%
vs. 9.3%) and 1 year (26% vs. 15%), as well as new atrial fibrillation at both 30 days (16% vs. 8.6%) and 1 year
(17% vs. 12%).
Echocardiographic findings indicated a small hemodynamic benefit with TAVR vs. surgery at 1 year,
but significantly increased paravalvular aortic regurgitation at 30 days, 6 months, and 1 year.
“TAVR and AVR [aortic valve replacement] are both
acceptable therapies in these high-risk patients; differing periprocedural hazards should influence case-based
decision making,” Dr. Smith said.
Dr. David Moliterno, chair of the intervention program (i2 Summit) at the meeting, told reporters that
they were witnessing history in the making.
“This will probably be seen as one of the biggest
steps in cardiovascular medicine, as far as intervention
is concerned, potentially in our lifetime,” said Dr. Moliterno, chief of cardiovascular medicine at the University of Kentucky, Lexington. “If we look back to balloon angioplasty, the advent of stents and drug-eluting
stents, … this will be seen as the next major turning
point.”
Last year, the PARTNER trial investigators reported a 20% survival benefit at 1 year in a separate cohort
of 358 inoperable patients with severe aortic stenosis
who underwent transfemoral TAVR vs. standard therapy, including balloon aortic valvuloplasty (N. Engl. J.
Med. 2010;363:1597-607).
Major vascular complications were significantly
more common with TAVR than with standard therapy, at 16% and 1%, respectively, and with a higher
incidence of major strokes, at 5% and 1%, respectively.
In the current portion of PARTNER, 699 patients at
26 centers were randomly assigned to undergo surgery
or transcatheter aortic valve replacement. The transfemoral approach was used in 244 of the 348 TAVR patients, and the transapical approach was used in 104 patients.
Severe stenosis was defined as an aortic valve area of
less than 0.8 cm2 and mean aortic valve gradient of
more than 40 mm Hg or a peak aortic jet velocity of
more than 4.0 m/second. The patients had a New York
Heart Association heart failure class II or greater, and
had a predicted risk of operative mortality of at least
I MAGES ©E LSEVIER I NC.
TAVR from page 1
The deflectable delivery system of the Sapien valve passes through the
aorta and native valve (left). The balloon is then inflated (right).
15% as determined by the site surgeon and cardiologist,
coupled with a Society of Thoracic Surgery score of at
least 10.
Their mean age was 83 years, and 94% were NYHA
class III or IV. In all, 42 patients were not treated as assigned, Dr. Smith said.
All-cause mortality at 1 year was similar for the transfemoral TAVR subgroup, at 22.2% and 26.4% for
surgery, as well as for the transapical TAVR subgroup
(29% vs. 28%, respectively).
A preliminary subgroup analysis suggests that there
may be a possible benefit with TAVR in women and patients without prior coronary artery bypass surgery, but
Dr. Smith said that those results should be interpreted
cautiously.
Overall, the TAVR mortality of 3.4% at 30-days was
the lowest reported in any series, despite the use of an
early-generation device and limited previous operator
experience, he said, noting that nine of the participating centers had never performed TAVR before the
trial.
Symptom improvement, including NYHA functional class and 6-minute walk distance, favored TAVR at
30 days and was similar to conventional surgery at 1
year, he said.
Co-investigator Dr. Murat Tuzcu, vice chair of the
department of cardiovascular medicine at the Cleveland
Clinic, stressed that the results were accomplished
only through unprecedented teamwork among cardiologists, surgeons, and imaging experts, who consulted on each case in the trial.
“I want to emphasize that if we fail to pay equal attention to what we have done in this trial after the device is approved, I don’t think we will be able to replicate the same results,” he said.
Several speakers at the press conference noted the
balancing act that all clinicians will face regarding public demand for the new procedure.
Dr. Michael Crawford, chief of clinical cardiology at
The fully expanded replacement
valve is shown above.
the University of California, San Francisco, observed
that centers will face substantial up-front costs in the
adoption of TAVR, including hybrid surgical/interventional suites, and that this will restrict initial uptake
to high-volume centers of excellence.
The 3.4% mortality rate represents an “amazing effort,” particularly in the use of the larger, first-generation device, said invited discussant Dr. Martyn
Thomas, clinical director of cardiothoracic services at
St. Thomas’ Hospital, London. The delivery catheters
used in PARTNER are sized at 22 and 24 French,
which corresponds to an outside diameter of 7-8
mm.
However, the size of catheters is down to 16-Fr in
Europe, where more than 5,000 transcatheter aortic valve replacement procedures have been performed and where both the Edwards Lifesciences
Corp. Sapien valve that was used in PARTNER and
the Medtronic Inc. CoreValve are already on the
market.
Recruitment began in February for the PARTNER II
trial to evaluate the smaller Edwards Sapien XT device
and the later generation NovaFlex delivery system
among inoperable patients with symptomatic severe
aortic stenosis. That trial is expected to enroll 600 patients, and is targeted for primary completion in December 2011.
When asked whether the advent of newer, thinner
devices will mean adoption in patients with lower
risk, Dr. Smith replied that the adoption of TAVR will
“march steadily down the risk categories.”
Edwards Lifesciences sponsored the trial. Dr. Smith
and his coauthors reported that
they had no conflicts of interest. ■
To see a video interview with Dr.
Smith, scan this QR code or go to
www.youtube.com/
watch?v=0xri_CPkpyg.
Transcatheter Valve Replacement Skips Sticker Shock
NEW ORLEANS – The cost of trans-
catheter aortic valve replacement among
patients with inoperable severe aortic
stenosis is in line with the cost of other
accepted cardiovascular procedures, according to an economic analysis of the
PARTNER trial.
The index hospitalization costs were
higher with TAVR, but the reduction in
subsequent hospitalizations, and the projected gain in survival, associated with
the procedure yielded overall lifetime
cost-effectiveness. “In this extremely
high-risk population, an elderly population, the intervention is adding roughly
2 years of life, and that is the return on
investment,” principal investigator Dr.
Matthew Reynolds said at the meeting.
The cost-effectiveness ratio “works out
to just over $50,000 per life-year gained.”
Efficacy data for the same 358 inoperable patients, known as cohort B,
showed a 20% survival benefit with
TAVR at 1 year, compared with standard
medical therapy, including balloon aortic valvuloplasty (N. Engl. J. Med. 2010;
363:1597-1607).
To determine the economic value of
the procedure, Dr. Reynolds and his colleagues assessed lifetime incremental
cost-effectiveness ratios (ICERs) and lifetime incremental costs per QALY using
hospital billing data or MEDPAR when
bills were unavailable. Costs from the
last 6 months for surviving patients were
used to project future costs beyond 12
months, while parametric survival models fit to the trial data were used to extrapolate patient-level life expectancy
beyond the follow-up period.
The initial $78,540 price tag for TAVR
includes $42,806 for procedural costs,
based on an estimated cost of $30,000 for
the investigational Edwards Sapien valve;
$30,756 for nonprocedural expenses; and
$4,978 for physician fees, said Dr.
Reynolds, director of the Economics and
Quality of Life Research Center at the
Harvard Clinical Research Institute,
Boston. Twelve-month follow-up costs
were $23,372 higher for patients treated
with standard medical therapy. This was
a result of significantly more hospitalizations in the control group than in the
TAVR group (2.15 vs. 1.02), mainly due
to cardiovascular causes (1.7 vs. 0.50).
The estimated life expectancy was 3.1
years for TAVR patients and 1.2 years for
patients treated with medical therapy, or
a difference of 1.9 years. The lifetime incremental cost per patient was $79,837,
and the lifetime incremental gain in life
expectancy was 1.59 years. This translated into an ICER of $50,212 per life-year
gained and $61,889 per QALY, he said.
On the basis of the data, TAVR in this
older inoperable cohort falls very close
to published cost-effectiveness estimates
for implantable defibrillators and atrial
fibrillation ablation, and is actually lower than current estimates for hemodialysis or percutaneous coronary intervention for stable coronary artery disease,
Dr. Reynolds said.
Edwards Lifesciences provided grant
support for the analysis.
■
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16
DES Beats BMS for Saphenous Vein Graft Stenosis
BY ALICE GOODMAN
NEW ORLEANS – Drug-eluting stents
outperformed bare-metal stents when
placed in saphenous vein graft lesions
that developed post–coronary artery bypass graft, in ISAR-CABG, the largest
study ever performed to compare these
two types of stents in this setting.
Specifically, DES significantly reduced
the rate for the combined primary end
point of death, MI, and repeat revascularization procedures.
“This study shows us that we don’t
have to be afraid of DES in patients with
these high-risk lesions, because use of
DES cuts down the need for target vessel revascularization by 50% and does
not increase myocardial infarction mortality and stent thrombosis formation
when compared with BMS [bare-metal
stents],” Dr. Julinda Mehilli, director of
clinical research and data coordinating
ISAR (Intracoronary Stenting and Antithrombotic Regimen) at the German
Heart Center in Munich, said at the
meeting.
ISAR-CABG enrolled 610 patients who
underwent a first CABG with a saphenous vein graft and developed at least
one stenotic lesion of at least 50% in the
PROFESSIONAL BRIEF SUMMARY
CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION
NIASPAN® (niacin extended-release tablets)
INDICATIONS AND USAGE
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at
signiŰcantly increased risk for atherosclerotic vascular disease due to hyperlipidemia. Niacin therapy is indicated as
an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic
measures alone has been inadequate.
1. NIASPAN is indicated to reduce elevated TC, LDL-C, Apo B and TG levels, and to increase HDL-C in patients with
primary hyperlipidemia and mixed dyslipidemia.
2. NIASPAN in combination with simvastatin or lovastatin is indicated for the treatment of primary hyperlipidemia
and mixed dyslipidemia when treatment with NIASPAN, simvastatin, or lovastatin monotherapy is considered
inadequate.
3. In patients with a history of myocardial infarction and hyperlipidemia, niacin is indicated to reduce the risk of
recurrent nonfatal myocardial infarction.
4. In patients with a history of coronary artery disease (CAD) and hyperlipidemia, niacin, in combination with a bile
acid binding resin, is indicated to slow progression or promote regression of atherosclerotic disease.
Limitations of Use No incremental beneŰt of NIASPAN coadministered with simvastatin or lovastatin on
cardiovascular morbidity and mortality over and above that demonstrated for niacin, simvastatin, or lovastatin
monotherapy has been established.
CONTRAINDICATIONS
NIASPAN is contraindicated in the following conditions:
• Active liver disease or unexplained persistent elevations in hepatic transaminases [see Warnings and Precautions]
• Patients with active peptic ulcer disease
• Patients with arterial bleeding
• Hypersensitivity to niacin or any component of this medication [see Adverse Reactions]
NIASPAN preparations should not be substituted for equivalent doses of immediate-release (crystalline)
niacin. For patients switching from immediate-release niacin to NIASPAN, therapy with NIASPAN should be
initiated with low doses (i.e., 500 mg at bedtime) and the NIASPAN dose should then be titrated to the desired
therapeutic response.
Caution should also be used when NIASPAN is used in patients with unstable angina or in the acute phase of an MI,
particularly when such patients are also receiving vasoactive drugs such as nitrates, calcium channel blockers, or
adrenergic blocking agents.
Niacin is rapidly metabolized by the liver, and excreted through the kidneys. NIASPAN is contraindicated in patients
with signiŰcant or unexplained hepatic impairment [see Contraindications and Warnings and Precautions] and should
be used with caution in patients with renal impairment. Patients with a past history of jaundice, hepatobiliary disease,
or peptic ulcer should be observed closely during NIASPAN therapy.
Skeletal Muscle Cases of rhabdomyolysis have been associated with concomitant administration of lipid-altering
doses (ū1 g/day) of niacin and statins. Physicians contemplating combined therapy with statins and NIASPAN should
carefully weigh the potential beneŰts and risks and should carefully monitor patients for any signs and symptoms
of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of
upward dosage titration of either drug. Periodic serum creatine phosphokinase (CPK) and potassium determinations
should be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence
of severe myopathy.
The risk for myopathy and rhabdomyolysis are increased when lovastatin or simvastatin are coadministered with
NIASPAN, particularly in elderly patients and patients with diabetes, renal failure, or uncontrolled hypothyroidism.
Liver Dysfunction Cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred
in patients who have substituted sustained-release (modiğed-release, timed-release) niacin products for
immediate-release (crystalline) niacin at equivalent doses.
NIASPAN should be used with caution in patients who consume substantial quantities of alcohol and/
or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are
contraindications to the use of NIASPAN.
Niacin preparations have been associated with abnormal liver tests. In three placebo-controlled clinical trials involving
titration to Űnal daily NIASPAN doses ranging from 500 to 3000 mg, 245 patients received NIASPAN for a mean duration
of 17 weeks. No patient with normal serum transaminase levels (AST, ALT) at baseline experienced elevations to more
than 3 times the upper limit of normal (ULN) during treatment with NIASPAN. In these studies, fewer than 1% (2/245) of
NIASPAN patients discontinued due to transaminase elevations greater than 2 times the ULN.
In three safety and efŰcacy studies with a combination tablet of NIASPAN and lovastatin involving titration to Űnal
daily doses (expressed as mg of niacin/ mg of lovastatin) 500 mg/10 mg to 2500 mg/40 mg, ten of 1028 patients
(1.0%) experienced reversible elevations in AST/ALT to more than 3 times the ULN. Three of ten elevations occurred
at doses outside the recommended dosing limit of 2000 mg/40 mg; no patient receiving 1000 mg/20 mg had 3-fold
elevations in AST/ALT.
Niacin extended-release and simvastatin can cause abnormal liver tests. In a simvastatin-controlled, 24 week study
with a Űxed dose combination of NIASPAN and simvastatin in 641 patients, there were no persistent increases (more
than 3x the ULN) in serum transaminases. In three placebo-controlled clinical studies of extended-release niacin there
were no patients with normal serum transaminase levels at baseline who experienced elevations to more than 3x
the ULN. Persistent increases (more than 3x the ULN) in serum transaminases have occurred in approximately 1% of
patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these
patients, the transaminases levels usually fell slowly to pretreatment levels. The increases were not associated with
jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.
In the placebo-controlled clinical trials and the long-term extension study, elevations in transaminases did not appear
to be related to treatment duration; elevations in AST levels did appear to be dose related. Transaminase elevations
were reversible upon discontinuation of NIASPAN.
Liver function tests should be performed on all patients during therapy with NIASPAN. Serum transaminase levels,
including AST and ALT (SGOT and SGPT), should be monitored before treatment begins, every 6 to 12 weeks for the
Űrst year, and periodically thereafter (e.g., at approximately 6-month intervals). Special attention should be paid to
patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated
promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if
they rise to 3 times ULN and are persistent, or if they are associated with symptoms of nausea, fever, and/or malaise,
the drug should be discontinued.
Laboratory Abnormalities Increase in Blood Glucose: Niacin treatment can increase fasting blood glucose.
Frequent monitoring of blood glucose should be performed to ascertain that the drug is producing no adverse effects.
Diabetic patients may experience a dose-related increase in glucose intolerance. Diabetic or potentially diabetic
patients should be observed closely during treatment with NIASPAN, particularly during the Űrst few months of use or
dose adjustment; adjustment of diet and/or hypoglycemic therapy may be necessary.
Reduction in platelet count: NIASPAN has been associated with small but statistically signiŰcant dose-related
reductions in platelet count (mean of -11% with 2000 mg). Caution should be observed when NIASPAN is administered
concomitantly with anticoagulants; platelet counts should be monitored closely in such patients.
Increase in Prothrombin Time (PT): NIASPAN has been associated with small but statistically signiŰcant increases
in prothrombin time (mean of approximately +4%); accordingly, patients undergoing surgery should be carefully
evaluated. Caution should be observed when NIASPAN is administered concomitantly with anticoagulants; prothrombin
time should be monitored closely in such patients.
Increase in Uric Acid: Elevated uric acid levels have occurred with niacin therapy, therefore use with caution in patients
predisposed to gout.
Decrease in Phosphorus: In placebo-controlled trials, NIASPAN has been associated with small but statistically
signiŰcant, dose-related reductions in phosphorus levels (mean of -13% with 2000 mg). Although these reductions
were transient, phosphorus levels should be monitored periodically in patients at risk for hypophosphatemia.
graft. Patients were randomized to receive either a DES or a BMS in a 1:1 ratio. In the DES group, patients were assigned 1:1:1 to three commonly used
types of stents (sirolimus, paclitaxel, and
biodegradable sirolimus) to mirror realworld use, Dr. Mehilli explained.
The primary end point was a composite of death, myocardial infarction,
and target-vessel revascularization at 1
year of follow-up after percutaneous
ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical
studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reűect the
rates observed in practice.
Clinical Studies Experience In the placebo-controlled clinical trials database of 402 patients (age range 21-75
years, 33% women, 89% Caucasians, 7% Blacks, 3% Hispanics, 1% Asians) with a median treatment duration of 16
weeks, 16% of patients on NIASPAN and 4% of patients on placebo discontinued due to adverse reactions. The most
common adverse reactions in the group of patients treated with NIASPAN that led to treatment discontinuation and
occurred at a rate greater than placebo were űushing (6% vs. 0%), rash (2% vs. 0%), diarrhea (2% vs. 0%), nausea (1%
vs. 0%), and vomiting (1% vs. 0%). The most commonly reported adverse reactions (incidence >5% and greater than
placebo) in the NIASPAN controlled clinical trial database of 402 patients were űushing, diarrhea, nausea, vomiting,
increased cough and pruritus.
In the placebo-controlled clinical trials, űushing episodes (i.e., warmth, redness, itching and/or tingling) were the most
common treatment-emergent adverse reactions (reported by as many as 88% of patients) for NIASPAN. Spontaneous
reports suggest that űushing may also be accompanied by symptoms of dizziness, tachycardia, palpitations, shortness
of breath, sweating, burning sensation/skin burning sensation, chills, and/or edema, which in rare cases may lead
to syncope. In pivotal studies, 6% (14/245) of NIASPAN patients discontinued due to űushing. In comparisons of
immediate-release (IR) niacin and NIASPAN, although the proportion of patients who űushed was similar, fewer űushing
episodes were reported by patients who received NIASPAN. Following 4 weeks of maintenance therapy at daily doses
of 1500 mg, the incidence of űushing over the 4-week period averaged 8.6 events per patient for IR niacin versus
1.9 following NIASPAN.
Other adverse reactions occurring in ū5% of patients treated with NIASPAN and at an incidence greater than placebo
are shown in 1 below.
Table 1. Treatment-Emergent Adverse Reactions by Dose Level in Ű 5% of Patients and at an Incidence
Greater than Placebo; Regardless of Causality Assessment in Placebo-Controlled Clinical Trials
Placebo-Controlled Studies
NIASPAN Treatment@
b
b
Recommended Daily
Maintenance Doses †
b
Placebo
500 mg‡
1000 mg
1500 mg
2000 mg
b
(n = 157)
(n = 87)
(n = 110)
(n = 136)
(n = 95)
b
%
%
%
%
%
b
b
b
b
b
Gastrointestinal Disorders
Diarrhea
13
7
10
10
14
Nausea
7
5
6
4
11
Vomiting
4
0
2
4
9
b
b
b
b
b
Respiratory
Cough, Increased
6
3
2
<2
8
b
b
b
b
b
Skin and Subcutaneous Tissue Disorders
Pruritus
2
8
0
3
0
Rash
0
5
5
5
0
b
b
b
b
b
Vascular Disorders
Flushing&
19
68
69
63
55
Note: Percentages are calculated from the total number of patients in each column.
†
Adverse reactions are reported at the initial dose where they occur.
@
Pooled results from placebo-controlled studies; for NIASPAN, n = 245 and median treatment duration = 16 weeks.
Number of NIASPAN patients (n) are not additive across doses.
‡
The 500 mg/day dose is outside the recommended daily maintenance dosing range.
&
10 patients discontinued before receiving 500 mg, therefore they were not included.
b
In general, the incidence of adverse events was higher in women compared to men.
Postmarketing Experience Because the below reactions are reported voluntarily from a population of uncertain
size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following additional adverse reactions have been identiŰed during post-approval use of NIASPAN:
Hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, űushing, dyspnea, tongue edema, larynx
edema, face edema, peripheral edema, laryngismus, and vesiculobullous rash; maculopapular rash; dry skin;
tachycardia; palpitations; atrial Űbrillation; other cardiac arrhythmias; syncope; hypotension; postural hypotension;
blurred vision; macular edema; peptic ulcers; eructation; űatulence; hepatitis; jaundice; decreased glucose tolerance;
gout; myalgia; myopathy; dizziness; insomnia; asthenia; nervousness; paresthesia; dyspnea; sweating; burning
sensation/skin burning sensation; skin discoloration, and migraine.
Clinical Laboratory Abnormalities Chemistry: Elevations in serum transaminases [see Warnings and Precautions], LDH,
fasting glucose, uric acid, total bilirubin, amylase and creatine kinase, and reduction in phosphorus.
Hematology: Slight reductions in platelet counts and prolongation in prothrombin time [see Warnings and Precautions].
DRUG INTERACTIONS
Statins Caution should be used when prescribing niacin (ū1 gm/day) with statins as these drugs can increase risk
of myopathy/rhabdomyolysis. Combination therapy with NIASPAN and lovastatin or NIASPAN and simvastatin should
not exceed doses of 2000 mg NIASPAN and 40 mg lovastatin or simvastatin daily. [see Warnings and Precautions ].
Bile Acid Sequestrants An in vitro study results suggest that the bile acid-binding resins have high niacin binding
capacity. Therefore, 4 to 6 hours, or as great an interval as possible, should elapse between the ingestion of bile acidbinding resins and the administration of NIASPAN.
Aspirin Concomitant aspirin may decrease the metabolic clearance of nicotinic acid. The clinical relevance of this
Űnding is unclear.
Antihypertensive Therapy Niacin may potentiate the effects of ganglionic blocking agents and vasoactive drugs
resulting in postural hypotension.
Other Vitamins or other nutritional supplements containing large doses of niacin or related compounds such as
nicotinamide may potentiate the adverse effects of NIASPAN.
Laboratory Test Interactions Niacin may produce false elevations in some űuorometric determinations of plasma
or urinary catecholamines. Niacin may also give false-positive reactions with cupric sulfate solution (Benedict’s
reagent) in urine glucose tests.
Pregnancy Pregnancy Category C.
Animal reproduction studies have not been conducted with niacin or with NIASPAN. It is also not known whether niacin
at doses typically used for lipid disorders can cause fetal harm when administered to pregnant women or whether it
can affect reproductive capacity. If a woman receiving niacin for primary hyperlipidemia becomes pregnant, the drug
should be discontinued. If a woman being treated with niacin for hypertriglyceridemia conceives, the beneŰts and risks
of continued therapy should be assessed on an individual basis.
All statins are contraindicated in pregnant and nursing women. When NIASPAN is administered with a statin in a
woman of childbearing potential, refer to the pregnancy category and product labeling for the statin.
Nursing Mothers Niacin is excreted into human milk but the actual infant dose or infant dose as a percent of the
maternal dose is not known. Because of the potential for serious adverse reactions in nursing infants from lipid-altering
doses of nicotinic acid, a decision should be made whether to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother. No studies have been conducted with NIASPAN in nursing
mothers.
Pediatric Use Safety and effectiveness of niacin therapy in pediatric patients (Ū16 years) have not been established.
Geriatric Use Of 979 patients in clinical studies of NIASPAN, 21% of the patients were age 65 and over. No overall
differences in safety and effectiveness were observed between these patients and younger patients, and other
reported clinical experience has not identiŰed differences in responses between the elderly and younger patients, but
greater sensitivity of some older individuals cannot be ruled out.
Renal Impairment No studies have been performed in this population. NIASPAN should be used with caution in
patients with renal impairment [see Warnings and Precautions].
Hepatic Impairment No studies have been performed in this population. NIASPAN should be used with caution in
patients with a past history of liver disease and/or who consume substantial quantities of alcohol. Active liver disease,
unexplained transaminase elevations and signiŰcant or unexplained hepatic dysfunction are contraindications to the
use of NIASPAN [see Contraindications and Warnings and Precautions].
Gender Data from the clinical trials suggest that women have a greater hypolipidemic response than men at
equivalent doses of NIASPAN.
OVERDOSAGE
Supportive measures should be undertaken in the event of an overdose.
PATIENT COUNSELING INFORMATION
Patient Counseling Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)
recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel.
Patients should be advised to inform other healthcare professionals prescribing a new medication that they are taking
NIASPAN.
The patient should be informed of the following:
Dosing Time NIASPAN tablets should be taken at bedtime, after a low-fat snack. Administration on an empty
stomach is not recommended.
Tablet Integrity NIASPAN tablets should not be broken, crushed or chewed, but should be swallowed whole.
Dosing Interruption If dosing is interrupted for any length of time, their physician should be contacted prior to
restarting therapy; re-titration is recommended.
Muscle Pain Notify their physician of any unexplained muscle pain, tenderness, or weakness promptly. They should
discuss all medication, both prescription and over the counter, with their physician.
Flushing Flushing (warmth, redness, itching and/or tingling of the skin) is a common side effect of niacin therapy
that may subside after several weeks of consistent NIASPAN use. Flushing may vary in severity and is more likely to
occur with initiation of therapy, or during dose increases. By dosing at bedtime, űushing will most likely occur during
sleep. However, if awakened by űushing at night, the patient should get up slowly, especially if feeling dizzy, feeling
faint, or taking blood pressure medications. Advise patients of the symptoms of űushing and how they differ from the
symptoms of a myocardial infarction.
Use of Aspirin Medication Taking aspirin (up to the recommended dose of 325 mg) approximately 30 minutes
before dosing can minimize űushing.
Diet Avoid ingestion of alcohol, hot beverages and spicy foods around the time of taking NIASPAN to minimize
űushing.
Supplements Notify their physician if they are taking vitamins or other nutritional supplements containing niacin
or nicotinamide.
Dizziness Notify their physician if symptoms of dizziness occur.
Diabetics If diabetic, to notify their physician of changes in blood glucose.
Pregnancy Discuss future pregnancy plans with your patients, and discuss when to stop NIASPAN if they are trying
to conceive. Patients should be advised that if they become pregnant, they should stop taking NIASPAN and call their
healthcare professional.
Breastfeeding Women who are breastfeeding should be advised to not use NIASPAN. Patients, who have a lipid
disorder and are breastfeeding, should be advised to discuss the options with their healthcare professional.
©2010 Abbott Laboratories
Manufactured for Abbott Laboratories, North Chicago, IL 60064, U.S.A.
500 mg tablets
by Norwich Pharmaceuticals, Inc., Norwich, NY 13815
or
500 mg, 750 mg and 1000 mg tablets
by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617
Ref: 03-A432-Revised December, 2010
303-516006 MASTER
303-515605
coronary intervention for stent placement. Secondary end points were each of
those events separately, as well as ARC
(Academic Research Consortium)-definite stent thrombosis.
Both groups had comparable characteristics at baseline. Their mean age was
about 71.5 years, and the age of their
stents averaged 13.5 years; about 15%
were female, about 72% had hypertension, about 36% had diabetes, about 7%
were current smokers, about 87% had
hyperlipidemia, and about 55% had a
previous MI. Also, disease characteristics
were similar between the two groups.
About 50% of patients had diffuse disease. More than 60% had unstable angina, and 99% had multivessel disease. Lesions were evenly distributed in the
saphenous vein graft. The degeneration
score for saphenous vein grafts and the
distribution of lesions within the graft
were similar between groups, with about
40% of patients having moderate or severely degenerative grafts.
At 1 year, the primary end point was
reduced by a significant 35% with DES,
compared with BMS, with rates of
15.4% and 22.1%, respectively. The reduction in the DES group was driven pri-
Keep Antiplatelet
Interruptions as
Brief as Possible
marily by a significant 52% reduction in
target vessel revascularizations, which
occurred in 7.2% of the DES patients,
compared with 13.1% of the BMS recipients.
Both types of stent were comparable
in safety, with a similar rate of stent
thrombosis, death, or myocardial infarction, said Dr. Mehilli. The rates of
all-cause death or MI were similar between the two groups, at 8.5% and
10.9% of patients in the DES and BMS
groups, respectively. One patient and
zero patients, respectively, experienced
ARC-definite stent thrombosis.
17
“Although saphenous vein graft lesions remain a challenging disease subset for angioplasty, this study demonstrates that DES can be safely used to
reduce adverse events in this high-risk
subset of patients,” Dr. Mehilli said.
She noted that, in Germany, the overwhelming majority of stents used in
saphenous vein graft lesions are DES,
and that the current study supports this
practice.
The study was funded by the German
Heart Center in Munich and by Cordis.
Dr. Mehilli has received lecture fees from
Abbott.
■
Reliable angina relief –
®
Nitrolingual Pumpspray
(nitroglycerin lingual spray)
EXPERT ANALYSIS FROM THE ANNUAL
ACADEMIC SURGICAL CONGRESS
–M. Alexander Otto
Stability & Potency
Rapid Pain Relief
Ease of Use
Indications and Usage Nitrolingual® Pumpspray is indicated for
acute relief of an attack or prophylaxis of angina pectoris due to
coronary artery disease.
Not actual size
stents who are on clopidogrel may need
to discontinue the drug to prevent excessive bleeding during surgery, but it
should be restarted as soon as possible,
according to Dr. Alan Dardik.
Continuing antiplatelet therapy during
the perioperative period is crucial, he noted, because “the risk of surgical bleeding,
if dual-antiplatelet therapy is continued,
is actually lower than the risk of coronary
thrombosis due to agent withdrawal.”
Antiplatelet drugs pose a considerable
bleeding risk: Aspirin can increase surgical blood loss up to 20%, and dual therapy up to 50%. According to Dr. Dardik,
however, although “many studies show
a small increase in complications from
this bleeding, particularly increased
transfusions, no study has actually
shown an increase in mortality.”
Meanwhile, the risk of a fatal myocardial infarction is high when antiplatelet
therapy is withdrawn, especially within 6
weeks of stent placement. The risk is especially high in patients with cancer, diabetes, and other hypercoagulable states,
and in those with long, multiple, or overlapping stents, Dr. Dardik said.
“Keep the nontherapeutic window
short, from about 3 days before the
surgery to 1-2 days afterward, [and] reload [patients] at high risk for thrombosis with 300 mg of clopidogrel,” Dr.
Dardik said at the meeting.
Since dual-antiplatelet therapy is standard for 6 months following stent placement, patients on clopidogrel (Plavix) will
almost certainly also be on aspirin. To offset the temporary loss of clopidogrel, he
recommended increasing the aspirin dose,
said Dr. Dardik, a vascular surgeon at Yale
University, New Haven, Conn.
The best option for recently stented patients is to postpone surgery for at least 6
months – the point at which dual-antiplatelet therapy can be stopped – or
even a year, when aspirin can also cease.
When that’s not possible, Dr. Dardik
recommends performing a less invasive
procedure, with easier hemostasis.
He said he has no relevant disclosures.
Fire extinguisher image does not depict actual product.
HUNTINGTON BEACH, CALIF. –
P atients with recently placed coronary
200 metered 60 metered
sprays
sprays
Important Safety Information Nitrolingual Pumpspray should
not be used while taking phosphodiesterase inhibitors which
are used for the treatment of erectile dysfunction. Nitrolingual
Pumpspray should be used with caution if patients have low
systolic blood pressure, are undergoing diuretic therapy, or show
hypersensitivity to this and other nitrates or nitrites. Headache
is the most commonly reported side effect with nitroglycerin.
Patients may also experience episodes of dizziness, weakness,
and other related side effects.
W W W. N I T R O L I N G U A L . C O M
© 2011 Arbor Pharmaceuticals, Inc.All rights reserved.
The following trademarks are either registered trademarks or trademarks of Pohl-Boskamp in the United States and/or other countries:Pohl-Boskamp word mark;
Pohl-Boskamp logo; Nitrolingual word mark; Peppermint flavor of nitroglycerin; Peppermint scent of nitroglycerin; Nitrolingual Pumpspray shapes; Nitrolingual
Pumpspray colors; and the sound of Nitrolingual Pumpspray.Arbor Pharmaceuticals' use of Nitrolingual is under license from G. Pohl-Boskamp GmbH & Co. KG.
Please see full Prescribing
Information on next page.
NL035.001
18
New Stent Showed Good Long-Term Safety
BY MITCHEL L. ZOLER
NEW ORLEANS – Presuming that the
Resolute zotarolimus-eluting coronary
stent enters the U.S. market within the
next year, interventionalists likely will
rely on data from two key studies to
weigh how it matches up against its
main competition, the Xience V/Promus
everolimus-eluting coronary stent.
Two features seemed to especially capture the attention of the cardiologists
who reported the data at the meeting
and those who heard it: the impressive
performance of the zotarolimus-eluting
stent (ZES) in patients with diabetes,
and the long-term safety of the ZES
compared with the everolimus-eluting
stent (EES) for stent thrombosis.
One of the two studies was the
(nitroglycerin lingual spray)
400 mcg per spray, 60 or 200 Metered Sprays
DESCRIPTION: Nitroglycerin, an organic nitrate, is a vasodilator which has effects on both arteries
and veins. The chemical name for nitroglycerin is 1,2,3-propanetriol trinitrate (C3H5N3O9). The
compound has a molecular weight of 227.09. The chemical structure is:
CH2 —ONO2
CH —ONO2
CH2 —ONO2
Nitrolingual® Pumpspray (nitroglycerin lingual spray 400 mcg) is a metered dose spray containing
nitroglycerin. This product delivers nitroglycerin (400 mcg per spray, 60 or 200 metered sprays) in the
form of spray droplets onto or under the tongue. Inactive ingredients: medium-chain triglycerides,
dehydrated alcohol, medium-chain partial glycerides, peppermint oil.
CLINICAL PHARMACOLOGY: The principal pharmacological action of nitroglycerin is relaxation
of vascular smooth muscle, producing a vasodilator effect on both peripheral arteries and veins
with more prominent effects on the latter. Dilation of the post-capillary vessels, including large veins,
promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing
left ventricular end-diastolic pressure (pre-load). Arteriolar relaxation reduces systemic vascular
resistance and arterial pressure (after-load).
The mechanism by which nitroglycerin relieves angina pectoris is not fully understood. Myocardial
oxygen consumption or demand (as measured by the pressure-rate product, tension-time index,
and stroke-work index) is decreased by both the arterial and venous effects of nitroglycerin and
presumably, a more favorable supply-demand ratio is achieved.
While the large epicardial coronary arteries are also dilated by nitroglycerin, the extent to which this
action contributes to relief of exertional angina is unclear.
Nitroglycerin is rapidly metabolized in vivo, with a liver reductase enzyme having primary
importance in the formation of glycerol nitrate metabolites and inorganic nitrate. Two active major
metabolites, 1,2- and 1,3-dinitroglycerols, the products of hydrolysis, although less potent as
vasodilators, have longer plasma half-lives than the parent compound. The dinitrates are further
metabolized to mononitrates (considered biologically inactive with respect to cardiovascular effects)
and ultimately glycerol and carbon dioxide.
Therapeutic doses of nitroglycerin may reduce systolic, diastolic and mean arterial blood pressure.
Effective coronary perfusion pressure is usually maintained, but can be compromised if blood
pressure falls excessively or increased heart rate decreases diastolic filling time.
Elevated central venous and pulmonary capillary wedge pressures, pulmonary vascular resistance
and systemic vascular resistance are also reduced by nitroglycerin therapy. Heart rate is usually slightly
increased, presumably a reflex response to the fall in blood pressure. Cardiac index may be increased,
decreased, or unchanged. Patients with elevated left ventricular filling pressure and systemic vascular
resistance values in conjunction with a depressed cardiac index are likely to experience an
improvement in cardiac index. On the other hand, when filling pressures and cardiac index are normal,
cardiac index may be slightly reduced.
In a pharmacokinetic study when a single 0.8 mg dose of Nitrolingual® Pumpspray was
administered to healthy volunteers (n = 24), the mean Cmax and Tmax were 1,041pg/mL · min
and 7.5 minutes, respectively. Additionally, in these subjects the mean area-under-the-curve
(AUC) was 12,769 pg/mL · min.
In a randomized, double-blind single-dose, 5-period cross-over study in 51 patients with exertional
angina pectoris significant dose-related increases in exercise tolerance, time to onset of angina and
ST-segment depression were seen following doses of 0.2, 0.4, 0.8 and 1.6 mg of nitroglycerin
delivered by metered pumpspray as compared to placebo.
Additionally the drug was well tolerated as evidenced by a profile of generally mild to moderate
adverse events.
INDICATIONS AND USAGE: Nitrolingual® Pumpspray is indicated for acute relief of an attack or
prophylaxis of angina pectoris due to coronary artery disease.
CONTRAINDICATIONS: Allergic reactions to organic nitrates are rare. Nitroglycerin is
contraindicated in patients who are allergic to it. Nitrolingual® Pumpspray is contraindicated in
patients taking certain drugs for erectile dysfunction (phosphodiesterase inhibitors), as their
concomitant use can cause severe hypotension. The time course and dose-dependency of this
interaction are not known.
WARNINGS: Amplification of the vasodilatory effects of Nitrolingual® Pumpspray by certain drugs
(phosphodiesterase inhibitors) used to treat erectile dysfunction can result in severe hypotension.
The time course and dose dependence of this interaction have not been studied. Appropriate
supportive care has not been studied, but it seems reasonable to treat this as a nitrate overdose,
with elevation of the extremities and with central volume expansion. The use of any form of
nitroglycerin during the early days of acute myocardial infarction requires particular attention to
hemodynamic monitoring and clinical status.
PRECAUTIONS: (General) Severe hypotension, particularly with upright posture, may occur even
with small doses of nitroglycerin. The drug, therefore, should be used with caution in subjects who
may have volume depletion from diuretic therapy or in patients who have low systolic blood
pressure (e.g., below 90 mm Hg). Paradoxical bradycardia and increased angina pectoris may
accompany nitroglycerin-induced hypotension.
Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.
Tolerance to this drug and cross-tolerance to other nitrates and nitrites may occur. Tolerance to the
vascular and anti-anginal effects of nitrates has been demonstrated in clinical trials, experience through
occupational exposure, and in isolated tissue experiments in the laboratory.
In industrial workers continuously exposed to nitroglycerin, tolerance clearly occurs. Moreover,
physical dependence also occurs since chest pain, acute myocardial infarction, and even sudden
death have occurred during temporary withdrawal of nitroglycerin from the workers. In various
clinical trials in angina patients, there are reports of anginal attacks being more easily provoked and
of rebound in the hemodynamic effects soon after nitrate withdrawal. The relative importance of these
observations to the routine, clinical use of nitroglycerin is not known.
PRECAUTIONS: (INFORMATION FOR PATIENTS)
Physicians should discuss with patients that Nitrolingual® Pumpspray should not be used with
certain drugs taken for erectile dysfunction (phosphodiesterase inhibitors) because of the risk of
lowering their blood pressure dangerously.
DRUG INTERACTIONS: Alcohol may enhance sensitivity to the hypotensive effects of nitrates.
Nitroglycerin acts directly on vascular muscle. Therefore, any other agents that depend on vascular
smooth muscle as the final common path can be expected to have decreased or increased effect
depending upon the agent.
Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers
and oral controlled-release nitroglycerin were used in combination. Dose adjustments of either
class of agents may be necessary.
Concomitant use of nitric oxide donors (like Nitrolingual® Pumpspray) and certain drugs for the
treatment of erectile dysfunction (phosphodiesterase inhibitors) can amplify their vasodilatory
effects, resulting in severe hypotension. The concomitant use of these drugs is contraindicated (see
CONTRAINDICATIONS) and alternative therapies should be used to treat acute angina episodes.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Animal carcinogenesis
studies with sublingual nitroglycerin have not been performed.
Rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years developed dose-related
fibrotic and neoplastic changes in liver, including carcinomas, and interstitial cell tumors in testes.
At high dose, the incidences of hepatocellular carcinomas in both sexes were 52% vs. 0% in
controls, and incidences of testicular tumors were 52% vs. 8% in controls. Lifetime dietary
administration of up to 1058 mg/kg/day of nitroglycerin was not tumorigenic in mice.
RESOLUTE All Comers trial, which
compared the ZES against the EES in
a randomized trial of 2,292 European patients for whom follow-up now extends
to 2 years.
The second study, RESOLUTE US,
evaluated the new ZES in a series of
1,402 U.S. patients with a high, 34%
prevalence of diabetes; this study had a
special focus on the stent’s performance
in the 150 narrow, 2.25-mm-diameter ar-
Nitroglycerin was weakly mutagenic in Ames tests performed in two different laboratories.
Nevertheless, there was no evidence of mutagenicity in an in vivo dominant lethal assay with
male rats treated with doses up to about 363 mg/kg/day, p.o., or in in vitro cytogenic tests in rat and
dog tissues.
In a three-generation reproduction study, rats received dietary nitroglycerin at doses up to about
434 mg/kg/day for six months prior to mating of the F0 generation with treatment continuing through
successive F1 and F2 generations. The high dose was associated with decreased feed intake and body
weight gain in both sexes at all matings. No specific effect on the fertility of the F0 generation was seen.
Infertility noted in subsequent generations, however, was attributed to increased interstitial cell tissue
and aspermatogenesis in the high-dose males. In this three-generation study there was no clear
evidence of teratogenicity.
PREGNANCY: Pregnancy Category C – Animal teratology studies have not been conducted with
nitroglycerin-pumpspray. Teratology studies in rats and rabbits, however, were conducted with topically
applied nitroglycerin ointment at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively. No toxic
effects on dams or fetuses were seen at any dose tested. There are no adequate and well-controlled
studies in pregnant women. Nitroglycerin should be given to pregnant women only if clearly needed.
NURSING MOTHERS: It is not known whether nitroglycerin is excreted in human milk. Because many
drugs are excreted in human milk, caution should be exercised when Nitrolingual® Pumpspray is
administered to a nursing woman.
PEDIATRIC USE: Safety and effectiveness of nitroglycerin in pediatric patients have not
been established.
ADVERSE REACTIONS: Adverse reactions to oral nitroglycerin dosage forms, particularly headache
and hypotension, are generally dose-related. In clinical trials at various doses of nitroglycerin, the
following adverse effects have been observed: Headache, which may be severe and persistent, is the
most commonly reported side effect of nitroglycerin with an incidence on the order of about 50% in
some studies. Cutaneous vasodilation with flushing may occur. Transient episodes of dizziness and
weakness, as well as other signs of cerebral ischemia associated with postural hypotension, may
occasionally develop. Occasionally, an individual may exhibit marked sensitivity to the hypotensive
effects of nitrates and severe responses (nausea, vomiting, weakness, restlessness, pallor, perspiration
and collapse) may occur even with therapeutic doses. Drug rash and/or exfoliative dermatitis have been
reported in patients receiving nitrate therapy. Nausea and vomiting appear to be uncommon.
Nitrolingual® Pumpspray given to 51 chronic stable angina patients in single doses of 0.4, 0.8 and 1.6
mg as part of a double-blind, 5-period single-dose cross-over study exhibited an adverse event profile
that was generally mild to moderate. Adverse events occurring at a frequency greater than 2% included:
headache, dizziness, and paresthesia. Less frequently reported events in this trial included (≤2%):
dyspnea, pharyngitis, rhinitis, vasodilation, peripheral edema, asthenia, and abdominal pain.
OVERDOSAGE: Signs and Symptoms:
Nitrate overdosage may result in: severe hypotension, persistent throbbing headache, vertigo,
palpitation, visual disturbance, flushing and perspiring skin (later becoming cold and cyanotic), nausea
and vomiting (possibly with colic and even bloody diarrhea), syncope (especially in the upright posture),
methemoglobinemia with cyanosis and anorexia, initial hyperpnea, dyspnea and slow breathing, slow
pulse (dicrotic and intermittent), heart block, increased intracranial pressure with cerebral symptoms of
confusion and moderate fever, paralysis and coma followed by clonic convulsions, and possibly death
due to circulatory collapse.
Methemoglobinemia:
Case reports of clinically significant methemoglobinemia are rare at conventional doses of organic
nitrates. The formation of methemoglobin is dose-related and in the case of genetic abnormalities of
hemoglobin that favor methemoglobin formation, even conventional doses of organic nitrates could
produce harmful concentrations of methemoglobin.
Treatment of Overdosage:
Keep the patient recumbent in a shock position and comfortably warm. Passive movement of the
extremities may aid venous return. Administer oxygen and artificial ventilation, if necessary. If
methemoglobinemia is present, administration of methylene blue (1% solution), 1-2 mg per kilogram of
body weight intravenously, may be required. If an excessive quantity of Nitrolingual® Pumpspray has
been recently swallowed gastric lavage may be of use.
WARNING: Epinephrine is ineffective in reversing the severe hypotensive events associated with
overdosage. It and related compounds are contraindicated in this situation.
DOSAGE AND ADMINISTRATION: At the onset of an attack, one or two metered sprays should be
administered onto or under the tongue. No more than three metered sprays are recommended within a
15-minute period. If the chest pain persists, prompt medical attention is recommended. Nitrolingual®
Pumpspray may be used prophylactically five to ten minutes prior to engaging in activities which might
precipitate an acute attack.
Each metered spray of Nitrolingual® Pumpspray delivers 48 mg of solution containing 400 mcg of
nitroglycerin after an initial priming of 5 sprays. It will remain adequately primed for 6 weeks. If the
product is not used within 6 weeks it can be adequately reprimed with 1 spray. Longer storage periods
without use may require up to 5 repriming sprays. There are 60 or 200 metered sprays per bottle. The
total number of available doses is dependent, however, on the number of sprays per use (1 or 2
sprays), and the frequency of repriming.
The transparent container can be used for continuous monitoring of the consumption. The end of the
pump should be covered by the fluid level. Once fluid falls below the level of the center tube, sprays
will not be adequate and the container should be replaced. As with all other sprays, there is a residual
volume of fluid at the bottom of the bottle which cannot be used.
During application the patient should rest, ideally in the sitting position. The container should be held
vertically with the valve head uppermost and the spray orifice as close to the mouth as possible. The
dose should preferably be sprayed onto the tongue by pressing the button firmly and the mouth should
be closed immediately after each dose. THE SPRAY SHOULD NOT BE INHALED. The medication
should not be expectorated or the mouth rinsed for 5 to 10 minutes following administration. Patients
should be instructed to familiarize themselves with the position of the spray orifice, which can be
identified by the finger rest on top of the valve, in order to facilitate orientation for administration at night.
HOW SUPPLIED: Each box of Nitrolingual® Pumpspray contains one glass bottle coated with red
transparent plastic which assists in containing the glass and medication should the bottle be shattered.
Each bottle contains 4.9 g or 12 g (Net Content) of nitroglycerin lingual spray which will deliver 60 or 200
metered sprays containing 400 mcg of nitroglycerin per spray after priming.
Nitrolingual® Pumpspray is available as:
• 60-dose (4.9 g) single bottle NDC 24338-300-65
• 200-dose (12 g) single bottle NDC 24338-300-20
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
Room Temperature].
Note: Nitrolingual® Pumpspray contains 20% alcohol. Do not forcefully open or burn container after use.
Do not spray toward flames. Rx Only.
Manufactured for
Arbor Pharmaceuticals, Raleigh, North Carolina 27609
by G. Pohl-Boskamp GmbH & Co. KG,
25551 Hohenlockstedt, Germany
Rev. 09/10
teries included in the series.
The roughly 2,500 ZES recipients included in these two studies form about
half of the 5,227 total–patient worldwide
experience with the stent to date, and constituted what Medronic, the company developing the Resolute ZES, submitted to
the Food and Drug Administration for
marketing approval and labeling.
One major take on these data by experts was that the ZES showed good
overall performance that matched well
with the performance of the EES.
The two stents “seemed to be fairly
equivalent for most of the important
safety and efficacy metrics. They are
‘The results were
quite substantial,’
with a 3.0% rate
of target-lesion
revascularization
among diabetes
patients.
DR. LEON
both superb,” said Dr. Martin B. Leon, director of the center for interventional
vascular therapy at Columbia University in New York, and lead investigator for
the RESOLUTE US study.
But other interventionalists hearing
the data from both studies weren’t as
completely convinced.
“My initial take on the data is that [the
ZES] doesn’t seem to be better than the
Xience stent, which is a very good stent
and the dominant stent we use [in the
United States] at this time,” Dr. Abhiram
Prasad, an interventional cardiologist and
professor of medicine at the Mayo Clinic
in Rochester, Minn., said in an interview.
Safety concerns with the ZES date
back to the initial, 12-month follow-up
report, the first indication that the ZES
fell short compared with the EES on the
rate of stent thrombosis in the RESOLUTE All Comers trial. The New England Journal of Medicine report last year
(2010;363:136-46) documented 18 patients (1.6%) with definite or probable
stent thrombosis in the ZES arm, compared with 8 cases (0.7%) of definite or
probable stent thrombosis in the EES
group, a significant difference.
The new, 24-month follow-up data
provided some reassurance on safety, in
that the stent thrombosis gap between
the two stents stayed stable. During an
extra year of follow-up, three new cases of definite or probable stent thrombosis occurred in each of the two treatment arms, said Dr. Patrick W. Serruys,
professor of interventional cardiology
at Erasmus University and the Thoraxcentrum, Rotterdam, and lead investigator for the RESOLUTE All Comers
trial. Aside from this one early safety deviation, the ZES and EES continued to
show virtually identical efficacy performance through the 2 years of study, he
showed in the updated data. Concurrently with his report at the meeting,
the results appeared in an article pubContinued on following page
Continued from previous page
lished in the Lancet ( 2011 [doi:10.
1016/S0140 6736(11)60404-2]).
Dr. Serruys, as well as others, chalked
up the early difference in stent thrombosis rates to chance, and to some isolated poor performance in certain sites
undertaking the coronary interventions.
“Numerically, the stent thrombosis is
very small, a difference of 21 vs. 11 patients in more than 2,000 total patients.
It could be the play of chance,” Dr. Serruys said.
The RESOLUTE US results seemed to
add to the safety assurance. In those
1,402 patients, two cases (0.1%) of stent
thrombosis occurred during 12 months
of tracking. Concurrently with Dr.
Leon’s report, the RESOLUTE US results appeared in the Journal of the
American College of Cardiology (2011
April 4 [doi:10.1016/j.jacc.2011.03.005]).
“This is one of the lowest 1-year stent
thrombosis rates ever reported,” noted
Dr. Leon. “I take from this that it’s a safe
stent.”
The pattern of some of the earliest cases of stent thrombosis in RESOLUTE All
Comers suggested that it may have been
caused more by operator failings and less
by problems with the stent itself. During
the study’s first 30 days, stent thrombosis occurred in nine ZES patients and one
Comers diabetes subgroup, you have a
robust enough population to justify consideration for approval, I think,” he said.
“The results were quite substantial,”
with a 3.0% rate of target-lesion revascularization among the patients with diabetes, compared with a 2.0% rate for
the entire main cohort of the study.”
But even if the diabetes indication
works out, will interventionalists be
swayed by that, or by the data?
“An issue is, to what extent can a single trial address a subgroup?” said Dr.
Krucoff. “To what degree is there statistical guidance that in the real world [the
ZES] would live up to this measure?”
“I don’t think I’d put a lot of emphasis in my decision making on the [RESOLUTE US] data, because a problem
with all [stenting] studies is that the rates
are constantly improving, so the new device can appear to be better. ... Even if
[the ZES] was approved for use in patients with diabetes, I don’t think in my
practice I’d pick it to use in those patients. They'd need to do a randomized
study in patients with diabetes to convince me” that it was better than the
EES, Dr. Prasad said.
Dr. Serruys and Dr. Prasad had no rel-
evant financial disclosures. Dr. Leon serves
as an unpaid consultant to Abbott, Boston
Scientific, and Medtronic. Dr. Yeung
serves on the scientific advisory board of
Medtronic; he is also a consultant for Abbott Vascular, Boston Scientific, and
Cordis, and has received research grants
from Boston Scientific, Edwards, and
Medtronic. Dr. Fontana is an employee of
Medtronic. Dr. Krucoff has been a consultant to or has received honoraria from
Abbott, Biosensors, Cardiomind, Cordis
Johnson & Johnson, Medtronic, Merck,
Micelle, OrbusNeich, Prescient, SanofiAventis, and Terumo.
■
The ZES and EES
continued to
show virtually
identical efficacy
performance
through the
2 years of study.
DR. SERRUYS
EES patient, making up most of the differential that wound up haunting the
ZES arm through the next 2 years. “Stent
thrombosis during the first 30 days is procedure related,” and generally the stent
itself plays no role, said Dr. Alan C.
Yeung, professor of medicine and director of cardiac catheterization at Stanford
(Calif.) University.
“Whether it’s a real difference or a play
of chance remains undetermined,” commented Dr. Mitchell W. Krucoff, a professor of medicine and interventional
cardiologist at Duke University in
Durham, N.C. “These types of differences [21 patients vs. 11 patients] are not
certain at a statistical level.”
So if the ZES hopes to wrest any
market share from the EES when it hits
the U.S. market, it may need to have
something to distinguish it, and that
something may be an FDA-approved
indication for treatment of coronary
stenoses in patients with diabetes. At
least that’s what Medtronic is hoping
for. The company included that application in its submission to the FDA, Jason Fontana, Ph.D., senior director for
clinical communication at Medtronic,
said in an interview.
“The diabetes subgroup was large
enough, and the diabetes analysis was
prespecified” in RESOLUTE US, Dr.
Leon said in an interview. “If you include
this subgroup, and the RESOLUTE All
19
A Critical Measure of Patient Health
20
ARRHYTHMIAS & ELECTROPHYSIOLOGY
BY ALICE GOODMAN
NEW ORLEANS – A specialized clin-
ic that relies on a three-pronged team
approach for the treatment of atrial fibrillation achieved substantial reductions
in cardiovascular hospitalizations and
cardiovascular deaths, compared with
usual care, in a randomized, open-label
trial.
Specifically, cardiovascular death was
reduced by nearly three-fourths with the
specialized intervention. The three pillars
of the program were nurse-led care,
guideline-directed management of atrial fibrillation (AF), and support software
based on clinical guidelines.
“Effective AF management can enhance appropriate treatment, coordinate
the delivery of care more efficiently, and
lead to improved outcomes, as we have
‘We can’t pinpoint the
nurses or guidelines or software
as the sole reason for our
results. I think the secret is the
integrated approach, combining
these three ingredients.’
shown in this trial. We can’t pinpoint the
nurses or guidelines or software as the
sole reason for our results. I think the secret is the integrated approach, combining these three ingredients,” said principal investigator Dr. Robert G. Tieleman
of Martini Hospital Groningen (the
Netherlands), who presented the results
jointly with Jeroen M.L. Hendriks, a
nurse at Maastricht (the Netherlands)
Hospital, at the meeting.
AF treatment guidelines are followed
only about 60% of the time, according to
the European Heart Survey of 5,000 patients in 35 countries. The survey findings led the Dutch researchers to design
an AF treatment program based on established guidelines.
At visit 1, nurses gave patients extensive questionnaires to fill out, took medical histories, performed physical exams, and administered additional tests
as needed. At visit 2, a supervising cardiologist and the nurse examined the
patient’s profile (created from a computerized database of information obtained on that patient at visit 1), and the
software provided a treatment plan for
each patient based on AF guidelines
and oral anticoagulation therapy to prevent clotting. Follow-up visits with the
nurse focused on treatment according
to guidelines, including medications,
devices, smoking cessation, lifestyle,
and education.
For the study, 712 patients with newly diagnosed AF were randomized to
nurse-led care or usual care by a general cardiologist, and were followed for at
least 1 year. The patients’ mean age was
66 years. About 55% of the nurse-led
group and 62% of the usual-care group
VITALS
Atrial Fib Clinic Cut Deaths, Hospitalizations
Major Finding: The combined end point of cardiovascular
death or hospitalization was met by 51 patients (14.3%) in the
nurse-led group and by 74 patients (20.8%) in the usual-care
group, for a significant relative risk reduction of 35%. Cardiovascular deaths were 72% lower in the nurse-led group.
Data Source: An open-label study in 712 patients with newly
diagnosed AF who were randomized to nurse-led care or usual
care by a general cardiologist.
Disclosures: Dr. Tieleman and Mr. Hendriks said they had no
relevant financial disclosures.
were men. Overall, about 54% of patients had paroxysmal AF, about 15% had persistent AF, and about 22%
had permanent AF. About 83% were symptomatic.
At a mean follow-up of 22 months, the primary composite end point of cardiovascular death or hospitalization occurred in 51 patients (14.3%) in the nurse-led
group and in 74 patients (20.8%) in the usual-care
group, representing a significant relative risk reduction
of 35% for those randomized to nurse-led care.
Cardiovascular death was reduced by 72% in the
nurse-led care group: 4 patients (1.1%) vs. 14 patients
Effient® (prasugrel) is indicated to reduce the rate of thrombotic cardiovascular (CV) events (including stent thrombosis)
in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI)
as follows: [1] patients with unstable angina (UA) or non–ST-elevation myocardial infarction (NSTEMI); [2] patients with
ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI.
ARRHYTHMIAS & ELECTROPHYSIOLOGY
(3.9%), respectively. Cardiovascular hos- the nurse-led group adhered to the rec- similar atrial fibrillation clinics.
Dr. Byron Kwock Lee of the Univerpitalizations were reduced by 34% in ommendation related to appropriate anthe nurse-led care group: 48 patients tithrombotic therapy, compared with sity of California, San Francisco, said
“this study underscores the complexity
(13.5%) vs. 68 patients (19.1%), respec- 83% of the usual-care group.
of AF and how important it is
tively. Guidelines for AF were
to stay on top of all the anfollowed much more often in
Cardiovascular mortality was reduced by
gles.”
the nurse-led group, as would
72% in the nurse-led care group: 4 patients
Dr. Prakash C. Deedwania,
be expected.
professor of medicine at the
Six different recommendavs. 14 patients in the usual care group.
University of California, San
tions (two related to diagnosThe AF clinic has been incorporated Francisco in Fresno, commented: “This
tics and four to therapy) were followed.
In the nurse-led group, these six guide- into the official outpatient clinic at the is a relevant study that touches on the
crux of the problem of managing AF in
lines were followed 80% of the time, university hospital.
The Maastricht team is helping other this current cost-control environment.
compared with 40% of the time in the
usual-care group. Importantly, 99% of hospitals in the Netherlands to set up I’m struck by the excellent outcomes
Effient plus aspirin (ASA) provided
STRONGER PROTECTION
vs Plavix® (clopidogrel bisulfate) plus ASA against thrombotic cardiovascular (CV)
events (including stent thrombosis)
In the overall UA/NSTEMI population, event rates* for Effient plus ASA and Plavix plus ASA were 9.3% and
11.2%, respectively (1.9% ARR†; P=0.002). In the overall STEMI population, event rates for Effient plus ASA
and Plavix plus ASA were 9.8% and 12.2%, respectively (2.4% ARR; P=0.02)1,2
Difference in treatments was primarily driven by a significant reduction in nonfatal myocardial infarctions (MIs),
with no significant difference in CV death or nonfatal stroke1
– In the overall study population, approximately 40% of MIs occurred periprocedurally and were detected
solely by changes in CK-MB
52% RRR‡ in stent thrombosis in the all-ACS population with Effient plus ASA vs Plavix plus ASA
(1.1% vs 2.2%; 1.1% ARR; P<0.0001) 3
TRITON-TIMI 38 was a head-to-head study comparing Effient (60-mg loading dose [LD], followed by 10-mg
once-daily maintenance dose) plus ASA with Plavix (300-mg LD, followed by a 75-mg once-daily maintenance dose)
plus ASA in 13,608 patients with ACS managed with PCI (median duration 14.5 months)
– In TRITON-TIMI 38, the LD of Plavix was delayed relative to the placebo-controlled trials that supported its
approval for ACS
For more information, please visit EffientHCP.com or Effientconferences.com.
SELECTED SAFETY, INCLUDING SIGNIFICANT BLEEDING RISK
Effient can cause significant, sometimes fatal, bleeding. In TRITON-TIMI 38, overall rates of non-CABG TIMI
major or minor bleeding were significantly higher with Effient plus ASA (4.5%) compared with Plavix plus ASA
(3.4%). In patients who underwent CABG (n=437), the rates of CABG-related TIMI major or minor bleeding
were 14.1% with Effient plus ASA and 4.5% with Plavix plus ASA.
IMPORTANT SAFETY INFORMATION
WARNING: BLEEDING RISK
Effient® (prasugrel) can cause significant, sometimes fatal, bleeding. Do not use Effient in patients with active
pathological bleeding or a history of transient ischemic attack or stroke. In patients ≥75 years of age, Effient is
generally not recommended, because of the increased risk of fatal and intracranial bleeding and uncertain
benefit, except in high-risk situations (patients with diabetes or a history of prior myocardial infarction [MI])
where its effect appears to be greater and its use may be considered. Do not start Effient in patients likely to
undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue Effient at least
7 days prior to any surgery. Additional risk factors for bleeding include: body weight <60 kg, propensity to
bleed, concomitant use of medications that increase the risk of bleeding (eg, warfarin, heparin, fibrinolytic
therapy, chronic use of nonsteroidal anti-inflammatory drugs [NSAIDs]). Suspect bleeding in any patient who
is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI),
CABG, or other surgical procedures in the setting of Effient. If possible, manage bleeding without discontinuing
Effient. Discontinuing Effient, particularly in the first few weeks after acute coronary syndrome, increases the
risk of subsequent cardiovascular events.
CONTRAINDICATIONS
Effient is contraindicated in patients with active pathological bleeding, such as from a peptic ulcer or intracranial
hemorrhage (ICH), or a history of transient ischemic attack (TIA) or stroke, and in patients with hypersensitivity
to prasugrel or any component of the product
Patients who experience a stroke or TIA while on Effient generally should have therapy discontinued.
Effient should also be discontinued for active bleeding and elective surgery
Premature discontinuation of Effient increases risk of stent thrombosis, MI, and death
Thrombotic thrombocytopenic purpura (TTP), a rare but serious condition that can be fatal, has been reported with
Effient, sometimes after a brief exposure (<2 weeks), and requires urgent treatment, including plasmapheresis
ADVERSE REACTIONS
Bleeding, including life-threatening and fatal bleeding,
is the most commonly reported adverse reaction
Please see Brief Summary of Prescribing
Information on subsequent pages.
*As measured by reduction in the primary composite endpoint
of CV death, nonfatal MI, or nonfatal stroke.
†
Absolute risk reduction.
‡
Relative risk reduction.
21
achieved by this team approach.”
Dr. Tieleman said that a cost analysis
will be conducted, but that he is confident that the team (nurse-led) approach
will be cost effective.
“Hospital admissions are costly. Nurses are cheaper,” he commented.
■
To see a video
interview with Dr.
Deedwania, scan this
QR code or visit
www.youtube.com/
watch?v=6zp_F1ffgc.
22
HEART FAILURE
Frequent Limb Movement Linked to LVH
BY ALICE GOODMAN
NEW ORLEANS – Frequent periodic
leg movements during sleep were associated with left ventricular hypertrophy
in patients with restless legs syndrome,
in a study presented at the meeting.
Moreover, patients who had sleep disturbance due to frequent periodic leg
movements and severe LVH were at increased risk for heart failure, recurrent
hospitalizations, and death.
“We have known for a long time that
LVH is a poor prognostic factor that increases the risk of cardiac events. What
is new ... is that it appears that restless
legs syndrome is another risk factor that
may predispose patients to, and lead to
more complications of, LVH,” Dr. Arshad Jahangir said at the meeting.
Dr. Jahangir, principal investigator in
the study and professor of medicine at
the Mayo Clinic in Scottsdale, Ariz., said
that the findings need to be confirmed in
larger studies. Also, it will be important
to evaluate whether effective treatments
for restless legs syndrome can prevent adverse outcomes associated with LVH.
Approximately 12 million Americans
have restless legs syndrome. The condition is increasingly common with age
and is implicated in about one-third of all
cases of insomnia. Up to 90% of patients
also have periodic limb movement disorder. The mechanisms that drive the disorder are not fully understood, Dr. Jahangir said, but the sympathetic nervous
system is involved and patients typically
have increased heart rate and blood pressure.
The study enrolled 584 restless legs
syndrome patients who underwent
Effient is indicated to reduce the rate of thrombotic
CV events (including stent thrombosis) in UA/NSTEMI
patients who are to be managed with PCI and in STEMI
patients when managed with primary or delayed PCI.
REDUCTIONS IN THROMBOTIC CV EVENTS
IN TRITON-TIMI 38 INCLUDING HIGH-RISK PATIENTS
SUCH AS THOSE WITH DIABETES*
†1,2
The reduction in the primary composite endpoint of CV death, nonfatal MI, or nonfatal stroke in patients with
diabetes treated with Effient plus ASA compared with Plavix plus ASA was consistent with those observed in
the overall UA/NSTEMI and STEMI populations
UA/NSTEMI
OVERALL
UA/NSTEMII
WITH DIABETES
ES
STEMI
WITH DIABETES
W
STEMI
OVERALL
Event rates:
Plavix + ASA 11.2%
(n=5030)
Event rates:
Plavix + ASA 15.0%
%
(n=1226)
Event rates:
Plavix + ASA 18.6%
P
(n=344)
Event rates:
Plavix + ASA 12.2%
(n=1765)
Effient + ASA 9.3%
(n= 5044)
P=0.002
Effient + ASA 10.8%
%
(n=1246)
P=0.002
Effient + ASA 13.6%
(n=330)
P=0.08
Effient + ASA 9.8%
(n=1769)
P=0.02
18% RRR
1.9% ARR
30% RRR
4.2% ARR
29% RRR
5.0% ARR
21% RRR
2.4% ARR
‡
§
*As measured by reduction in the primary composite endpoint off CV
V death, non
nonfatal
onf
nfat
nf
ata
t lM
MI,I, or nno
non
nonfatal
oonfatal stro
stroke.
oke. †TThe LD of Effient was 60 mg followed by a 10-mg daily dose
aily do
ddose
ose
se (p
((plus
(pl
ppllus ASA).
ASA ‡Relat
ASA
Relative
tive rrisk reduction. §Absolute risk reduction.
(plus ASA) and the loading dose of Plavix was 300 mg followed by a 75-mg da
daily
Difference in treatments was primarily driven
ven bbyy a significant
n reduction iinn nonfatal MIs, with no significant difference
in CV death or nonfatal stroke1
– In the overall study population, approximately
ately 4
0 of MIs oc
0%
ccurred per
40%
occurred
periprocedurally and were detected solely by
changes in CK-MB
In TRITON-TIMI 38, the LD of Plavix was delayed rela
relative
lative to the pl
placeboplacebo-controlled trials that supported its approval
for ACS
TRITON-TIMI 38 was not designed or powered
wered to demons
demonstrate
nstrate independ
independent
n
efficacy or safety in the diabetes subgroup
SELECTED SAFETY, INCLUDING SIGNIFICANT BLEEDING RISK
Effient can cause significant, sometimes fatal, bleeding. In TRITON-TIMI 38, overall rates of non-CABG TIMI major or minor bleeding
were significantly higher with Effient plus ASA (4.5%) compared with Plavix plus ASA (3.4%). In patients who underwent CABG
(n=437), the rates of CABG-related TIMI major or minor bleeding were 14.1% with Effient plus ASA and 4.5% with Plavix plus ASA.
HEART FAILURE
overnight polysomnography studies. Patients were stratified according to frequency of leg movements during sleep:
45% had frequent leg movements, defined as a Periodic Movement Index
[PMI] of more than 35 per hour, and
55% had infrequent leg movements, defined as a PMI of 35 or fewer movements
per hour. Despite having a left ventricular ejection fraction of around 60% at
baseline, the group with frequent periodic limb movements had a significantly higher left ventricular mass, mass index, and posterior wall thickness,
indicating the presence of LVH.
At baseline, the groups with frequent
versus infrequent periodic limb movements had similar clinical and echocardiographic parameters, and were comparable for the presence of cardiovascular
risk factors, including hypertension, diabetes, heart failure, and renal dysfunction. Patients with frequent periodic limb
movements were older (median age 67
vs. 61 years), more often male, had more
atrial fibrillation (30% vs. 17%), and more
underlying coronary heart disease than
those with infrequent periodic limb
movements.
The presence of severe LVH [defined as
left ventricular mass index >116 g/m2]
and atrial fibrillation led to a significantly
greater likelihood of heart failure, recurrent hospitalizations, and death over a
mean follow-up of 3 years. Dr. Jahangir
said that even in participants with frequent periodic limb movements and no
atrial fibrillation, patients with severe LVH
had a greater number of cardiac events.
Severe LVH was found in 37% of
those with atrial fibrillation and 20% of
those without it, suggesting that underlying electrical dysfunction and restless
legs syndrome may act together to lead
to adverse cardiovascular outcomes.
NON–CABG-RELATED BLEEDING:
TRITON-TIMI 38 ALL-ACS POPULATION,
INCLUDING DIABETES SUBGROUP*
1,4
Non-CABG TIMI major† bleeding
5.5
All–ACS
5
P=0.029
Diabetes§
Non-CABG TIMI major or minor‡ bleeding
All–ACS
Diabetes§
P=0.002
4.5
Patients (%)
3.5
3
2
1
3.8
3.4
2.5
1.5
4.9
4.5
4
1.7
2.2
2.2
2.3
Effient
+ ASA
(n=6741)
Plavix
+ ASA
(n=1553)
Effient
+ ASA
(n=1555)
.5
0
Plavix
+ ASA
(n=6716)
Plavix
+ ASA
(n=6716)
Effient
+ ASA
(n=6741)
Plavix
+ ASA
(n=1553)
Effient
+ ASA
(n=1555)
*Observed event rates. †Intracranial hemorrhage or clinically overt bleeding associated with a fall in hemoglobin ≥5 g/dL. ‡Clinically overt bleeding associated with a fall in
hemoglobin of ≥3 g/dL but <5 g/dL. §P value not provided because the trial was not designed to prospectively evaluate bleeding differences in subgroups.
In TRITON-TIMI 38, overall rates of non-CABG TIMI major and non-CABG TIMI major or minor bleeding were
significantly higher with Effient plus ASA compared with Plavix plus ASA1
In patients who underwent CABG (n=437), the rates of CABG-related TIMI major or minor bleeding were 14.1%
with Effient plus ASA and 4.5% with Plavix plus ASA. Do not start Effient in patients likely to undergo urgent CABG1
Patients at highest risk for non-CABG TIMI major or minor bleeding were those ≥75 years of age and/or those
<60 kg (132 lb)1
Effient is contraindicated in patients with active pathological bleeding, such as from a peptic ulcer or intracranial
hemorrhage (ICH), or a history of transient ischemic attack (TIA) or stroke, and in patients with hypersensitivity to
prasugrel or any component of the product1
– Patients who experience a stroke or TIA while on Effient generally should have therapy discontinued
Please see Important Safety Information, including Boxed Warning regarding bleeding risk, on previous page.
See also Brief Summary of Prescribing Information on subsequent pages.
23
The study was funded by the National Heart, Lung, and Blood Institute and
the Angel and Paul Harvey Cardiovascular Research Endowment to CardioGerontology Research Laboratory at
Mayo Clinic Arizona. Dr. Jahangir had no
relevant financial disclosures.
■
To see a video
interview with Dr.
Jahangir, scan this
QR code or visit
www.youtube.com/
watch?v=qvm1sSQ9
LdM&NR=1.
24
HEART FAILURE
STE-Guided Lead Placement Improved Outcomes
NEW ORLEANS – Using speckle-track-
ing echocardiography to guide pacemaker lead placement improved the outcomes
of cardiac resynchronization therapy
for patients with severe heart failure in the
TARGET trial.
When speckle-tracking echocardiogra-
phy (STE) was used to identify target sites
for pacemaker lead placement for individual patients, leads were more likely to
be placed at concordant sites. The result
was improved echocardiographic response
at 6 months – defined as a greater than
15% change in left ventricular end systolic
volume (LVESV) from baseline to 6month follow-up. The STE group had a
70% response as compared with a 55% response in the group with conventional
in 5IFSBQFVUJD 0VUDPNFT CZ 0ptimizing Platelet InhibitioN with
1SBTVHSFM
QBUJFOUT XJUI B IJTUPSZ PG 5*" PS JTDIFNJD TUSPLF >3
months prior to enrollment) had a higher rate of stroke on Effient
(6.5%; of which 4.2% were thrombotic stroke and 2.3% were
intracranial hemorrhage [ICH]) than on clopidogrel (1.2%; all
thrombotic). In patients without such a history, the incidence of stroke
was 0.9% (0.2% ICH) and 1.0% (0.3% ICH) with Effient and
clopidogrel, respectively. Patients with a history of ischemic stroke
within 3 months of screening and patients with a history of
IFNPSSIBHJDTUSPLFBUBOZUJNFXFSFFYDMVEFEGSPN53*50/5*.*
1BUJFOUTXIPFYQFSJFODFBTUSPLFPS5*"XIJMFPO&GýFOUHFOFSBMMZ
should have therapy discontinued [see Adverse Reactions (6.1) and
Clinical Studies (14)].
4.3 Hypersensitivity: Effient is contraindicated in patients with
hypersensitivity (e.g., anaphylaxis) to prasugrel or any component
of the product [see Adverse Reactions (6.2)].
5 WARNINGS AND PRECAUTIONS
5.1 General Risk of Bleeding: 5IJFOPQZSJEJOFT JODMVEJOH &GýFOU
increase the risk of bleeding. With the dosing regimens used in
53*50/5*.* 5*.*5ISPNCPMZTJTJO.ZPDBSEJBM*OGBSDUJPO
.BKPS
(clinically overt bleeding associated with a fall in hemoglobin ≥5 g/dL,
PSJOUSBDSBOJBMIFNPSSIBHF
BOE5*.*.JOPSPWFSUCMFFEJOHBTTPDJBUFE
with a fall in hemoglobin of ≥3 g/dL but <5 g/dL) bleeding events were
more common on Effient than on clopidogrel [see Adverse Reactions
(6.1)] 5IF CMFFEJOH SJTL JT IJHIFTU JOJUJBMMZ BT TIPXO JO 'JHVSF (events through 450 days; inset shows events through 7 days).
Figure 1: Non-CABG-Related TIMI Major or Minor Bleeding Events
with Effient persisted up to 7 days from the most recent dose of study
drug. For patients receiving a thienopyridine within 3 days prior to
$"#( UIFGSFRVFODJFTPG5*.*.BKPSPS.JOPSCMFFEJOHXFSF
BRIEF SUMMARY: Please see Full Prescribing Information
(12 of 45 patients) in the Effient group, compared with 5.0% (3 of 60
for additional information about Effient.
patients) in the clopidogrel group. For patients who received their last
dose of thienopyridine within 4 to 7 days prior to CABG, the frequencies
WARNING: BLEEDING RISK
EFDSFBTFEUPPGQBUJFOUT
JOUIFQSBTVHSFMHSPVQBOE
Effient can cause significant, sometimes fatal, bleeding [see
PGQBUJFOUT
JOUIFDMPQJEPHSFMHSPVQ
Warnings and Precautions (5.1 and 5.2) and Adverse Reactions
%POPUTUBSU&GýFOUJOQBUJFOUTMJLFMZUPVOEFSHPVSHFOU$"#( $"#(
(6.1)].
related bleeding may be treated with transfusion of blood products,
Do not use Effient in patients with active pathological bleeding
including packed red blood cells and platelets; however, platelet
or a history of transient ischemic attack or stroke [see
transfusions within 6 hours of the loading dose or 4 hours of the
Contraindications (4.1 and 4.2)].
maintenance dose may be less effective.
In patients ≥75 years of age, Effient is generally not
5.3 Discontinuation of Effient: Discontinue thienopyridines, including
recommended, because of the increased risk of fatal and
&GýFOUGPSBDUJWFCMFFEJOHFMFDUJWFTVSHFSZTUSPLFPS5*"5IFPQUJNBM
intracranial bleeding and uncertain benefit, except in highrisk situations (patients with diabetes or a history of prior MI)
duration of thienopyridine therapy is unknown. In patients who are
where its effect appears to be greater and its use may be
managed with PCI and stent placement, premature discontinuation of
considered [see Use in Specific Populations (8.5)].
any antiplatelet medication, including thienopyridines, conveys an
Do not start Effient in patients likely to undergo urgent
increased risk of stent thrombosis, myocardial infarction, and death.
coronary artery bypass graft surgery (CABG). When possible,
Patients who require premature discontinuation of a thienopyridine
discontinue Effient at least 7 days prior to any surgery.
will be at increased risk for cardiac events. Lapses in therapy should
be avoided, and if thienopyridines must be temporarily discontinued
Additional risk factors for bleeding include:
because of an adverse event(s), they should be restarted as soon as
tCPEZXFJHIU<60 kg
possible [see Contraindications (4.1 and 4.2) and Warnings and
tQSPQFOTJUZUPCMFFE
Precautions (5.1)].
tDPODPNJUBOUVTFPGNFEJDBUJPOTUIBUJODSFBTFUIFSJTLPG
bleeding (e.g., warfarin, heparin, fibrinolytic therapy,
5.4 Thrombotic Thrombocytopenic Purpura: 5ISPNCPUJD
chronic use of non-steroidal anti-inflammatory drugs
UISPNCPDZUPQFOJDQVSQVSB551
IBTCFFOSFQPSUFEXJUIUIFVTF
[NSAIDs])
PG&GýFOU 551DBOPDDVSBGUFSBCSJFGFYQPTVSFXFFLT
551
is a serious condition that can be fatal and requires urgent
Suspect bleeding in any patient who is hypotensive and has
USFBUNFOU JODMVEJOHQMBTNBQIFSFTJTQMBTNBFYDIBOHF
551JT
recently undergone coronary angiography, percutaneous
coronary intervention (PCI), CABG, or other surgical procedures
characterized by thrombocytopenia, microangiopathic hemolytic
in the setting of Effient.
anemia (schistocytes [fragment red blood cells] seen on
peripheral smear), neurological findings, renal dysfunction, and
If possible, manage bleeding without discontinuing Effient.
fever [see Adverse Reactions (6.2)].
Discontinuing Effient, particularly in the first few weeks after
6 ADVERSE REACTIONS
acute coronary syndrome, increases the risk of subsequent
6.1 Clinical Trials Experience: 5IF GPMMPXJOH TFSJPVT BEWFSTF
cardiovascular events [see Warnings and Precautions (5.3)].
reactions are also discussed elsewhere in the labeling:
t #MFFEJOH [see Boxed Warning and Warnings and Precautions
1 INDICATIONS AND USAGE
(5.1, 5.2)]
1.1 Acute Coronary Syndrome: Effient® is indicated to reduce t 5ISPNCPUJD UISPNCPDZUPQFOJD QVSQVSB [see Warnings and
the rate of thrombotic cardiovascular (CV) events (including stent
Precautions (5.4)]
thrombosis) in patients with acute coronary syndrome (ACS) who Suspect bleeding in any patient who is hypotensive and has recently
are to be managed with percutaneous coronary intervention (PCI) undergone coronary angiography, PCI, CABG, or other surgical Safety in patients with ACS undergoing PCI was evaluated in a
as follows:
procedures even if the patient does not have overt signs of bleeding. DMPQJEPHSFMDPOUSPMMFETUVEZ53*50/5*.* JOXIJDIQBUJFOUT
t1BUJFOUTXJUIVOTUBCMFBOHJOB6"
PSOPO45FMFWBUJPONZPDBSEJBM %POPUVTF&GýFOUJOQBUJFOUTXJUIBDUJWFCMFFEJOH QSJPS5*"PSTUSPLF were treated with Effient (60 mg loading dose and 10 mg once daily)
GPSBNFEJBOPGNPOUITQBUJFOUTXFSFUSFBUFEGPSPWFS
JOGBSDUJPO/45&.*
[see Contraindications (4.1 and 4.2)].
NPOUIT QBUJFOUT XFSF USFBUFE GPS NPSF UIBO ZFBS
5IF
t1BUJFOUT XJUI 45FMFWBUJPO NZPDBSEJBM JOGBSDUJPO 45&.*
XIFO
0UIFSSJTLGBDUPSTGPSCMFFEJOHBSF
population treated with Effient was 27 to 96 years of age, 25%
managed with primary or delayed PCI.
Effient has been shown to reduce the rate of a combined endpoint of t"HF≥75 years. Because of the risk of bleeding (including fatal GFNBMFBOE$BVDBTJBO"MMQBUJFOUTJOUIF53*50/5*.*TUVEZ
bleeding)
and
uncertain
effectiveness
in
patients
≥75
years
of
age,
XFSFUPSFDFJWFBTQJSJO 5IFEPTFPGDMPQJEPHSFMJOUIJTTUVEZXBTB
cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal
use of Effient is generally not recommended in these patients, 300 mg loading dose and 75 mg once daily.
TUSPLFDPNQBSFEUPDMPQJEPHSFM 5IFEJGGFSFODFCFUXFFOUSFBUNFOUT
FYDFQUJOIJHISJTLTJUVBUJPOTQBUJFOUTXJUIEJBCFUFTPSIJTUPSZ
PG
was driven predominantly by MI, with no difference on strokes and
myocardial infarction) where its effect appears to be greater and Because clinical trials are conducted under widely varying conditions,
little difference on CV death [see Clinical Studies (14)].
its use may be considered [see Adverse Reactions (6.1), Use in adverse reaction rates observed in the clinical trials cannot be directly
It is generally recommended that antiplatelet therapy be administered
Specific Populations (8.5), Clinical Pharmacology (12.3), and compared with the rates observed in other clinical trials of another
promptly in the management of ACS because many cardiovascular
ESVHBOENBZOPUSFþFDUUIFSBUFTPCTFSWFEJOQSBDUJDF
Clinical Trials (14)].
events occur within hours of initial presentation. In the clinical trial that
Drug Discontinuation5IFSBUFPGTUVEZESVHEJTDPOUJOVBUJPOCFDBVTF
t$"#(
PS
PUIFS
TVSHJDBM
QSPDFEVSF
[see
Warnings
and
established the efficacy of Effient, Effient and the control drug were
of adverse reactions was 7.2% for Effient and 6.3% for
Precautions (5.2)].
OPUBENJOJTUFSFEUP6"/45&.*QBUJFOUTVOUJMDPSPOBSZBOBUPNZXBT
clopidogrel. Bleeding was the most common adverse reaction
established. For the small fraction of patients that required urgent t#PEZXFJHIULH $POTJEFSBMPXFSNH
NBJOUFOBODFEPTF leading to study drug discontinuation for both drugs (2.5% for
[see Dosage and Administration (2), Adverse Reactions (6.1), Use
CABG after treatment with Effient, the risk of significant bleeding was
Effient and 1.4% for clopidogrel).
in Specific Populations (8.6)].
substantial [see Warnings and Precautions (5.2)]. Because the large
majority of patients are managed without CABG, however, treatment t1SPQFOTJUZUPCMFFEFH SFDFOUUSBVNB SFDFOUTVSHFSZ SFDFOUPS Bleeding: Bleeding Unrelated to CABG Surgery *O53*50/5*.*
recurrent gastrointestinal (GI) bleeding, active peptic ulcer disease, PWFSBMM SBUFT PG 5*.* .BKPS PS .JOPS CMFFEJOH BEWFSTF SFBDUJPOT
can be considered before determining coronary anatomy if need for
or severe hepatic impairment) [see Adverse Reactions (6.1) and unrelated to coronary artery bypass graft surgery (CABG) were
$"#(JTDPOTJEFSFEVOMJLFMZ5IFBEWBOUBHFTPGFBSMJFSUSFBUNFOUXJUI
TJHOJýDBOUMZIJHIFSPO&GýFOUUIBOPODMPQJEPHSFMBTTIPXOJO5BCMF
Use in Specific Populations (8.8)].
Effient must then be balanced against the increased rate of bleeding
t.FEJDBUJPOT UIBU JODSFBTF UIF SJTL PG CMFFEJOH e.g., oral Table 1: Non-CABG-Related Bleedinga (TRITON-TIMI 38)
in patients who do need to undergo urgent CABG.
BOUJDPBHVMBOUT DISPOJD VTF PG OPOTUFSPJEBM BOUJJOþBNNBUPSZ
2 DOSAGE AND ADMINISTRATION
Effient (%) Clopidogrel (%) p-value
drugs [NSAIDs], and fibrinolytic agents).Aspirin and heparin were
Initiate Effient treatment as a single 60 mg oral loading dose and
(N=6741) (N=6716)
DPNNPOMZ
VTFE
JO53*50/5*.*
[see
Drug
Interactions
(7),
then continue at 10 mg orally once daily. Patients taking Effient
5*.*.BKPSPS.JOPSCMFFEJOH
4.5
3.4
p=0.002
Clinical
Studies
(14)].
should also take aspirin (75 mg to 325 mg) daily [see Drug
2.2
1.7
p=0.029
Interactions (7) and Clinical Pharmacology (12.3)]. Effient may be 5IJFOPQZSJEJOFT JOIJCJU QMBUFMFU BHHSFHBUJPO GPS UIF MJGFUJNF PG UIF 5*.*.BKPSCMFFEJOHb
administered with or without food [see Clinical Pharmacology (12.3) QMBUFMFU EBZT
TP XJUIIPMEJOH B EPTF XJMM OPU CF VTFGVM JO -JGFUISFBUFOJOH
1.3
p=0.015
managing a bleeding event or the risk of bleeding associated with an
and Clinical Studies (14)].
Fatal
0.3
0.1
Dosing in Low Weight Patients: Compared to patients weighing ≥60 JOWBTJWF QSPDFEVSF #FDBVTF UIF IBMGMJGF PG QSBTVHSFMT BDUJWF
Symptomatic intracranial 0.3
0.3
hemorrhage (ICH)
kg, patients weighing <60 kg have an increased exposure to the metabolite is short relative to the lifetime of the platelet, it may be
Requiring inotropes
0.3
0.1
active metabolite of prasugrel and an increased risk of bleeding on a possible to restore hemostasis by administering exogenous platelets;
Requiring surgical
10 mg once daily maintenance dose. Consider lowering the however, platelet transfusions within 6 hours of the loading dose or 4
0.3
0.3
intervention
maintenance dose to 5 mg in patients <LH5IFFGGFDUJWFOFTTBOE hours of the maintenance dose may be less effective.
Requiring transfusion
safety of the 5 mg dose have not been prospectively studied.
5.2 Coronary Artery Bypass Graft Surgery-Related Bleeding: 5IF
0.7
0.5
(≥4 units)
4 CONTRAINDICATIONS
risk of bleeding is increased in patients receiving Effient who undergo 5*.*.JOPSCMFFEJOH
b
2.4
1.9
p=0.022
4.1 Active Bleeding: Effient is contraindicated in patients with active CABG. If possible, Effient should be discontinued at least 7 days prior
a
Patients may be counted in more than one row.
pathological bleeding such as peptic ulcer or intracranial hemorrhage to CABG.
b
[see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
0GUIFQBUJFOUTXIPVOEFSXFOU$"#(EVSJOH53*50/5*.*UIF See 5.1 for definition.
4.2 Prior Transient Ischemic Attack or Stroke: Effient is SBUFTPG$"#(SFMBUFE5*.*.BKPSPS.JOPSCMFFEJOHXFSFJOUIF 'JHVSF EFNPOTUSBUFT OPO$"#( SFMBUFE 5*.* .BKPS PS .JOPS
contraindicated in patients with a history of prior transient ischemic Effient group and 4.5% in the clopidogrel group [see Adverse CMFFEJOH 5IFCMFFEJOHSBUFJTIJHIFTUJOJUJBMMZ BTTIPXOJO'JHVSF
BUUBDL5*"
PSTUSPLF*O53*50/5*.*53ial to Assess Improvement Reactions (6.1)]5IFIJHIFSSJTLGPSCMFFEJOHFWFOUTJOQBUJFOUTUSFBUFE (inset: Days 0 to 7) [see Warnings and Precautions (5.1)].
Effient® (prasugrel) tablets
Brief Summary of Prescribing Information
VITALS
BY ALICE GOODMAN
Major Finding: For the primary end point of echocardiographic response, defined
as a greater than 15% change in left ventricular end systolic volume from baseline
to 6-month follow-up, the speckle-tracking echocardiography group had a 70% response and the standard placement group had a 55% response (P = .031).
Data Source: A single-blinded, randomized, controlled trial of 220 patients recruited from three different hospitals in the United Kingdom. Participants were
in sinus rhythm, had NYHA class III/IV heart failure, left ventricular ejection
fractions less than 35%, and QRS intervals greater than 120 milliseconds.
Disclosures: Dr. Khan said he had no relevant financial disclosures.
HEART FAILURE
lead placement without echocardiography guidance (P = .031), said Dr. Fakhar
Z. Khan of Cambridge (England) University, who reported the results of the
TARGET (Targeted Left Ventricular
Lead Placement to Guide Cardiac Resynchronization Therapy in Patients
with Heart Failure) trial at the meeting.
Lower rates were also seen with STE
for the combined end point of all-cause
mortality and heart failure hospitalization. The difference was primarily driven
by fewer heart failure hospitalizations.
Looking at mortality alone at a mean follow-up of 400 days, the investigators
Bleeding rates in patients with the risk factors of age ≥75 years and
weight <LHBSFTIPXOJO5BCMF
Table 2: Bleeding Rates for Non-CABG-Related Bleeding by
Weight and Age (TRITON-TIMI 38)
Major/Minor
Fatal
Effient Clopidogrel Effient Clopidogrel
(%)
(%)
(%)
(%)
Weight <LH/
Effient, N=356 clopidogrel)
Weight ≥60kg (N=6373
Effient, N=6299 clopidogrel)
Age <ZFBST/
&GýFOU/DMPQJEPHSFM
Age ≥ZFBST/
&GýFOU/DMPQJEPHSFM
10.1
6.5
0.0
0.3
4.2
3.3
0.3
0.1
2.9
0.2
0.1
9.0
6.9
1.0
0.1
Bleeding Related to CABG *O 53*50/5*.* QBUJFOUT XIP
received a thienopyridine underwent CABG during the course of the
TUVEZ 5IF SBUF PG $"#(SFMBUFE5*.* .BKPS PS .JOPS CMFFEJOH XBT
GPSUIF&GýFOUHSPVQBOEJOUIFDMPQJEPHSFMHSPVQ5BCMF
5IFIJHIFSSJTLGPSCMFFEJOHBEWFSTFSFBDUJPOTJOQBUJFOUTUSFBUFEXJUI
Effient persisted up to 7 days from the most recent dose of study drug.
Table 3: CABG-Related Bleedinga (TRITON-TIMI 38)
Effient (%) Clopidogrel (%)
(N=213)
(N=224)
14.1
4.5
11.3
3.6
0.9
0
0.5
6.6
2.2
0
0
0.9
5*.*.BKPSPS.JOPSCMFFEJOH
5*.*.BKPSCMFFEJOH
Fatal
Reoperation
5SBOTGVTJPOPG≥5 units
Intracranial hemorrhage
5*.*.JOPSCMFFEJOH
Patients may be counted in more than one row.
Bleeding Reported as Adverse Reactions)FNPSSIBHJDFWFOUT
SFQPSUFE BT BEWFSTF SFBDUJPOT JO 53*50/5*.* XFSF GPS
Effient and clopidogrel, respectively: epistaxis (6.2%, 3.3%),
gastrointestinal hemorrhage (1.5%, 1.0%), hemoptysis (0.6%,
TVCDVUBOFPVT IFNBUPNB QPTUQSPDFEVSBM
hemorrhage (0.5%, 0.2%), retroperitoneal hemorrhage (0.3%,
0.2%), pericardial effusion/hemorrhage/tamponade (0.3%,
0.2%), and retinal hemorrhage (0.0%, 0.1%).
Malignancies%VSJOH53*50/5*.*OFXMZEJBHOPTFENBMJHOBODJFT
were reported in 1.6% and 1.2% of patients treated with prasugrel
BOEDMPQJEPHSFM SFTQFDUJWFMZ 5IFTJUFTDPOUSJCVUJOHUPUIFEJGGFSFODFT
were primarily colon and lung. It is unclear if these observations are
DBVTBMMZSFMBUFEPSBSFSBOEPNPDDVSSFODFT
0UIFS"EWFSTF&WFOUT*O53*50/5*.*DPNNPOBOEPUIFSJNQPSUBOU
OPOIFNPSSIBHJD BEWFSTF FWFOUT XFSF GPS &GýFOU BOE DMPQJEPHSFM
respectively: severe thrombocytopenia (0.06%, 0.04%), anemia (2.2%,
2.0%), abnormal hepatic function (0.22%, 0.27%), allergic reactions
BOEBOHJPFEFNB
5BCMFTVNNBSJ[FT
the adverse events reported by at least 2.5% of patients.
Table 4: Non-Hemorrhagic Treatment Emergent Adverse Events
Reported by at Least 2.5% of Patients in Either Group
a
Effient (%) Clopidogrel (%)
(N=6741)
(N=6716)
Hypertension
7.5
7.1
Hypercholesterolemia/Hyperlipidemia
7.0
7.4
Headache
5.5
5.3
Back pain
5.0
4.5
Dyspnea
4.9
4.5
Nausea
4.6
4.3
Dizziness
4.1
4.6
Cough
3.9
4.1
Hypotension
3.9
Fatigue
3.7
/PODBSEJBDDIFTUQBJO
3.1
3.5
Atrial fibrillation
2.9
3.1
Bradycardia
2.9
2.4
3.5
Leukopenia (<4 x 109 WBC/L)
Rash
2.4
Pyrexia
2.7
2.2
Peripheral edema
2.7
3.0
Pain in extremity
2.6
2.6
Diarrhea
2.3
2.6
6.2 Postmarketing Experience: 5IF GPMMPXJOH BEWFSTF
reactions have been identified during post approval use of
Effient. Because these reactions are reported voluntarily
from a population of uncertain size, it is not always possible
found the two groups did not significantly differ.
“This is a well-designed, well-conducted study with impressive differences in
clinical outcomes,” said Dr. Byron Kwock
Lee, who is with the University of California, San Francisco, and chaired the session where the TARGET results were
presented. “Other studies have shown
echocardiographic outcomes but have
had difficulty showing clinical differences.”
“I am impressed that the modest
echocardiographic changes translated to
dramatic clinical effects,” commented Dr.
Michael Crawford, also of the University
to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Blood and lymphatic system disorders — 5ISPNCPDZUPQFOJB
5ISPNCPUJDUISPNCPDZUPQFOJDQVSQVSB551
[see Warnings and
Precautions (5.4) and Patient Counseling Information (17.3)]
Immune system disorders — Hypersensitivity reactions
including anaphylaxis [see Contraindications (4.3)]
7 DRUG INTERACTIONS
7.1 Warfarin: Coadministration of Effient and warfarin increases the
risk of bleeding [see Warnings and Precautions (5.1) and Clinical
Pharmacology (12.3)].
7.2 Non-Steroidal Anti-Inflammatory Drugs: Coadministration of
Effient and NSAIDs (used chronically) may increase the risk of bleeding
[see Warnings and Precautions (5.1)].
7.3 Other Concomitant Medications: Effient can be administered
with drugs that are inducers or inhibitors of cytochrome P450
enzymes [see Clinical Pharmacology (12.3)].
Effient can be administered with aspirin (75 mg to 325 mg per day),
heparin, GPIIb/IIIa inhibitors, statins, digoxin, and drugs that elevate
gastric pH, including proton pump inhibitors and H2 blockers [see
Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy: Pregnancy Category B 5IFSFBSFOPBEFRVBUFBOE
well controlled studies of Effient use in pregnant women. Reproductive
and developmental toxicology studies in rats and rabbits at doses of
up to 30 times the recommended therapeutic exposures in humans
(based on plasma exposures to the major circulating human
metabolite) revealed no evidence of fetal harm; however, animal
studies are not always predictive of a human response. Effient should
be used during pregnancy only if the potential benefit to the mother
justifies the potential risk to the fetus.
In embryo fetal developmental toxicology studies, pregnant rats and
rabbits received prasugrel at maternally toxic oral doses equivalent to
more than 40 times the human exposure. A slight decrease in pup
body weight was observed; but, there were no structural malformations
in either species. In prenatal and postnatal rat studies, maternal
treatment with prasugrel had no effect on the behavioral or
reproductive development of the offspring at doses greater than 150
times the human exposure [see Nonclinical Toxicology (13.1)].
8.3 Nursing Mothers: It is not known whether Effient is excreted in
human milk; however, metabolites of Effient were found in rat milk.
Because many drugs are excreted in human milk, prasugrel should be
used during nursing only if the potential benefit to the mother justifies
the potential risk to the nursing infant.
8.4 Pediatric Use: Safety and effectiveness in pediatric patients have
not been established [see Clinical Pharmacology (12.3)].
8.5 Geriatric Use: *O53*50/5*.* PGQBUJFOUTXFSF≥65
years of age and 13.2% were ≥ZFBSTPGBHF5IFSJTLPGCMFFEJOH
increased with advancing age in both treatment groups, although the
relative risk of bleeding (Effient compared with clopidogrel) was
similar across age groups.
Patients ≥75 years of age who received Effient had an increased risk
of fatal bleeding events (1.0%) compared to patients who received
clopidogrel (0.1%). In patients ≥75 years of age, symptomatic
JOUSBDSBOJBMIFNPSSIBHFPDDVSSFEJOQBUJFOUT
XIPSFDFJWFE
Effient and in 3 patients (0.3%) who received clopidogrel. Because of
the risk of bleeding, and because effectiveness is uncertain in patients
≥75 years of age [see Clinical Studies (14)], use of Effient is generally
OPUSFDPNNFOEFEJOUIFTFQBUJFOUT FYDFQUJOIJHISJTLTJUVBUJPOT
(diabetes and past history of myocardial infarction) where its effect
appears to be greater and its use may be considered [see Warnings
and Precautions (5.1), Clinical Pharmacology (12.3), and Clinical
Studies (14)].
8.6 Low Body Weight: *O53*50/5*.* PGQBUJFOUTUSFBUFE
with Effient had body weight <60 kg. Individuals with body weight <60
kg had an increased risk of bleeding and an increased exposure to the
active metabolite of prasugrel [see Dosage and Administration (2),
Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].
$POTJEFSMPXFSJOHUIFNBJOUFOBODFEPTFUPNHJOQBUJFOUTLH
5IF FGGFDUJWFOFTT BOE TBGFUZ PG UIF NH EPTF IBWF OPU CFFO
prospectively studied.
8.7 Renal Impairment: No dosage adjustment is necessary for
QBUJFOUTXJUISFOBMJNQBJSNFOU5IFSFJTMJNJUFEFYQFSJFODFJOQBUJFOUT
XJUIFOETUBHFSFOBMEJTFBTF[see Clinical Pharmacology (12.3)].
8.8 Hepatic Impairment: No dosage adjustment is necessary in
QBUJFOUTXJUINJMEUPNPEFSBUFIFQBUJDJNQBJSNFOU$IJME1VHI$MBTT
"BOE#
5IFQIBSNBDPLJOFUJDTBOEQIBSNBDPEZOBNJDTPGQSBTVHSFM
in patients with severe hepatic disease have not been studied, but
such patients are generally at higher risk of bleeding [see Warnings
and Precautions (5.1) and Clinical Pharmacology (12.3)].
8.9 Metabolic Status: In healthy subjects, patients with stable
atherosclerosis, and patients with ACS receiving prasugrel, there was
of California, San Francisco, and a panelist
at the presentation of the study results.
Up to 40% of patients fail to gain significant clinical benefit from cardiac resynchronization therapy, Dr. Khan noted. The position of the left ventricular
lead has emerged as an important determinant of response, with better results achieved when pacing at the latest
site of contraction and lesser responses
noted when pacing areas of scar.
Speckle-tracking radial strain imaging
correlates with delayed enhanced cardiac MRI for determination of scar, Dr.
Khan said. In patients undergoing cardiac
no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19,
PS$:1"POUIFQIBSNBDPLJOFUJDTPGQSBTVHSFMTBDUJWFNFUBCPMJUF
or its inhibition of platelet aggregation.
10 OVERDOSAGE
10.1 Signs and Symptoms: Platelet inhibition by prasugrel is rapid
and irreversible, lasting for the life of the platelet, and is unlikely to be
increased in the event of an overdose. In rats, lethality was observed
after administration of 2000 mg/kg. Symptoms of acute toxicity in
dogs included emesis, increased serum alkaline phosphatase, and
hepatocellular atrophy. Symptoms of acute toxicity in rats included
mydriasis, irregular respiration, decreased locomotor activity, ptosis,
staggering gait, and lacrimation.
10.2 Recommendations about Specific Treatment: Platelet
USBOTGVTJPONBZSFTUPSFDMPUUJOHBCJMJUZ5IFQSBTVHSFMBDUJWFNFUBCPMJUF
is not likely to be removed by dialysis.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis /PDPNQPVOESFMBUFEUVNPSTXFSFPCTFSWFEJOB
ZFBSSBUTUVEZXJUIQSBTVHSFMBUPSBMEPTFTVQUPNHLHEBZ
(>100 times the recommended therapeutic exposures in humans
(based on plasma exposures to the major circulating human
NFUBCPMJUF
5IFSF XBT BO JODSFBTFE JODJEFODF PG UVNPST
(hepatocellular adenomas) in mice exposed for 2 years to high doses
(>250 times the human metabolite exposure).
Mutagenesis 1SBTVHSFMXBTOPUHFOPUPYJDJOUXPin vitro tests (Ames
bacterial gene mutation test, clastogenicity assay in Chinese hamster
fibroblasts) and in one in vivo test (micronucleus test by intraperitoneal
route in mice).
Impairment of Fertility 1SBTVHSFMIBEOPFGGFDUPOGFSUJMJUZPGNBMFBOE
GFNBMFSBUTBUPSBMEPTFTVQUPNHLHEBZUJNFTUIFIVNBO
major metabolite exposure at daily dose of 10 mg prasugrel).
17 PATIENT COUNSELING INFORMATION
See Medication Guide
17.1 Benefits and Risks
t 4VNNBSJ[FUIFFGGFDUJWFOFTTGFBUVSFTBOEQPUFOUJBMTJEFFGGFDUT
of Effient.
t5FMMQBUJFOUTUPUBLF&GýFOUFYBDUMZBTQSFTDSJCFE
t3FNJOEQBUJFOUTOPUUPEJTDPOUJOVF&GýFOUXJUIPVUýSTUEJTDVTTJOH
it with the physician who prescribed Effient.
t3FDPNNFOEUIBUQBUJFOUTSFBEUIF.FEJDBUJPO(VJEF
17.2 Bleeding: Inform patients that they:
tXJMMCSVJTFBOECMFFENPSFFBTJMZ
tXJMMUBLFMPOHFSUIBOVTVBMUPTUPQCMFFEJOH
tTIPVMESFQPSUBOZVOBOUJDJQBUFEQSPMPOHFEPSFYDFTTJWFCMFFEJOH
or blood in their stool or urine.
17.3 Other Signs and Symptoms Requiring Medical Attention
t *OGPSNQBUJFOUTUIBU551JTBSBSFCVUTFSJPVTDPOEJUJPOUIBU
has been reported with Effient.
t*OTUSVDUQBUJFOUTUPHFUQSPNQUNFEJDBMBUUFOUJPOJGUIFZFYQFSJFODF
any of the following symptoms that cannot otherwise be explained:
fever, weakness, extreme skin paleness, purple skin patches,
yellowing of the skin or eyes, or neurological changes.
17.4 Invasive Procedures: Instruct patients to:
tJOGPSNQIZTJDJBOTBOEEFOUJTUTUIBUUIFZBSFUBLJOH&GýFOUCFGPSF
any invasive procedure is scheduled.
tUFMMUIFEPDUPSQFSGPSNJOHUIFJOWBTJWFQSPDFEVSFUPUBMLUPUIF
prescribing health care professional before stopping Effient.
17.5 Concomitant Medications: Ask patients to list all prescription
NFEJDBUJPOT PWFSUIFDPVOUFSNFEJDBUJPOT PSEJFUBSZTVQQMFNFOUT
they are taking or plan to take so the physician knows about other
treatments that may affect bleeding risk (e.g., warfarin and NSAIDs).
Literature revised: December 6, 2010
Manufactured by Eli Lilly and Company,
Indianapolis, IN, 46285
Marketed by Daiichi Sankyo, Inc. and Eli Lilly and Company
Copyright © 2009, 2010, Daiichi Sankyo, Inc. and
Eli Lilly and Company.All rights reserved.
1(1()$1#4%FD
PV 7311 AMP
13*/5&%*/64"
References: 1. Effient® (prasugrel) prescribing information. Daiichi Sankyo, Inc. and Eli Lilly and Company. 2. Data on file: #EFF20100129h: DSI/Lilly.
3. Data on file: #EFF20091204b: DSI/Lilly. 4. Data on file: #EFF20100129f: DSI/Lilly.
®
Effient and the Effient logo are registered trademarks of Eli Lilly and Company.
Plavix® is a registered trademark of sanofi-aventis Corp.
Copyright © 2010 Daiichi Sankyo, Inc. and Lilly USA, LLC. All Rights Reserved.
PG68406. PGHCPISI10Dec2010. Printed in USA. December 2010.
25
resynchronization therapy, less than 10%
amplitude of radial strain at the left ventricular pacing site has a high negative
predictive value (91%) for response.
Using STE, “we found that concordant lead placement, baseline dyssynchrony, and pacing away from areas of
scar are strongly related to improved
outcomes,” he said.
The single-blinded, randomized, controlled trial enrolled 220 patients recruited from three different hospitals in
the United Kingdom. Participants were
in sinus rhythm, had severe heart failure
(New York heart Association class
III/IV), left ventricular ejection fractions
less than 35%, and QRS intervals greater
than 120 msec. Patients were randomized in a 1:1 ratio to receive either standard lead placement without the benefit of echocardiographic guidance or
targeted lead placement using STE to
Using STE, ‘we found that
concordant lead placement,
baseline dyssynchrony, and
pacing away from areas of
scar are strongly related to
improved outcomes.’
position the lead at the latest site of contraction and away from areas of scar.
Following implantation, all devices were
optimized using echocardiography.
Concordant lead placement was
achieved in 61% of the STE group vs.
45% of control group. Placement was
adjacent in 25% of the STE group and
28% of the control group, and was remote in 10% and 24%, respectively.
At baseline, both groups were comparable in demographic and disease characteristics. Mean age was about 70 years,
about 86% were male, about 94% had
NYHA class III heart failure, and 56% had
underlying ischemic cardiomyopathy.
Both groups had a 14% rate of implant-related complications. Procedural
length of time was similar for both
groups.
In addition to the primary end point
improvements in echocardiographic response at 6-month follow-up, the STE
group also had significantly improved
clinical end points, compared with the
standard placement group. Statistically
significant differences from baseline to
follow-up for the STE group vs. the
standard placement group included improvement in heart failure class, 6-mile
walk test results, and quality of life
scores.
Patients in the study will continue to
have ongoing follow-up.
“STE software can be applied to any
existing echocardiographic image at no
additional risk to the patient,” Dr. Khan
said.
“STE makes targeting of the lead feasible at any facility that performs
echocardiography and has the software
available to analyze their images, so it is
widely accessible at smaller centers and
nonacademic hospitals where more and
more pacemakers are being implanted.
That being said, it requires training and
experience.”
■
26
HYPERTENSION
Nearly 40% of Resistant HT Was White Coat
VITALS
BY DENISE NAPOLI
Major Finding: Among 8,295 patients with resistant office hypertension,
63% had ambulatory 24-hour blood pressure values greater than or equal
to 130 mm Hg systolic and/or 80 mm Hg diastolic and were diagnosed as
true resistant hypertension, whereas 37% showed 24-hour BP values below
this limit and therefore were considered to have white-coat resistant HT.
Data Source: An analysis of data on more than 68,000 patients in the
Spanish Ambulatory Blood Pressure Monitoring (ABPM) Registry.
Disclosures: The Spanish ABPM Registry was initiated and is maintained
by Lacer Laboratories. The authors disclosed having attended meetings
funded by Lacer.
AVAILABLE
NOW!
FROM HYPERTENSION
p to 37% of resistant office hypertension is actually white-coat hypertension, according to an analysis of
ambulatory blood pressure monitoring data
from more than 8,000 patients.
Meanwhile, the remaining 63% who are
truly resistant have a starkly worse clinical
profile than do their white-coat counter-
U
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Visit www.cardiologynewsnetwork.com
for the latest advances from key symposia at the
th
60 Annual Scientific
Session and Innovation in
Intervention: i2 Summit
New Orleans, LA
April 2-5, 2011
www.cardiologynewsnetwork.com
CARDIOLOGY NEWS NETWORK Custom Conference Coverage provides onsite coverage of
selected key sessions from the 60th Annual Scientific Session and Innovation in
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This news site is brought to you by the Custom Conference Coverage Department of CARDIOLOGY NEWS
NETWORK, and is not an official site of the Foundation nor its sponsor, the American College of Cardiology
Foundation (ACC).
parts, including significantly higher likelihoods of smoking, and having diabetes,
left ventricular hypertrophy, microalbuminuria, and cardiovascular disease.
Dr. Alejandro de la Sierra of the University of Barcelona and colleagues,
looked at 2009 data from the Spanish
Ambulatory Blood Pressure Monitoring
(ABPM) Registry, which included 68,045
patients with good-quality office BP data,
ambulatory BP data, and information
about prescribed antihypertensives, including at least one diuretic.
Ambulatory BP measurements were
acquired using an automated, noninvasive oscillometric device placed by a
physician, and which registered BP at 20minute intervals over a 24-hour period.
Patients returned the following day to
their doctors for removal of the device.
Overall, 12% of participants in the registry (8,295 patients; 51% male, mean
age 64 years) met Dr. de la Sierra’s criteria for resistant hypertension (RH): office
BP greater than or equal to 140 mm Hg
systolic and/or 90 mm Hg diastolic while
being treated with three or more antihypertensive agents at “appropriate” doses.
ABPM patients were classified in two
groups: 5,182 patients (62.5%) had ambulatory 24-hour BP values greater than
or equal to 130 and/or 80 mm Hg and
were diagnosed as true RH, and 3,113 patients (37.5%) showed 24-hour BP values
below this limit and were considered as
having white-coat RH, wrote the authors (Hypertension 2011 March 28 [doi:
1 0 . 1 1 6 1 / H Y P E RT E N S I O NA H A .
110.168948]).
White-coat RH patients were slightly
but significantly older (65 vs. 64 years),
and more likely to be female (54%).
Truly resistant patients, however, were
more likely to be smokers (15% vs. 10%),
to be diabetic (35% vs. 28%), and to
have cardiovascular disease (19% vs.
16%), compared with the white-coat RH
patients. Moreover, 19% of the true RH
patients had left ventricular hypertrophy, as seen on an electrocardiogram, vs.
14% of white-coat patients.
They also had higher creatinine levels
than did their white-coat counterparts
(75 vs. 72 micromol/L), higher urinary
albumin excretion (11 vs. 7 mg/g), and
a higher percentage of patients with a
urinary albumin excretion greater than
30 mg/g (30% vs. 20%).
Body mass index and total cholesterol
did not vary significantly between groups.
According to the authors, the study
represents the first time that the prevalence of resistant hypertension was assessed in such a large cohort of patients.
However, the researchers pointed to
one major weakness of the study: the inability to confirm that patients prescribed antihypertensive drugs were adherent to their medication regimen,
“thus possibly overestimating the true
prevalence of RH.”
And despite the findings of significant
differences in clinical characteristics between groups, “their discriminating value in clinical practice is probably low,”
cautioned the authors.
■
HYPERTENSION
27
BY ALICE GOODMAN
NEW ORLEANS – Pulse pressure mea-
VITALS
sured by a physician may help discriminate between patients with white coat
hypertension and true hypertension, according to a South Korean study.
About a third of the more than 1,000
patients in the study who were receiving
ongoing antihypertensive treatment actually had white coat hypertension
(WCH), suggesting that the costs and potential side effects of drug therapy could
have been avoided in these patients, said
Dr. Young Keun Ahn of the Chonnam
National University Hospital, Gwangju,
South Korea, and associates.
©D R . H EINZ L INKE / I S TOCKPHOTO. COM
Pulse Pressure Helps Identify
White Coat Hypertension
stressful encounter like seeing a doctor can
cause white coat hypertension, then perhaps
this response would be replicated in other
stressful situations. It would be useful to
monitor these patients to determine if they
are at risk for ongoing hypertension.”
Dr. Zoghbi is the chief of cardiovascular
imaging at Methodist DeBakey Heart and
Vascular Center in Houston.
■
About a third of
the patients in
the study who
were receiving
ongoing
antihypertensive
treatment
actually had
white coat
hypertension.
Major Finding: Pulse pressure was
correlated with a systolic white
coat effect (r = 0.063, P less than
.001) and a diastolic white coat
effect (0.037, P less than .001).
Data Source: The study enrolled
1,087 patients undergoing treatment for chronic hypertension in
outpatient academic hospital settings.
Disclosures: The study was funded by the Korean Institute of
Medicine; the Korea Healthcare
Technology R&D Project; the Korean Ministry of Health, Welfare,
& Family Affairs; and the Republic of Korea.
Twenty-four hour ambulatory blood
pressure monitoring or self-blood pressure monitoring can diagnose white coat
hypertension, he said, but pulse pressure
is simpler to use and is suitable for patients without aortic valvular insufficiency or aortic disease, he added.
Dr. Ahn and his colleagues found that
pulse pressure as measured by a physician was more significantly related to
WCH than was systolic blood pressure,
a value that had been shown in earlier
studies to be helpful in identifying patients with WCH.
The study enrolled 1,087 patients being
treated for chronic hypertension in outpatient academic hospitals settings. Patients were trained to self-measure their
blood pressure twice a day and record it
every morning and evening for 2 weeks.
Thirty-one percent of patients were
found to have WCH, which was defined
as a difference above 20 mm Hg in systole or 10 mm Hg in diastole.
Pulse pressure was positively correlated with a systolic white coat effect (r =
0.063, P less than .001) and diastolic white
coat effect (0.037, P less than .001).
No association was found between a
white coat effect and age or gender.
However, patients with a family history
of premature heart disease were more
likely to experience white coat hypertension. Patients with diabetes and smokers were less likely to have it.
Dr. William Zoghbi noted that “if a
Cardiac research that gets to the
heart of world-class care.
At UPMC, our physicians aren’t just utilizing
the latest treatments for heart failure – they’re
working to find newer and better ones. We
have a rich tradition of clinical research and
innovation as one of the first heart
transplant centers in the country and as
developers of one of the first heart-assist
devices. Whether researching gene therapy for
coronary artery disease or novel noninvasive
therapies for heart failure, UPMC physicians
consistently are at the cutting edge, exploring
and employing new technologies and
treatments for the benefit of patients. To learn
more, visit UPMCPhysicianResources.com.
Affiliated with the University of Pittsburgh School of Medicine,
UPMC is ranked among the nation’s best hospitals by U.S. News & World Report.
28
HYPERTENSION
BY MITCHEL L. ZOLER
NEW ORLEANS – A novel way to
manage drug-resistant hypertension using an implanted device to deliver a
small, continuous electrical current to
both carotid sinuses will need more testing as results from a 265-patient pivotal
trial failed to clearly prove efficacy.
The trial results “justify further development” of baroreflex activation therapy,
Dr. John D. Bisognano said at the
meeting.
“This treatment
is coming. The
data were very encouraging. This is
a modality that
will work. I anticipate further studies to better define
which patients get the greatest benefit,”
said Dr. Bisognano, director of cardiac rehabilitation and clinical preventive cardiology at the University of Rochester
(N.Y.).
Cardiologists who heard the results
had a mixed read on the potential role of
this approach, which involved implanting a small device below the patient’s
clavicle and placing a pair of electrical
leads that wrap around the carotid sinus
on each side of the patient’s neck.
The device delivers a continuous electrical current of 1-6 V to each carotid sinus, activating the reflex and producing
a reduction in blood pressure in most
patients.
“When the device becomes available,
the greatest benefit will be in patients
with end-stage renal failure.
“No matter what you do, their blood
pressure does not go down,” commented Dr. C. Venkata S. Ram, professor of
medicine at the University of Texas
Southwestern Medical Center in Dallas.
“I just hope that patients tolerate” having leads in their necks, he added in an
interview.
In the study results reported by Dr.
Bisognano, 25% of the patients who received the device had at least one procedure-related adverse event within 30 days
of device placement, including 4% with
permanent nerve injury that resulted in
numbness, dysphagia, or dysphonia; 5%
with a transient nerve injury; 4% with
surgical complication (most of which
resolved); and 3% with respiratory complaints (all of which resolved). Overall,
76% of the adverse events resolved, but
about 2% of patients required explant of
the device.
Dr. Prakesh C. Deedwania took a
more skeptical view of the approach.
“This device would require battery
changes and is subject to malfunctions.
In my opinion, renal artery denervation
is probably better, right now, for patients
with treatment-resistant hypertension,”
he said.
The current study’s design also “left
many unanswered questions,” said Dr.
Deedwania, professor of medicine at the
University of California, San Francisco,
in Fresno. (See View on the News at bottom right.)
The pivotal study for the Rheos
baroreflex activation device enrolled patients at 37 U.S. sites and 2 centers in Europe. All 265 patients who were enrolled
received placement of the device.
One month after surgery, a 2:1
‘I anticipate
randomization
further studies to
scheme led to
better define
blinded activation
which patients
of the device in
get the greatest
181 patients and
benefit.’
no activation in
the other 84. Six
DR. BISOGNANO
months later, the
researchers activated all the devices.
The patients averaged 54 years old,
about 60% were men, and about threequarters were white.
Participants had failed to have their
blood pressure controlled by an average
of five drugs, and they had been on a stable regimen for at least a month at the
time of entry.
During the course of the study their
treating physicians could freely change
antihypertensive drug dosages and also
add or remove drugs.
Their systolic and diastolic blood pressure at baseline averaged about 177/103
mm Hg, and their heart rate averaged 74
beats/min.
To qualify for the study, patients needed a minimum blood pressure of at least
160/80 mm Hg and a 24-hour average
ambulatory pressure of at least 135 mm
Hg, and they had to be on at least three
antihypertensive medications.
The study included five primary end
points, with a prespecified definition of
success for each of the end points.
One end point assessed short-term response after 6 months, defining success
as at least a 10–mm Hg drop in systolic
pressure compared with baseline. This
criterion for success occurred in 54% of
patients with an activated device in the
study’s first 6 months and in 46% of
those with an inactive device, an 8% difference in response rate between the active and control arms that failed to meet
the prespecified goal of a 20% difference.
Dr. Bisognano speculated that the
placebo response may have been so high
because of continued drug treatment
optimization during this period.
The second end point assessed the 12month response in all 265 patients, again
using a 10–mm Hg drop in systolic pressure relative to baseline as the criterion
for a positive response. This reduction occurred in 88% of patients, surpassing the
prespecified success threshold of 65%.
Major Finding: Continuous low-voltage stimulation of the carotid sinus by an
implanted device led to blood pressure reductions in patients with drug-resistant hypertension. The trial results fulfilled three of five prespecified efficacy
and safety goals.
Data Source: The Rheos Pivotal Trial, which enrolled 265 patients with drugresistant hypertension who received an implanted baroreflex activation device
at 37 U.S. centers and 2 centers in Europe.
Disclosures: Dr. Bisognano said that he has received consulting fees or honoraria from CVrx, the company that is developing the carotid baroreflex activation device. Dr. Ram has served on the speakers bureau for the Peer Group
and for Advanced Health Media.
The third end point focused on 30-day
safety. The 25% of patients with an adverse event exceeded the prespecified
threshold of 18%.
The fourth end point looked at safety
at 6 months, with an adverse-event
threshold in the active-treatment arm of
no more than 15% greater than in the
control arm.
The results showed that patients receiving activation had a 2% reduced
rate of adverse events compared with
the inactive, control arm, which meant
the results fulfilled this criterion of
success.
The fifth end point looked at the overall adverse event rate on active therapy
in all 265 patients after 12 months.
The 13% actual rate fell within the
prespecified goal of less than 28%,
meaning the results fulfilled this criterion of success.
The study also assessed efficacy another way, by tallying the percentage of
patients whose systolic pressure dropped
below 140 mm Hg.
At the 6-month mark, this degree of
blood pressure reduction occurred in
42% of patients receiving activation and
in 24% of patients whose device had not
yet been activated, a statistically significant difference.
At the 12-month mark, 53% of the patients on continuous active treatment
and 51% of those who switched from 6
months off treatment to 6 months on
treatment reached this systolic pressure
goal.
In addition, the study included an
echocardiography substudy designed to
assess the impact of baroreflex activation
on left ventricular mass and shape.
At baseline, these 60 patients had an
average left ventricular mass index of 117
kg/m2.
A year later, the average had dropped
to 102 kg/m2, a statistically significant
difference.
Patients also shifted toward having
more normalized left ventricular shapes,
Dr. Bisognano reported in a separate
talk at the meeting.
■
Efficacy Questions Left Unanswered
VIEW ON THE NEWS
Only three of the five efficacy and safety goals
were met in a pivotal study of 265 patients.
VITALS
Baroreflex Activation Device Gets Mixed Results
he results from this study leave
many questions unanswered
about the efficacy of this
approach to treating persistent, treatment-resistant hypertension.
Patients enrolled in the
study should have been
thoroughly assessed for
neuroendocrine hypertension. About a third of
patients with treatmentresistant hypertension
have a neuroendocrine cause.
The study’s design also left unclear how many enrolled patients
were truly treatment resistant. One
month on stable treatment with at
least three drugs may not identify
patients who are unresponsive to
drugs, as some drugs, such as the direct renin inhibitor aliskiren, take
longer than 1 month to start having
a complete effect.
In addition, current hypertension
treatment guidelines from the
American Heart Association call for
using a mineralocorticoid receptor
antagonist such as spironolactone
or amiloride in patients with persistent hypertension that remains unresponsive to combinations of oth-
T
er drugs (Hypertension 2008;51:
1403-19). The current report gives
no information on
whether all enrolled patients had first received
spironolactone, a very inexpensive drug that often
works in otherwise unresponsive patients.
I participated in research several years ago
that tested baroreflex activation as a treatment for
refractory angina. This approach
did not pan out because, while the
treatment showed initial efficacy,
the effect declined over the longer
term.
In my opinion, renal artery denervation is, for now, a more proven,
novel way to manage patients with
hypertension that is truly drug resistant. Carotid baroreflex activation
will require more study and better
evidence before we can consider it a
new option for these patients.
PRAKASH C. DEEDWANIA, M.D., is
professor of medicine with the
University of California, San
Francisco, in Fresno. He said he had
no relevant financial disclosures.
Another
heart attack
is this far away
Are you
helping to
keep it away?
Despite medical guidelines,
millions of at-risk patients
remain unprotected by aspirin.1,2
Aspirin can reduce the risk of
recurrent MI by 30%.3,4
Counsel your patients today.
Say aspirin.
Help save lives.
30
ACUTE CORONARY SYNDROMES
Taking Ambulance Cuts Time to Cath Lab 26%
NEW ORLEANS – Patients with suspected ST-eleva-
VITALS
tion myocardial infarction who called an ambulance received lifesaving care in half the time as patients who
got to the hospital by other means, according to a study
conducted at two San Francisco hospitals.
“Patients who take an ambulance get a prehospital
ECG,” said lead investigator Dr. James M. McCabe of
the University of California, San Francisco, at the meeting. “These patients move through the emergency
room and get to the cath lab much faster.”
“We found that almost half of patients referred for
a potential heart attack don’t take an ambulance but
come in on their own, and it turns out they are doing
Major Finding: After adjustment for multiple risk
factors, severity of illness and extent of ECG
changes, patients with suspected STEMI who
did not arrive by ambulance at the emergency
department spent 62% more time in the emergency department before undergoing catheterization.
Data Source: A study of 356 consecutive patients referred for emergent cardiac catheterization for a suspected STEMI by emergency physicians at a tertiary care hospital and a county
hospital in San Francisco in 2009.
Disclosures: Dr. McCabe and Dr. Wright reported
no relevant conflicts of interest.
themselves a great disservice,” Dr. McCabe said.
The study analyzed 356 consecutive patients referred
for emergent cardiac catheterization for a suspected
STEMI by emergency physicians at a tertiary care hospital and a county hospital in 2009. Of the 356 patients,
199 (56%) arrived by ambulance and 157 (44%) did not.
Variables affecting the time interval from the inciting
ECG to STEMI pager activation, and door-to-balloon
time, were analyzed in univariate and stepwise multivariate regression models.
All components of care
911 did not ensure that
were affected.
patients with suspected
“The ultimate metric,
STEMI arrived at the hosdoor-to-balloon time, was
pital with ECG results in
reduced by 26% in patients
hand. Among the 356 pataken by ambulance,” Dr.
tients in the study, 68%
McCabe reported. This
did not receive an ECG,
highly significant finding
either because they did
is important because studnot travel by ambulance
ies show mortality risks
or because, in 43% of the
are higher when door-tocases, they were not given
balloon times exceed 90
an ECG en route.
minutes, he added.
Dr. McCabe suspects
The investigators then Patients who arrive by ambulance at the ED get to the that patients who did not
broke down the door-to- cath lab faster than do those arriving by other means. receive an ECG in the amballoon time into its varibulance may have had
ous components and compared the groups. After ad- vague presenting symptoms when paramedics arrived.
justing for demographic factors, traditional Of patients with symptoms more indicative of an MI,
cardiovascular risk factors, severity of illness and extent 78% got an ECG in the ambulance, he said.
of ECG changes, merely not presenting by ambulance
“Our community is diverse, and we feel that barrito the emergency department (ED), and therefore not ers in communication with non–English speakers may
receiving a prehospital ECG, significantly lengthened also have played a role,” he added.
by 62% the total time in the ED before undergoing
He further noted that in San Francisco, paramedics
catheterization.
did not have the technology to forward the ECGs elecAmong patients arriving by ambulance, “each inter- tronically to the receiving hospital. San Francisco will
val that occurred within the emergency room was re- be implementing citywide remote transmission of
duced by more than 50%,” he reported.
ECGs soon, and the investigators plan to study whether
The procedural time for revascularization, however, this makes for even more efficient transfer of STEMI
did not vary based on how the patient arrived at the patients to the cath lab.
hospital. This finding supports the conclusion that
“These data suggest better triage systems may be neccare was made more efficient prior to the catheteriza- essary for patients with likely STEMIs, particularly for
tion itself, he said.
[more than] 40% of patients who do not arrive by amThe one observable difference was that patients ar- bulance,” Dr. McCabe concluded.
riving by ambulance were more critically ill. They had
Dr. Janet Wright, ACC senior vice president of science
more cardiac arrests, and required more cardiopul- and quality, said that “This is a safety message for pamonary resuscitation and intubation. “While these patients: ‘Your local ER wants you to come by ambulance!’
tients are sicker and require more care in the ER, they And for physicians and health care systems, the message
are still getting through the ER faster, after adjusting for is that there are critical intervals within the overall patmultiple risk factors and elements in the decision-mak- tern of care that need scrutiny,” said Dr. Wright, a caring process,” Dr. McCabe noted. “Taking the ambulance diologist in Chico, Calif. “The person who arrives by priresults in efficiency, and this translates into faster ER vate transportation may languish within those time
throughput and shorter door-to-balloon times.”
intervals,” she said. “The message is to focus on every
Of some concern to the researchers was that calling handoff. They accumulate in precious minutes.”
■
©A ARON K OHR / I S TOCKPHOTO. COM
UA/NSTEMI Guidelines Add Prasugrel, Quicker Angiography
BY JENNIE SMITH
FROM THE JOURNAL OF THE AMERICAN
COLLEGE OF CARDIOLOGY
he American College of Cardiology
Foundation and the American Heart
Association have published updated
guidelines for managing patients with
unstable angina/non–ST elevation myocardial infarction, taking into consideration the use of a newer agent, prasugrel, as an alternative to clopidogrel, and
recommending diagnostic angiography
sooner for patients at high risk, among
other changes.
The guidelines (Am. J. Cardiol. 2011
March 28 [doi:10.1016/j.jacc.2011.02.009])
are based on the most recent clinical trial evidence available. They update recommendations from 2007, and include
several changes clinicians should be aware
of, the guidelines’ lead author, Dr. R.
Scott Wright of the Mayo Clinic in
Rochester, Minn., said in an e-mail interview. These are, in order of importance:
P The timing of invasive therapy in
medium- and high-risk patients.
P The role of triple- vs. dual-antiplatelet
T
therapy in patients at medium and high
risk.
P The role of invasive therapy in patients with chronic kidney disease.
P The importance of participating in
quality improvement processes.
P The role of prasugrel in non–ST elevation acute coronary syndrome.
Clinicians face tough decisions about
when to use an invasive strategy such as
diagnostic coronary angiography –
whether within hours of presentation or
days, Dr. Wright and his colleagues
wrote in their analysis. Immediate
catheterization with revascularization of
unstable coronary lesions may prevent ischemic events that would otherwise occur during medical therapy – but pretreatment with antithrombotics “may
diminish thrombus burden and ‘passivate’ unstable plaques,” improving the
safety of the procedure and reducing
the risk of ischemic complications.
The new guidelines, based on three
randomized controlled trials evaluating
the timing of angiography, recommend
an early invasive strategy (12-24 hours after presentation) over a delayed invasive
strategy (more than 24 hours after presentation) for initially stabilized highrisk patients with UA/NSTEMI.
“For patients not at high risk, a delayed
invasive approach is also reasonable,”
Dr. Wright and his colleagues wrote.
Several changes to earlier recommendations for antiplatelet therapy are contained in the new guidelines, including altered loading doses for clopidogrel to
counter the potential for the drug to be
less effective in some patient groups,
and the addition of prasugrel, which
was approved by the Food and Drug Administration after the last guidelines
were published.
Prasugrel, in a randomized controlled
trial comparing it with clopidogrel, was
shown to be superior in reducing clinical
events but at the expense of an increased
risk of bleeding, the guideline writers
noted. In March 2010 the FDA issued a
warning that in some patient groups
clopidogrel is less effective than it should
be because of a genetic variant that inhibits the body’s conversion of the prodrug to the drug.
However, Dr. Wright and his col-
leagues stopped short of endorsing prasugrel as a first choice over clopidogrel
because of the higher bleeding risk and
other considerations. People aged 75
years or older, those with a history of
transient ischemic attack or stroke or
with active pathological bleeding, and
people weighing less than 60 kg saw no
benefit and/or net harm from prasugrel,
they noted.
Dr. Wright and his colleagues also
changed recommendations involving
glycoprotein IIB/IIIa inhibitors, noting
that recent studies “more strongly support a strategy of selective rather than
provisional use of GP IIb/IIIa inhibitor
therapy as part of triple-antiplatelet therapy,” due to concerns about the potential bleeding risks.
Dr. Wright declared no conflicts of interest. Several of Dr. Wright’s coauthors,
including Dr. Jeffrey L. Anderson, the
writing committee’s vice chair, disclosed
consultant relationships with pharmaceutical firms Sanofi-Aventis, Bristol Myers-Squibb, Lilly, and Daiichi. Members
with conflicts were not permitted to vote
on recommended drug therapies.
■
BYSTOLIC.
Helping patients get
the blood pressure
reductions they need.
NOW w
e
d
i
w
n
ith eve
y
t
i
l
i
b
a
l
i
a
v
a
y
r
a
l
u
r form
BYSTOLIC. Significant blood pressure
reductions with a low incidence of side effects.
Effective as monotherapy or in combination1,2 *
■ DBP/SBP reductions of up to -15.3/-29.0 mm Hg for BYSTOLIC when used in combination with HCTZ 25 mg
(vs -1.4/-0.2 mm Hg for placebo)†
■ DBP/SBP reductions of -9.3/-16.7 and -13.8/-17.6 for BYSTOLIC monotherapy 5 mg and 10 mg,
respectively (vs -1.4/-0.2 for placebo)‡
Low incidence of side effects and overall low discontinuation rate3
■ Discontinuation rate due to adverse events was 2.8% for BYSTOLIC vs 2.2% for placebo3
* Results from a 3-month, multicenter, randomized, double-blind, parallel-group, placebo-controlled, multifactorial-design study of BYSTOLIC and hydrochlorothiazide, alone or in
combination, for the treatment of mild to moderate hypertension.
†
Primary endpoint was sitting DBP at trough. Mean values at baseline: sitting DBP at trough, 102.1 mm Hg; sitting SBP at trough, 158.1 mm Hg (N=240; n=100).
‡
Primary endpoint was sitting DBP at trough. Mean values at baseline: sitting DBP at trough, 100.5 mm Hg; sitting SBP at trough, 158.1 mm Hg (N=240; n=59).
BYSTOLIC is indicated for the treatment of hypertension. BYSTOLIC may be used alone or in combination with other antihypertensive agents.
Important Safety Information
Adverse Reactions
■ The most common adverse events with BYSTOLIC versus placebo (approximately ≥1% and greater than placebo) were headache, fatigue, dizziness, diarrhea, nausea,
insomnia, chest pain, bradycardia, dyspnea, rash, and peripheral edema. The most common adverse events that led to discontinuation of BYSTOLIC were headache (0.4%),
nausea (0.2%), and bradycardia (0.2%).
Contraindications
■ BYSTOLIC is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus
syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.
Warnings and Precautions
■ Do not abruptly discontinue BYSTOLIC therapy in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction, and ventricular arrhythmias
■
■
■
■
■
■
■
have been reported following the abrupt discontinuation of therapy with beta blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding
exacerbation of the angina pectoris. Caution patients without overt coronary artery disease against interruption or abrupt discontinuation of therapy. As with other beta
blockers, when discontinuation of BYSTOLIC is planned, carefully observe and advise patients to minimize physical activity. Taper BYSTOLIC over 1 to 2 weeks when possible.
If the angina worsens or acute coronary insufficiency develops, restart BYSTOLIC promptly, at least temporarily.
BYSTOLIC was not studied in patients with angina pectoris or who had a recent MI.
In general, patients with bronchospastic diseases should not receive beta blockers.
Because beta blocker withdrawal has been associated with an increased risk of MI and chest pain, patients already on beta blockers should generally continue treatment
throughout the perioperative period. If BYSTOLIC is to be continued perioperatively, monitor patients closely when anesthetic agents which depress myocardial function,
such as ether, cyclopropane, and trichloroethylene are used. If beta-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to
reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
The beta-blocking effects of BYSTOLIC can be reversed by beta agonists, eg, dobutamine or isoproterenol. However, such patients may be subject to protracted severe
hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with beta blockers.
Beta blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Advise patients subject to spontaneous hypoglycemia and diabetic patients
receiving insulin or oral hypoglycemic agents about these possibilities.
Beta blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta blockers in these patients may be followed by an exacerbation of
symptoms or may precipitate a thyroid storm.
Beta blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.
Because of significant negative inotropic and chronotropic effects in patients treated with beta blockers and calcium channel blockers of the verapamil and diltiazem type,
monitor the ECG and blood pressure of patients treated concomitantly with these agents.
©2010 Forest Laboratories, Inc.
44-1019844
12/10
BYSTOLIC.
Widely available on managed care formularies.
COMMERCIAL
87%
unrestricted access4
NEW
Medco
NEW
ESI
MEDICARE PART D
78%
NEW
UnitedHealthcare
Aetna
CIGNA
Humana
MedImpact
CVS Caremark
unrestricted access4
Medco Part D
UnitedHealthcare Part D
Aetna Part D
CIGNA Part D
Humana Part D
SilverScript
MemberHealth/CCRx
Health Net Part D
WellPoint Part D
Formulary status information is valid as of October 2010. Coverage is subject to change.
Warnings and Precautions (continued)
■ Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc). When BYSTOLIC is co-administered with an inhibitor
■
■
■
■
or an inducer of CYP2D6, monitor patients closely and adjust the nebivolol dose according to blood pressure response. The dose of BYSTOLIC may need to be reduced. When
BYSTOLIC is administered with fluoxetine, significant increases in d-nebivolol may be observed (ie, an 8-fold increase in AUC and a 3-fold increase in Cmax for d-nebivolol).
Renal clearance of nebivolol is decreased in patients with severe renal impairment. In patients with severe renal impairment (ClCr less than 30 mL/min) the recommended
initial dose is 2.5 mg once daily; titrate up slowly if needed. BYSTOLIC has not been studied in patients receiving dialysis.
Metabolism of nebivolol is decreased in patients with moderate hepatic impairment. In patients with moderate hepatic impairment, the recommended initial dose is 2.5 mg once
daily; titrate up slowly if needed. BYSTOLIC has not been studied in patients with severe hepatic impairment and therefore it is not recommended in that population.
Patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of
epinephrine while taking beta blockers.
In patients with known or suspected pheochromocytoma, initiate an alpha blocker prior to the use of any beta blocker.
Drug Interactions
■ Do not use BYSTOLIC with other beta blockers.
■ Both digitalis glycosides and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
■ BYSTOLIC can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine
[verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide.
Use in Specific Populations
■ Use BYSTOLIC during pregnancy only if the potential benefit justifies the potential risk to the fetus. BYSTOLIC is not
recommended during nursing.
■ The safety and effectiveness of BYSTOLIC have not been established in pediatric patients.
■ In a placebo-controlled trial of 2128 patients (1067 BYSTOLIC, 1061 placebo) over 70 years of age with chronic heart
failure receiving a maximum dose of 10 mg per day for a median of 20 months, no worsening of heart failure was
reported with nebivolol compared to placebo. However, if heart failure worsens, consider discontinuation of BYSTOLIC.
Please see brief summary of full Prescribing Information on last page of this advertisement.
References: 1. Lacourcière Y, Lefebvre J, Poirier L, Archambault F, Arnott W. Treatment of ambulatory hypertensives with nebivolol or hydrochlorothiazide alone
and in combination: a randomized, double-blind, placebo-controlled, factorial-design trial. Am J Hypertens. 1994;7:137-145. 2. Data on file. Forest Laboratories,
Inc. 3. BYSTOLIC [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2010. 4. MediMedia Information Technologies, LLC, as of October 2010.
Data is subject to change.
www.BYSTOLIC.com
PRACTICE TRENDS
34
MedPAC Recommends 1% Physician Fee Raise
B Y N A S E E M S. M I L L E R
edicare physician fees should
be increased by 1% in 2012,
and an alternative must be
found for the Sustainable Growth Rate
formula, according to recommendations
in the Medicare Payment Advisory Committee annual March report to Congress.
“For a long time, I’ve been able to sit before this subcommittee and say that SGR
M
BYSTOLIC® (nebivolol) tablets
Brief Summary of full Prescribing Information
Initial U.S. Approval: 2007
is a problem but we don’t see an imminent
threat to access,” Medicare Payment Advisory Commission (MedPAC) Chairman
Glenn Hackbarth testified at a hearing of
the Health Subcommittee of the House
Ways and Means Committee. But “we
think we’re getting closer to that tipping
point” when that is no longer the case.
In 2009, fee-for-service Medicare spent
about $64 billion on physician and other health professional services, accountRx Only
INDICATIONS AND USAGE: Hypertension - BYSTOLIC is indicated for the treatment of hypertension [see Clinical Studies (14.1)]. BYSTOLIC may be used alone or in combination with other
antihypertensive agents [see Drug Interactions (7)].
CONTRAINDICATIONS: BYSTOLIC is contraindicated in the following conditions: Severe bradycardia; Heart block greater than first degree; Patients with cardiogenic shock; Decompensated
cardiac failure; Sick sinus syndrome (unless a permanent pacemaker is in place); Patients with
severe hepatic impairment (Child-Pugh >B); Patients who are hypersensitive to any component
of this product.
WARNINGS AND PRECAUTIONS: Abrupt Cessation of Therapy - Do not abruptly discontinue
BYSTOLIC therapy in patients with coronary artery disease. Severe exacerbation of angina,
myocardial infarction and ventricular arrhythmias have been reported in patients with coronary
artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the
angina pectoris. Caution patients without overt coronary artery disease against interruption or
abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of BYSTOLIC
is planned, carefully observe and advise patients to minimize physical activity. Taper BYSTOLIC
over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, restart BYSTOLIC promptly, at least temporarily. Angina and Acute Myocardial Infarction
- BYSTOLIC was not studied in patients with angina pectoris or who had a recent MI. Bronchospastic Diseases - In general, patients with bronchospastic diseases should not receive
β-blockers. Anesthesia and Major Surgery - Because beta-blocker withdrawal has been associated with an increased risk of MI and chest pain, patients already on beta-blockers should
generally continue treatment throughout the perioperative period. If BYSTOLIC is to be continued perioperatively, monitor patients closely when anesthetic agents which depress myocardial
function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is
withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The β-blocking effects of BYSTOLIC can be reversed by β-agonists, e.g., dobutamine or isoproterenol.
However, such patients may be subject to protracted severe hypotension. Additionally, difficulty
in restarting and maintaining the heartbeat has been reported with β-blockers. Diabetes and
Hypoglycemia - β-blockers may mask some of the manifestations of hypoglycemia, particularly
tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay
recovery of serum glucose levels. It is not known whether nebivolol has these effects. Advise
patients subject to spontaneous hypoglycemia and diabetic patients receiving insulin or oral
hypoglycemic agents about these possibilities. Thyrotoxicosis - β-blockers may mask clinical
signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed
by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.
Peripheral Vascular Disease - β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Non-dihydropyridine Calcium Channel
Blockers - Because of significant negative inotropic and chronotropic effects in patients treated
with β-blockers and calcium channel blockers of the verapamil and diltiazem type, monitor the
ECG and blood pressure in patients treated concomitantly with these agents. Use with CYP2D6
Inhibitors - Nebivolol exposure increases with inhibition of CYP2D6 [see Drug Interactions (7)].
The dose of BYSTOLIC may need to be reduced. Impaired Renal Function - Renal clearance of
nebivolol is decreased in patients with severe renal impairment. BYSTOLIC has not been studied
in patients receiving dialysis [see Clinical Pharmacology (12.4) and Dosage and Administration
(2.1)]. Impaired Hepatic Function - Metabolism of nebivolol is decreased in patients with
moderate hepatic impairment. BYSTOLIC has not been studied in patients with severe hepatic
impairment [see Clinical Pharmacology (12.4) and Dosage and Administration (2.1)]. Risk of
Anaphylactic Reactions - While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic,
or therapeutic challenge. Such patients may be unresponsive to the usual doses of epinephrine
used to treat allergic reactions. Pheochromocytoma - In patients with known or suspected
pheochromocytoma, initiate an α-blocker prior to the use of any β-blocker.
ADVERSE REACTIONS: Clinical Studies Experience - BYSTOLIC has been evaluated for safety
in patients with hypertension and in patients with heart failure. The observed adverse reaction profile was consistent with the pharmacology of the drug and the health status of the patients in the
clinical trials. Adverse reactions reported for each of these patient populations are provided below.
Excluded are adverse reactions considered too general to be informative and those not reasonably associated with the use of the drug because they were associated with the condition being
treated or are very common in the treated population. The data described below reflect worldwide
clinical trial exposure to BYSTOLIC in 6545 patients, including 5038 patients treated for hypertension and the remaining 1507 subjects treated for other cardiovascular diseases. Doses ranged
from 0.5 mg to 40 mg. Patients received BYSTOLIC for up to 24 months, with over 1900 patients
treated for at least 6 months, and approximately 1300 patients for more than one year. HYPERTENSION: In placebo-controlled clinical trials comparing BYSTOLIC with placebo, discontinuation of therapy due to adverse reactions was reported in 2.8% of patients treated with nebivolol
and 2.2% of patients given placebo. The most common adverse reactions that led to discontinuation of BYSTOLIC were headache (0.4%), nausea (0.2%) and bradycardia (0.2%). Table 1 lists
treatment-emergent adverse reactions that were reported in three 12-week, placebo-controlled
monotherapy trials involving 1597 hypertensive patients treated with either 5 mg, 10 mg, or 2040 mg of BYSTOLIC and 205 patients given placebo and for which the rate of occurrence was at
least 1% of patients treated with nebivolol and greater than the rate for those treated with placebo
in at least one dose group. Table 1. Treatment-Emergent Adverse Reactions with an Incidence
(over 6 weeks) ≥1% in BYSTOLIC-Treated Patients and at a Higher Frequency than PlaceboTreated Patients are listed below in the following order: System Organ Class Preferred Term
[Placebo (n = 205), Nebivolol 5 mg (n = 459), Nebivolol 10 mg (n = 461), Nebivolol 20-40 mg
(n = 677)] Cardiac Disorders: Bradycardia (0, 0, 0, 1); Gastrointestinal Disorders: Diarrhea
(2, 2, 2, 3); Nausea (0, 1, 3, 2); General Disorders: Fatigue (1, 2, 2, 5); Chest pain (0, 0, 1, 1);
Peripheral edema (0, 1, 1, 1); Nervous System Disorders: Headache (6, 9, 6, 7); Dizziness
( 2, 2, 3, 4); Psychiatric Disorders: Insomnia (0, 1, 1, 1); Respiratory Disorders: Dyspnea (0, 0,
1, 1); Skin and Subcutaneous Tissue Disorders: Rash (0, 0, 1, 1). Listed below are other
reported adverse reactions with an incidence of at least 1% in the more than 4300 patients treated
with BYSTOLIC in controlled or open-label trials except for those already appearing in Table 1,
terms too general to be informative, minor symptoms, or adverse reactions unlikely to be attributable to drug because they are common in the population. These adverse reactions were in most
cases observed at a similar frequency in placebo-treated patients in the controlled studies. Body
as a Whole: asthenia. Gastrointestinal System Disorders: abdominal pain. Metabolic and
Nutritional Disorders: hypercholesterolemia. Nervous System Disorders: paraesthesia. Laboratory Abnormalities - In controlled monotherapy trials of hypertensive patients, BYSTOLIC was
associated with an increase in BUN, uric acid, triglycerides and a decrease in HDL cholesterol and
platelet count. Postmarketing Experience - The following adverse reactions have been identified
from spontaneous reports of BYSTOLIC received worldwide and have not been listed elsewhere.
ing for 13% of total Medicare spending,
according to the 2011 MedPAC report,
which noted that “among the 1 million
clinicians in Medicare’s registry, about
half are physicians who actively bill
Medicare.” MedPAC is charged with advising Congress on setting payment rates
for physicians, hospitals, and other health
care providers.
In addressing the SGR, the report notes
that “a main flaw of the SGR is its blunt
These adverse reactions have been chosen for inclusion due to a combination of seriousness,
frequency of reporting or potential causal connection to BYSTOLIC. Adverse reactions common
in the population have generally been omitted. Because these adverse reactions were reported
voluntarily from a population of uncertain size, it is not possible to estimate their frequency or
establish a causal relationship to BYSTOLIC exposure: abnormal hepatic function (including
increased AST, ALT and bilirubin), acute pulmonary edema, acute renal failure, atrioventricular
block (both second- and third-degree), bronchospasm, erectile dysfunction, hypersensitivity
(including urticaria, allergic vasculitis and rare reports of angioedema), myocardial infarction,
pruritus, psoriasis, Raynaud’s phenomenon, peripheral ischemia/claudication, somnolence,
syncope, thrombocytopenia, various rashes and skin disorders, vertigo, and vomiting.
DRUG INTERACTIONS: CYP2D6 Inhibitors - Use caution when BYSTOLIC is co-administered
with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.) [see Clinical Pharmacology (12.5)]. Hypotensive Agents - Do not use BYSTOLIC with other β-blockers. Closely
monitor patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine,
because the added β-blocking action of BYSTOLIC may produce excessive reduction of sympathetic activity. In patients who are receiving BYSTOLIC and clonidine, discontinue BYSTOLIC for
several days before the gradual tapering of clonidine. Digitalis Glycosides - Both digitalis
glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant
use can increase the risk of bradycardia. Calcium Channel Blockers - BYSTOLIC can exacerbate
the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium
antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem]
classes), or antiarrhythmic agents, such as disopyramide.
USE IN SPECIFIC POPULATIONS: Pregnancy: Teratogenic Effects, Category C - Decreased pup
body weights occurred at 1.25 and 2.5 mg/kg in rats, when exposed during the perinatal period
(late gestation, parturition and lactation). At 5 mg/kg and higher doses (1.2 times the MRHD),
prolonged gestation, dystocia and reduced maternal care were produced with corresponding
increases in late fetal deaths and stillbirths and decreased birth weight, live litter size and pup
survival. Insufficient numbers of pups survived at 5 mg/kg to evaluate the offspring for reproductive performance. In studies in which pregnant rats were given nebivolol during organogenesis,
reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day
(5 and 10 times the MRHD), and small reversible delays in sternal and thoracic ossification
associated with the reduced fetal body weights and a small increase in resorption occurred at
40 mg/kg/day (10 times the MRHD). No adverse effects on embryo-fetal viability, sex, weight or
morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses
as high as 20 mg/kg/day (10 times the MRHD). Labor and Delivery - Nebivolol caused prolonged
gestation and dystocia at doses ≥5 mg/kg in rats (1.2 times the MRHD). These effects were associated with increased fetal deaths and stillborn pups, and decreased birth weight, live litter size
and pup survival rate, events that occurred only when nebivolol was given during the perinatal
period (late gestation, parturition and lactation). No studies of nebivolol were conducted in pregnant women. Use BYSTOLIC during pregnancy only if the potential benefit justifies the potential
risk to the fetus. Nursing Mothers - Studies in rats have shown that nebivolol or its metabolites
cross the placental barrier and are excreted in breast milk. It is not known whether this drug is
excreted in human milk. Because of the potential for β-blockers to produce serious adverse
reactions in nursing infants, especially bradycardia, BYSTOLIC is not recommended during
nursing. Pediatric Use - Safety and effectiveness in pediatric patients have not been established.
Pediatric studies in ages newborn to 18 years old have not been conducted because of
incomplete characterization of developmental toxicity and possible adverse effects on long-term
fertility [see Nonclinical Toxicology (13.1)]. Geriatric Use - Of the 2800 patients in the U.S.sponsored placebo-controlled clinical hypertension studies, 478 patients were 65 years of age or
older. No overall differences in efficacy or in the incidence of adverse events were observed
between older and younger patients. Heart Failure - In a placebo-controlled trial of 2128
patients (1067 BYSTOLIC, 1061 placebo) over 70 years of age with chronic heart failure receiving a maximum dose of 10 mg per day for a median of 20 months, no worsening of heart failure
was reported with nebivolol compared to placebo. However, if heart failure worsens consider
discontinuation of BYSTOLIC.
OVERDOSAGE: In clinical trials and worldwide postmarketing experience there were reports of
BYSTOLIC overdose. The most common signs and symptoms associated with BYSTOLIC overdosage are bradycardia and hypotension. Other important adverse reactions reported with
BYSTOLIC overdose include cardiac failure, dizziness, hypoglycemia, fatigue and vomiting. Other
adverse reactions associated with β-blocker overdose include bronchospasm and heart block. The
largest known ingestion of BYSTOLIC worldwide involved a patient who ingested up to 500 mg
of BYSTOLIC along with several 100 mg tablets of acetylsalicylic acid in a suicide attempt. The
patient experienced hyperhidrosis, pallor, depressed level of consciousness, hypokinesia,
hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure, and vomiting.
The patient recovered. Because of extensive drug binding to plasma proteins, hemodialysis is not
expected to enhance nebivolol clearance. If overdose occurs, provide general supportive and
specific symptomatic treatment. Based on expected pharmacologic actions and recommendations
for other β-blockers, consider the following general measures, including stopping BYSTOLIC,
when clinically warranted: Bradycardia: Administer IV atropine. If the response is inadequate,
isoproterenol or another agent with positive chronotropic properties may be given cautiously.
Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary. Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may be useful.
Heart Block (second- or third-degree): Monitor and treat with isoproterenol infusion.
Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary. Congestive Heart Failure: Initiate therapy with digitalis glycosides and diuretics. In certain
cases, consider the use of inotropic and vasodilating agents. Bronchospasm: Administer bronchodilator therapy such as a short-acting inhaled β2-agonist and/or aminophylline. Hypoglycemia:
Administer IV glucose. Repeated doses of IV glucose or possibly glucagon may be required.
Supportive measures should continue until clinical stability is achieved. The half-life of low doses
of nebivolol is 12-19 hours. Call the National Poison Control Center (800-222-1222) for the most
current information on β-blocker overdose treatment.
Forest Pharmaceuticals, Inc.
Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045, USA
Licensed from Mylan Laboratories, Inc.
Under license from Janssen Pharmaceutica N.V., Beerse, Belgium
Rev. 02/10
© 2010 Forest Laboratories, Inc.
approach. In setting across-the-board updates to Medicare’s physician fee schedule, the system neither rewards individual providers who restrain unnecessary
volume growth nor penalizes those who
contribute most to volume increases.
Also, the SGR does little to counter the
volume incentives that are inherent in
[fee-for-service] payments. In fact, volume growth is one of the major factors
that has caused cumulative spending to
exceed the SGR’s cumulative target.”
In the absence of congressional action,
the SGR requires physician payments to
be cut by approximately 30% in 2012, according to MedPAC calculations.
Every year since 2002, Medicare spending has exceeded SGR targets, causing
physician pay, by law, to be reduced.
However, just about every year, Congress has stepped in to legislate a way to
avoid those cuts. The avoided cuts are becoming an ever-growing debt being carried on the federal ledger.
The White House, in its fiscal 2012
budget proposal, is proposing to reduce
that debt over the next 10 years, at a cost
of $370 billion. But the administration
has figured out only how to pay for that
fix for the first 2 years.
Mr. Hackbarth told the subcommittee
that MedPAC will look into options for
a new payment system, but he added
that any new payment system will have
a budget score attached to it. The question for Congress is “whether we’re going to spend more by making last-minute
adjustments piling more money into the
existing payment system, or whether
we’re going to spend more strategically
to achieve important goals for the
Medicare program,” he said.
MedPAC’s struggles to find a way
around the SGR formula were on display
at a February meeting where staff analysts
presented options to commissioners. Multiple options exist to permanently fix the
formula, but each has its cost to physicians, patients, and the program.
Among those options were adjusting
the SGR’s spending targets so that they
are no longer cumulative, but are calculated on an annual basis and allowing
some flexibility in the target. Both of
those options would forgive any excess
over the target, removing the annual pay
cut threat doctors have endured since
2002 under the SGR, according to Cristina Boccuti, a principal policy analyst for
MedPAC. However, forgiving any overage will lead to higher costs for the
Medicare program. Neither option
would leave any room to offer incentives
for improved quality and efficiency, she
added.
In the past, MedPAC has recommended setting target growth rates – and payment rates – according to particular service categories; the commission is looking
in this direction again. For example, separate categories could be established for
primary care, imaging, minor procedures,
and anesthesia, allowing rates to more
closely track volume of services.
■
Alicia Ault contributed to this article.
Pages 34a—34bG
PRACTICE TRENDS
35
IMPLEMENTING HEALTH REFORM
Community Health Centers
he Affordable Care Act includes
$11 billion in new funding to significantly expand the reach of federally qualified health centers, known as
community health centers. The bulk of
the funding, $9.5 billion, will be used to
fund new health centers and to expand
patient capacity at existing centers. Over
the next 5 years, that funding is expect-
T
Hypertriglyceridemia: Patients with fasting
serum TG levels above 500 mg/dL were
excluded from the diabetes clinical trials.
In the phase 3 diabetes trials, 637 (63%)
patients had baseline fasting serum TG
levels less than 200 mg/dL, 261 (25%)
had baseline fasting serum TG levels
between 200 and 300 mg/dL, 111 (11%)
had baseline fasting serum TG levels
between 300 and 500 mg/dL, and 9 (1%)
had fasting serum TG levels greater than
or equal to 500 mg/dL. The median
baseline fasting TG concentration for the
study population was 172 mg/dL; the
median post-treatment fasting TG was
195 mg/dL in the WELCHOL group and
177 mg/dL in the placebo group.
WELCHOL therapy resulted in a median
placebo-corrected increase in serum TG
of 5% (p=0.22), 22% (p<0.001), and 18%
(p<0.001) when added to metformin,
insulin and sulfonylureas, respectively
[See Warnings and Precautions (5.2)
and Clinical Studies (14.2) in the full
prescribing information]. In comparison,
WELCHOL resulted in a median increase
in serum TG of 5% compared to placebo
(p=0.42) in a 24-week monotherapy
lipid-lowering trial [See Clinical Studies
(14.1) in the full prescribing information].
Treatment-emergent fasting TG
concentrations 500 mg/dL occurred
in 4.1% of WELCHOL-treated patients
compared to 2.0% of placebo-treated
patients. Among these patients, the TG
concentrations with WELCHOL (median
604 mg/dL; interquartile range 538-712
mg/dL) were similar to that observed with
placebo (median 644 mg/dL; interquartile
range 574-724 mg/dL). Two (0.4%)
patients on WELCHOL and 2 (0.4%)
patients on placebo developed TG
elevations 1000 mg/dL. In all WELCHOL
clinical trials, including studies in patients
with type 2 diabetes and patients with
primary hyperlipidemia, there were no
reported cases of acute pancreatitis
associated with hypertriglyceridemia.
It is unknown whether patients with more
uncontrolled, baseline hypertriglyceridemia
would have greater increases in serum
TG levels with WELCHOL [See
Contraindications (4) and Warnings
and Precautions (5.2)].
Cardiovascular adverse events: During
the diabetes clinical trials, the incidence
of patients with treatment-emergent
serious adverse events involving the
cardiovascular system was 3% (17/566)
in the WELCHOL group and 2% (10/562)
in the placebo group. These overall rates
included disparate events (e.g., myocardial
infarction, aortic stenosis, and bradycardia);
therefore, the significance of this imbalance
is unknown.
Hypoglycemia: Adverse events of
hypoglycemia were reported based on
the clinical judgment of the blinded
investigators and did not require
confirmation with fingerstick glucose
testing. The overall reported incidence of
hypoglycemia was 3.0% in patients treated
with WELCHOL and 2.3% in patients
treated with placebo. No WELCHOL
treated patients developed severe
hypoglycemia.
6.2 Post-marketing Experience
The following additional adverse reactions
have been identified during post-approval
use of WELCHOL. Because these reactions
are reported voluntarily from a population
of uncertain size, it is generally not
possible to reliably estimate their
frequency or establish a causal
relationship to drug exposure.
ed to double community health center
capacity to about 40 million patients.
The first $1 billion in funding is being distributed this year.
Dr. Gary Wiltz, who runs a network
of community health centers in rural
Louisiana, explains how the new funding
and other provisions of the ACA will impact primary care in underserved areas.
CARDIOLOGY NEWS: The ACA would
help expand services to an additional 20
million patients. Will that begin to address the need for primary care services
in underserved areas?
Dr. Wiltz: It most definitely will. This
funding, if it’s fully implemented, will
help us to get close to 40 million patients
who don’t have a regular source of med-
c
Drug Interactions with concomitant
Type 2 Diabetes Mellitus: Of the 1128
Cyclosporine levels should be monitored
patients enrolled in the four diabetes
WELCHOL administration include:
and, based on theoretical grounds,
studies, 249 (22%) were 65 years old,
cyclosporine should be administered at
K!>3B51C54C59JEB513D9F9DI?B453B51C54
and 12 (1%) were 75 years old. In these
least 4 hours prior to WELCHOL.
phenytoin levels in patients receiving
trials, WELCHOL 3.8 g/day or placebo was
phenytoin. Phenytoin should be
In an in vivo drug interaction study,
added onto background anti-diabetic
administered 4 hours prior to WELCHOL. WELCHOL and warfarin coadministration
K)54E354!>D5B>1D9?>1<&?B=1<9J54)1D9?
had no effect on warfarin drug levels. This therapy. No overall differences in safety or
effectiveness were observed between the
!&)9>@1D95>DCB5359F9>7G1B61B9>
study did not assess the effect of
elderly and younger patients, but greater
D85B1@I!>G1B61B9>DB51D54@1D95>DC!&) WELCHOL and warfarin coadministration
sensitivity of some older individuals
should be monitored frequently during
?>!&)!>@?CD=1B;5D9>7B5@?BDC
cannot be ruled out.
WELCHOL initiation then periodically
concomitant use of WELCHOL and
thereafter.
warfarin has been associated with reduced 8.6 Hepatic Impairment
K<5F1D54D8IB?94CD9=E<1D9>78?B=?>5
!&)+85B56?B59>@1D95>DC?>G1B61B9>
No special considerations or dosage
(TSH) in patients receiving thyroid
D85B1@ID85!&)C8?E<425=?>9D?B54
adjustments are recommended when
hormone replacement therapy. Thyroid
before initiating WELCHOL and frequently
WELCHOL is administered to patients
hormone replacement should be
enough during early WELCHOL therapy to with hepatic impairment.
administered 4 hours prior to WELCHOL 5>CEB5D81D>?C97>96931>D1<D5B1D9?>9>!&)
[See Drug Interactions (7)].
?33EBC'>35D85!&)9CCD12<53?>D9>E5D? 8.7 Renal Impairment
Type 2 Diabetes Mellitus: Of the 1128
1CDB?9>D5CD9>1<4F5BC5)513D9?>C
=?>9D?BD85!&)1D9>D5BF1<CECE1<<I
patients enrolled in the four diabetes
recommended for patients on warfarin.
Bowel obstruction (in patients with a
studies, 696 (62%) had mild renal
history of bowel obstruction or resection), [See Post-marketing Experience (6.2)]
insufficiency (creatinine clearance [CrCl]
dysphagia or esophageal obstruction
8 USE IN SPECIFIC POPULATIONS
50-<80 mL/min), 53 (5%) had moderate
(occasionally requiring medical
8.1 Pregnancy
renal insufficiency (CrCl 30-<50 mL/ min),
intervention), fecal impaction, pancreatitis,
and none had severe renal insufficiency
Pregnancy Category B. There are no
abdominal distension, exacerbation of
(CrCl <30 mL/min), as estimated from
adequate and well-controlled studies of
hemorrhoids, and increased
baseline serum creatinine using the
colesevelam use in pregnant women.
transaminases.
%?496931D9?>?695D9>)5>1<9C51C5
Animal reproduction studies in rats and
Laboratory Abnormalities
rabbits revealed no evidence of fetal harm. %)5AE1D9?>&??F5B1<<49665B5>35C
Hypertriglyceridemia
in safety or effectiveness were observed
)5AE9B5=5>DC6?BF9D1=9>C1>4?D85B
between patients with CrCl <50 mL/min
nutrients are increased in pregnancy.
7 DRUG INTERACTIONS
(n=53) and those with a CrCl 50 mL/min
However, the effect of colesevelam on the
Table 4 lists the drugs that have been
(n=1075).
absorption of fat-soluble vitamins has not
tested in in vitro binding or in vivo drug
been studied in pregnant women. This
interaction studies with colesevelam
10 OVERDOSAGE
drug should be used during pregnancy
and/or drugs with postmarketing reports
Doses of WELCHOL in excess of 4.5 g/day
only
if
clearly
needed.
consistent with potential drug-drug
have not been tested. Because WELCHOL
interactions. Orally administered drugs
In animal reproduction studies,
is not absorbed, the risk of systemic
that have not been tested for interaction
colesevelam revealed no evidence of
toxicity is low. However, excessive doses
with colesevelam, especially those with a
fetal harm when administered to rats
of WELCHOL may cause more severe local
narrow therapeutic index, should also be
and rabbits at doses 50 and 17 times
gastrointestinal effects (e.g., constipation)
administered at least 4 hours prior to
the maximum human dose, respectively.
than recommended doses.
WELCHOL. Alternatively, the physician
Because animal reproduction studies are
should monitor drug levels of the conot always predictive of human response,
administered drug.
this drug should be used in pregnancy
only if clearly needed.
Table 4
Drugs Tested in In Vitro Binding
8.3 Nursing Mothers
or In Vivo Drug Interaction Testing or
Colesevelam hydrochloride is not expected
With Post-Marketing Reports
to be excreted in human milk because
colesevelam hydrochloride is not absorbed
systemically from the gastrointestinal tract.
cyclosporinec,
glyburidea,
8.4 Pediatric Use
Drugs with a
levothyroxinea, and
The safety and effectiveness of WELCHOL
known interaction oral contraceptives
as monotherapy or in combination with a
with colesevelama containing ethinyl
statin were evaluated in children, 10 to 17
estradiol and
years of age with heFH [See Clinical
norethindrone
Studies (14.1) in the full prescribing
information]. The adverse reaction profile
Drugs with
was similar to that of patients treated with
postmarketing
placebo. In this limited controlled study,
reports consistent
there were no significant effects on
with potential
phenytoina,
growth, sexual maturation, fat-soluble
drug-drug
warfarinb
vitamin levels or clotting factors in the
interactions when
adolescent boys or girls relative to placebo
coadministered
/*554F5BC5)513D9?>C0.
with WELCHOL
Due to tablet size, WELCHOL for Oral
Suspension is recommended for use in the
cephalexin,
pediatric population. Dose adjustments are
ciprofloxacin,
not required when WELCHOL is administered
digoxin, warfarinb,
to children 10 to 17 years of age.
fenofibrate,
Drugs that do
lovastatin,
WELCHOL has not been studied in
not interact with metformin,
children younger than 10 years of age
colesevelam
metoprolol,
or in pre-menarchal girls.
based on in vitro pioglitazone,
8.5 Geriatric Use
or in vivo testing quinidine,
Primary Hyperlipidemia: Of the 1350
repaglinide,
patients enrolled in the hyperlipidemia
valproic acid,
clinical studies, 349 (26%) were
verapamil
65 years old, and 58 (4%) were 75
years old. No overall differences in safety
a Should be administered at least 4 hours
or effectiveness were observed between
prior to WELCHOL
these subjects and younger subjects,
b No significant alteration of warfarin drug
and other reported clinical experience
Daiichi Sankyo, Inc.
has not identified differences in responses Marketed by:
levels with warfarin and WELCHOL
Parsippany, New Jersey
coadministration in an in vivo study which between the elderly and younger patients,
07054
did not evaluate warfarin pharmacodynamics but greater sensitivity of some older
!&) [See Post-marketing Experience (6.2)] individuals cannot be ruled out.
P1801115
ical care or a medical home, by 2015.
We’ll have the largest network of primary care providers in the nation. Along
with that funding, there is a tripling of
funding for the National Health Service
Corps, which also will help to address the
shortage of primary care providers. But
we’re certainly not going to solve all of
the nation’s ills. If we continue to invest
in building capacity and getting folks
good primary, comprehensive preventive
care where they live, we can solve some
of these problems by getting them out of
the emergency department.
The ACA carries a
provision that’s
specific to
teaching in
community health
centers.
DR. WILTZ
CN: Where are the greatest unmet
needs?
Dr. Wiltz: One of the things we see a
lot in our practice is that people go
without care because they don’t have insurance. They come in for just acute,
episodic care and they do it in the emergency department, which is the most expensive care they can get. If you don’t
have a payer source, it’s very difficult to
navigate the system. Even if you have insurance, a lot of people don’t know
how to navigate the system. That’s why
we want to be their medical home.
What we attempt to do is provide a wide
array of services in one place.
CN: The ACA also includes funding to
develop medical residency programs at
community health centers. What is the
advantage of offering training through
health centers?
Dr. Wiltz: A few years ago, the National Association of Community Health
Centers (NACHC) came up with the idea
of “growing our own.” I’m an internist,
and it wasn’t until I got into a community health center setting that I recognized
that where you can make a difference is
in outpatient primary care clinics. So we
came up with the idea of NACHC U. We
started with a dental school. Now it’s
spread to a medical school model. The
natural progression was to offer a residency training program. So in the ACA,
lawmakers included a provision that’s
specific to teaching in community health
centers. In the last round of funding, several centers received funds. This introduces residents to primary care where the
needs are the greatest. But most importantly, it increases the number of primary care residencies.
■
DR. WILTZ is CEO of Teche Action
Clinic, a network of community health
centers based in Franklin, La., andis also
the treasurer and a member of the
executive committee of NACHC.
36
PRACTICE TRENDS
HHS Puts $1 Billion Into Reducing Readmissions
seeking to reduce hospital readmissions within 30 days
of discharge by 20% compared to 2010 rates. HHS officials estimate that the quality initiative will save
60,000 lives and up to $35 billion
in health care costs, including up
to $10 billion in savings for
Medicare alone.
The $1 billion investment of
federal funds comes from the Affordable Care Act. HHS officials
said they were making $500 million available right away through
the Community-Based Care Transitions Program to support efforts to improve care transitions between hospitals and
physicians in the community. Starting on April 12, hospitals and community-based organizations that team up
to provide transition services can submit applications
to HHS for funding.
An additional $500 million will become available
from the CMS Innovation Center to fund demonstration projects aimed at reducing hospital-acquired conditions.
B Y M A RY E L L E N S C H N E I D E R
ederal officials are pouring a $1 billion into a new
initiative aimed at reducing hospital readmissions
and preventable injuries.
The “Partnership for Patients” brings together physicians, nurses, hospitals, patient advocates, insurers, and
employers for a 3-year project that will help spread the
lessons of successful quality improvement initiatives
across the country and provide tools for health care
providers.
Many hospitals have already had success in reducing
readmissions or nearly eliminating hospital-acquired infections, but those initiatives have not been adopted
widely enough, Health and Human Services Secretary
Kathleen Sebelius said at a press conference to launch
the Partnership for Patients.
“The challenge is how to figure out how to make
these models spread and accelerate this care improvement,” she said.
The goal of the program is to reduce preventable
hospital-acquired conditions by 40% compared to
2010 rates by the end of 2013. And officials are also
F
Under the Partnership for Patients, HHS officials are
asking hospitals to focus on nine types of adverse
events including drug reactions, pressure ulcers, childbirth complications, and surgical
‘We can no longer site infections.
Officials at Health and Huaccept a health
man Services also plan to recare system in
cruit a group of “pioneer” hoswhich only some
Americans get the pitals that would seek to
improve care for all forms of
best possible
harm and complications, excare.’
plained Dr. Donald Berwick, administrator of the Centers for
SEC. SEBELIUS
Medicare and Medicaid Services.
Dr. Berwick added that these hospitals would go beyond the list of nine conditions set forth and seek to
transform themselves into “safer, high reliability organizations.”
“By assembling this partnership and committing to
these ambitious goals, we’re sending a clear message
that we can no longer accept a health care system in
which only some Americans get the best possible care,”
Ms. Sebelius said.
■
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CONTINUING EDUCATION
PRODUCTS
The Philadelphia Prenatal Diagnosis Update &
Obstetrics/Medical Complications of Pregnancy Meeting
June 10-11, 2011
Hilton Philadelphia City Avenue, PA
Topic highlights for 2nd day: Maternal Heart (Dr Elkayam, Dr Bove, Dr Eisen) &
Renal Diseases (Dr Silva) in Pregnancy, Maternal Mortality and Obesity and more.
Information/Registration: http://philapregnancycenter.com/index_files/Page667.htm
Contact: 215-627-2229; [email protected]
Online registration: https://cme.med.upenn.edu/eventschedule.html
This activity has been planned and implemented in accordance with the Essential Areas
and policies of the Accreditation Council for Continuing Medical Education (ACCME)
through the joint sponsorship of the University of Pennsylvania School of Medicine, Philadelphia Pregnancy, Ultrasound & Genetic Center and the Obstetrics Society of Philadelphia.
The University of Pennsylvania School of Medicine is accredited by the ACCME to provide
continuing medical education for physicians.
The University of Pennsylvania School of Medicine designates this educational activity for
a maximum of 15.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
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PRACTICE TRENDS
37
CMS Issues Long-Awaited Proposal on ACOs
fter months of deliberation, officials at the Centers for Medicare
and Medicaid Services released a
proposed rule outlining how physicians,
hospitals, and long-term care facilities
can work together to form accountable
care organizations and share in the savings they achieve for Medicare.
The voluntary program was created
under the Affordable Care Act and will
begin in January 2012.
Under the proposal, accountable care
organizations (ACOs) could include
physicians in group practice, networks of
individual practices, hospitals that employ physicians, and partnerships among
these entities, as well as other providers.
The idea is for ACOs to be a partnership
among a range of physicians, including
specialists and primary care providers.
However, only primary care providers
will be able to form an ACO, according
to CMS.
According to the proposed rule, providers in the ACO would continue to receive their regular fee-for-service payments under Medicare, but they could
also qualify for additional payment if
their care resulted in savings to the program.
The proposed framework requires
that ACOs meet certain quality stan-
A
dards and demonstrate that they have re- is already coordinated.
duced costs in order to be eligible to
But Dr. Berwick said that the proposshare in any savings. The proposal out- al allows for ACOs at various levels of delines 65 quality measures in five quality velopment to participate. For example,
domains: patient experience, care coor- less-developed ACOs can choose to redination, patient safety, preventive ceive shared savings for 2 years before ashealth, and care of at-risk and frail el- suming risk. Organizations that are more
derly populations.
mature can assume risk immediately but
“ACOs aren’t just a new way to pay for be eligible for greater levels of shared
care; they’re a new model for the orga- savings.
nization and de“Our aim is
Less-developed ACOs can choose
livery of the
to create oncare
under
ramps that will
to receive shared savings for 2
Medicare,” said
allow many to
years before assuming risk.
Dr.
Donald
participate, deBerwick, CMS
pending on the
Organizations that are more mature
administrator,
different levels
can assume risk immediately.
during a press
of
maturity
conference to
they are startannounce the proposed rule.
ing with,” said Dr. Berwick.
Dr. Berwick said he doesn’t know how
CMS officials estimate that the promany ACOs will form under the program could result in as much as $960 milgram, but that the level of interest is lion in Medicare savings over a period of
“enormous.”
3 years.
Since the Affordable Care Act was
Although federal officials said that they
passed last year, the health care com- expect the coordinated care to pay divimunity has been buzzing about how dends in savings to Medicare, ACOs will
ACOs might be structured and if they not be set up like HMOs. Medicare bencould succeed in reducing health care eficiaries will continue to be able to see
costs.
their choice of providers under fee-forIntegrated care organizations like service Medicare. Providers will be the
Geisinger Health System in Danville, ones that enroll in ACOs and must noPa., are considered to have a leg up be- tify patients that they are receiving care
cause their hospital and outpatient care within an ACO.
In addition to the ACO proposed rule,
the Department of Justice and the Federal Trade Commission have issued guidance on how physicians and hospitals
that form an ACO can steer clear of
antitrust laws.
Officials at the CMS and the Office of
the Inspector General have also issued a
notice on potential waivers that could be
granted to ACOs in connection with the
shared savings program, and the Internal
Revenue Service has issued new guidance for tax-exempt hospitals that are
seeking to participate in the program.
The CMS will be accepting comments
on the proposed rule for 60 days. The
agency also plans a series of open-door
forums and listening sessions to explain
the proposal and to get feedback from
the public.
At press time, the American Medical
Association said that it was reviewing
the proposed rule and the policy statements from the Federal Trade Commission and the Department of Justice. In a statement, Dr. Jeremy A.
Lazarus, the speaker of the AMA
House of Delegates, said that ACOs offer “great promise” but that there are
still a number of barriers to success, including the large capital requirements
to fund an ACO and to make the necessary changes to individual physician
practices.
■
Medicare Now Accepting ‘Meaningful Use’ Submissions
2012 to get all the available incentives.
A similar program is in place under the Medicaid program, with physicians eligible to receive up to $64,000
over 6 years for the adoption and use of certified EHR
technology.
As part of the attestation process, physicians and other eligible providers must go online to report data on
a number of meaningful use and quality measures es-
hysicians can now send data to the federal government to qualify for thousands of dollars in bonus
payments under the new Medicare electronic health
record incentive program.
The program officially began on Jan. 3, but April 18
was the first day that physicians and other eligible
providers could submit data on their
“meaningful use” of electronic health
records (EHRs). In order to qualify for
Medicare incentive payments for 2011,
physicians must report on at least 90 days
of meaningful use occurring during this
calendar year. Oct. 1, 2011, is the last day
that physicians can begin their 90-day reporting period to receive a 2011 incentive
payment.
The first checks for the Medicare incentive program are expected to go out
in May, according to the Centers for
Medicare and Medicaid Services.
The incentive program, which was authorized under the 2009 Health Information Technology for Economic and
Clinical Health (HITECH) Act, offers
payments to physicians who use health
information technology to improve pa- Oct. 1, 2011, is the last day that physicians can begin their
tient care. Federal regulations governing 90-day reporting period to receive a 2011 incentive payment.
the program spell out how physicians
and hospitals can meet standards for the meaningful use tablished by CMS. Through the online portal, physiof certified EHR technology.
cians can report the numerator, denominator, and any
Physicians that meet the criteria are eligible to re- potential exclusions for the objectives.
ceive up to $44,000 over 5 years under the Medicare
They can also attest that they have successfully met
program. Physicians can still receive bonuses if they the program requirements. For example, the meanbegin their meaningful use of the technology later, but ingful use regulations require that providers maintain
they must qualify for the program before the end of an up-to-date accounting of current and active diag-
P
©YANIK C HAUVIN / I S TOCKPHOTO. COM
noses. To be eligible for incentives, providers must report that more than 80% of all unique patients seen by
the provider have at least one entry, or an indicator that
no problems are known for the patients. The data must
be recorded in a structured format.
“There is a great deal of interest in the meaningful
use program,” said William Underwood, a senior associate in the division of medical practice, professionalism, and quality at the American College of Physicians.
But while interest is high, that doesn’t mean physicians will be clamoring to report on meaningful use immediately. Right now, physicians in both small and large
practices are struggling with logistical hurdles, Mr.
Underwood said.
For example, there is currently not a process in place
to allow practice administrators to submit meaningful
use data to CMS on behalf of large physician practices.
The current setup requires a physician to report the information.
While CMS officials plan to address this, it hasn’t happened yet, Mr. Underwood said.
Some small practices are having difficulty meeting
meaningful use thresholds because other entities are
not exchanging information with them regarding labs
and referrals. And practices of all sizes are waiting for
vendors to finish rolling out updates that show they are
in compliance with meaningful use certification, he
said.
Dr. Steven Waldren, director of the Center for Health
IT at the American Academy of Family Physicians,
agreed that while some physicians will submit data immediately, a large portion are still trying to figure out
what they need to do to meet meaningful use requirements and ensure that their EHR system is certified. It
may take until at least October to get a real sense of
how many physicians plan to participate, he said. ■
PRACTICE TRENDS
38
POLICY & PRACTICE
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College Overhauls CME
The American College of Cardiology
announced that it is abandoning its current model for continuing medical education at scientific sessions, essentially to
segregate industry-sponsored symposia
from other sessions. The college “was
prompted in part by ongoing concerns
about real and/or perceived bias in interactions with industry, specifically related to non-independence of certified
satellite symposia,” said the group in a
statement. There will be two educational tracks starting with next year’s annual scientific session: One will have indepth sessions developed by the ACC,
and the other will be made up of uncertified satellite symposia. The latter can be
industry sponsored and will be managed
through the ACC’s business development division. The policies guiding those
seminars will be consistent with the
Food and Drug Administration’s and
other regulatory agencies’ rules governing industry-sponsored CME. “The move
is important because it will allow for
transparency in the two separate approaches and meet the educational needs
of our members,” said Dr. Rick Nishimura, cochair of the college’s 2012 annual
scientific session next March.
Advocacy for Cardiology
The ACC’s advocacy committee issued
its five policy priorities for 2011. No. 1 is
to overhaul the physician payment system by – among other efforts – repealing
theSustainable Growth Rate formula for
Medicare payments. No. 2: Make sure
cardiologists are part of new care-delivery plans stemming from health reform,
such as Accountable Care Organizations.
INDEX OF
ADVERTISERS
Abbott Laboratories
Niaspan
15-16
Arbor Pharmaceuticals, Inc.
Nitrolingual
17-18
AstraZeneca L.P.
Atacand
3-5
Bayer HealthCare LLC
Aspirin
29
Boehringer Ingelheim Pharmaceuticals, Inc.
Pradaxa
Daiichi Sankyo, Inc.
Welchol
9-12
34a-34b, 35
Daiichi Sankyo, Inc. and Lilly USA, LLC
Effient
20-25
Forest Laboratories, Inc.
Bystolic
31-34
LipoScience Inc.
Corporate
6a-6b
Otsuka America Pharmaceutical, Inc.
SAMSCA
Pfizer Inc.
Revatio
12a-12d
Third is tort reform, and the advocacy
committee’s fourth priority is to help
ACC members get ready to meet meaningful use criteria for health information
technology. Finally, the committee said
that it would also stay on top of coding
changes, imaging-accreditation requirements, and the FDA’s device-safety initiatives.
FDA Device Review Questioned
The Government Accountability Office
said that the FDA has not done enough to
ensure the efficiency and effectiveness of
its recall procedures for high-risk medical
devices. Back in January 2009, the GAO
found fault with the 510(k) device-approval process and recalls. The agency is
again urging the FDA to quickly issue final rules to more strictly and clearly regulate 510(k) devices. Since the 2009 report,
the FDA has published a strategic plan but
issued a final rule on only one type of device, the GAO said. The agency is not collecting data that would let it identify risks
REVATIO® (SILDENAFIL)
Brief Summary of Prescribing Information
INDICATIONS AND USAGE: REVATIO® is indicated for the treatment of pulmonary arterial
hypertension (PAH) (WHO Group I) to improve exercise ability and delay clinical worsening.
Delay in clinical worsening was demonstrated when REVATIO was added to background
epoprostenol therapy. Studies establishing effectiveness included predominantly patients
with NYHA Functional Class II-III symptoms and etiologies of primary pulmonary
hypertension (71%) or pulmonary hypertension associated with connective tissue disease
(25%). The efficacy of REVATIO has not been adequately evaluated in patients taking
bosentan concurrently.
DOSAGE AND ADMINISTRATION
Pulmonary Arterial Hypertension (PAH)
REVATIO Tablets
The recommended dose of REVATIO is 20 mg three times a day (TID). REVATIO tablets
should be taken approximately 4-6 hours apart, with or without food.
In the clinical trial no greater efficacy was achieved with the use of higher doses.
Treatment with doses higher than 20 mg TID is not recommended. Dosages lower
than 20 mg TID were not tested. Whether dosages lower than 20 mg TID are effective
is not known.
REVATIO Injection
REVATIO injection is for the continued treatment of patients with pulmonary arterial
hypertension (PAH) who are currently prescribed oral REVATIO and who are temporarily
unable to take oral medication.
The recommended dose is 10 mg (corresponding to 12.5 mL) administered as an
intravenous bolus injection three times a day. The dose of REVATIO injection does not need
to be adjusted for body weight.
A 10 mg dose of REVATIO injection is predicted to provide pharmacological effect of
sildenafil and its N-desmethyl metabolite equivalent to that of a 20 mg oral dose.
CONTRAINDICATIONS
Use with Organic Nitrates
Do not use REVATIO in patients taking organic nitrates in any form, either regularly or
intermittently. Consistent with its known effects on the nitric oxide/cGMP pathway,
sildenafil was shown to potentiate the hypotensive effects of nitrates.
Hypersensitivity Reactions
REVATIO is contraindicated in patients with a known hypersensitivity to sildenafil or any
component of the tablet.
Rare cases of hypersensitivity have been reported in association with the use of sildenafil
including anaphylactic reaction/shock events and anaphylactoid reaction. The majority of
reported events were non-serious hypersensitivity reactions.
Cardiovascular Effects
REVATIO has vasodilatory properties, resulting in mild and transient decreases in blood
pressure. Before prescribing REVATIO, carefully consider whether patients with certain
underlying conditions could be adversely affected by such vasodilatory effects
(e.g., patients with resting hypotension [BP < 90/50], fluid depletion, severe left ventricular
outflow obstruction, or autonomic dysfunction).
Pulmonary vasodilators may significantly worsen the cardiovascular status of patients
with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on
administration of REVATIO to patients with veno-occlusive disease, administration of
REVATIO to such patients is not recommended. Should signs of pulmonary edema occur
when REVATIO is administered, consider the possibility of associated PVOD.
As there are no controlled clinical data on the safety or efficacy of REVATIO in the following
groups, prescribe with caution for:
• Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia
within the last 6 months;
• Patients with coronary artery disease causing unstable angina;
• Patients with hypertension (BP > 170/110);
• Patients currently on bosentan therapy.
Use with Alpha-blockers
PDE5 inhibitors, including sildenafil, and alpha-adrenergic blocking agents are both
vasodilators with blood pressure-lowering effects.When vasodilators are used in combination,
an additive effect on blood pressure may be anticipated. In some patients, concomitant use of
these two drug classes can lower blood pressure significantly, leading to symptomatic
hypotension. In the sildenafil interaction studies with alpha-blockers, cases of symptomatic
hypotension consisting of dizziness and lightheadedness were reported [see Drug Interactions].
No cases of syncope or fainting were reported during these interaction studies. The safety of
combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables,
including intravascular volume depletion and concomitant use of anti-hypertensive drugs.
Effects on Bleeding
In humans, sildenafil has no effect on bleeding time when taken alone or with aspirin.
In vitro studies with human platelets indicate that sildenafil potentiates the anti-aggregatory
effect of sodium nitroprusside (a nitric oxide donor).The combination of heparin and
sildenafil had an additive effect on bleeding time in the anesthetized rabbit, but this interaction
has not been studied in humans.
The incidence of epistaxis was 13% in patients taking sildenafil with PAH secondary to
connective tissue disease (CTD). This effect was not seen in primary pulmonary hypertension
(PPH) (sildenafil 3%, placebo 2%) patients. The incidence of epistaxis was also higher in
sildenafil-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in
those not treated with concomitant vitamin K antagonist).
The safety of REVATIO is unknown in patients with bleeding disorders or active peptic ulceration.
University of Pittsburgh Medical Center
Corporate
27
Verathon Inc.
AortaScan
19
FDA Sued Over Generic Lipitor
Generic drugmaker Mylan has sued to
force the FDA to speed up the introduction of generic versions of Pfizer’s blockbuster drug Lipitor (atorvastatin). Mylan
and its Indian partner, Matrix Laborato-
Use with Ritonavir and Other Potent CYP3A Inhibitors
The concomitant administration of the protease inhibitor ritonavir (a highly potent
CYP3A inhibitor) substantially increases serum concentrations of sildenafil; therefore,
co-administration of ritonavir or other potent CYP3A inhibitors with REVATIO is not recommended.
Effects on the Eye
Advise patients to seek immediate medical attention in the event of a sudden loss of vision
in one or both eyes while taking PDE5 inhibitors, including REVATIO. Such an event may be
a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased
vision including permanent loss of vision, that has been reported postmarketing in temporal
association with the use of all PDE5 inhibitors, including sildenafil, when used in the
treatment of erectile dysfunction. It is not possible to determine whether these events are
related directly to the use of PDE5 inhibitors or to other factors. Physicians should also
discuss the increased risk of NAION with patients who have already experienced NAION in
one eye, including whether such individuals could be adversely affected by use of
vasodilators, such as PDE5 inhibitors [see Adverse Reactions].
There are no controlled clinical data on the safety or efficacy of REVATIO in patients with
retinitis pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases.
Prescribe REVATIO with caution in these patients.
Hearing Impairment
Advise patients to seek prompt medical attention in the event of sudden decrease or loss of
hearing while taking PDE5 inhibitors, including REVATIO.These events, which may be
accompanied by tinnitus and dizziness, have been reported in temporal association to the intake
of PDE5 inhibitors, including REVATIO. It is not possible to determine whether these events are
related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions].
Combination with other PDE5 inhibitors
Sildenafil is also marketed as VIAGRA®. The safety and efficacy of combinations of REVATIO
with VIAGRA or other PDE5 inhibitors have not been studied. Inform patients taking REVATIO
not to take VIAGRA or other PDE5 inhibitors.
Prolonged Erection
Use REVATIO with caution in patients with anatomical deformation of the penis
(e.g., angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients who have
conditions, which may predispose them to priapism (e.g., sickle cell anemia, multiple
myeloma, or leukemia). In the event of an erection that persists longer than 4 hours,
the patient should seek immediate medical assistance. If priapism (painful erection
greater than 6 hours in duration) is not treated immediately, penile tissue damage
and permanent loss of potency could result.
Pulmonary Hypertension Secondary to Sickle Cell Anemia
In a small, prematurely terminated study of patients with PH secondary to sickle cell disease,
vaso-occlusive crises requiring hospitalization were more commonly reported by patients who
received REVATIO than by those randomized to placebo. The effectiveness of REVATIO in
pulmonary hypertension (PH) secondary to sickle cell anemia has not been established.
ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
• Hypotension [see Warnings and Precautions]
• Vision loss [see Warnings and Precautions]
• Hearing loss [see Warnings and Precautions]
• Priapism [see Warnings and Precautions]
• Vaso-occlusive crisis [see Warnings and Precautions]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in practice.
Safety data were obtained from the 12 week, placebo-controlled clinical study and an
open-label extension study in 277 treated patients with pulmonary arterial hypertension.
Doses up to 80 mg TID were studied.
The overall frequency of discontinuation in REVATIO-treated patients at the recommended
dose of 20 mg TID was 3% and was the same for the placebo group.
In the placebo-controlled trial in pulmonary arterial hypertension, the adverse drug reactions
that were reported by at least 3% of REVATIO patients treated at the recommended dosage
(20 mg TID) and were more frequent in REVATIO patients than placebo patients, are shown
in Table 1. Adverse events were generally transient and mild to moderate in nature.
Table 1. REVATIO All Causality Adverse Events in ≥ 3% of Patients and More Frequent
(> 1%) than Placebo
ADVERSE EVENTS
%
Placebo
(n=70)
Revatio 20 mg TID
(n=69)
PlaceboSubtracted
Epistaxis
Headache
Dyspepsia
Flushing
Insomnia
Erythema
Dyspnea exacerbated
Rhinitis nos
Diarrhea nos
Myalgia
Pyrexia
Gastritis nos
Sinusitis
Paresthesia
1
39
7
4
1
1
3
0
6
4
3
0
0
0
9
46
13
10
7
6
7
4
9
7
6
3
3
3
8
7
6
6
6
5
4
4
3
3
3
3
3
3
nos: Not otherwise specified
38-40
posed by devices, even though 3,510 were
voluntarily recalled for problems in 20052009, said the GAO. “Taken together,
GAO’s preliminary work suggests that
the combined effect of these gaps [in the
FDA’s recall process] may increase the risk
that unsafe medical devices could remain
on the market,” said the new report.
ries, said they could be ready to sell
generic atorvastatin in late June. The
companies claim the FDA must allow
generic versions to enter the market then
because Pfizer’s key patent on Lipitor expires that month. Rival generic drugmaker Ranbaxy Laboratories has agreed
in a patent settlement with Pfizer to wait
until Nov. 30 to bring generic atorvastatin
to market, when Ranbaxy expects to
have exclusive rights to market the generic for 6 months. However, Ranbaxy may
not be ready to market its product by November, pushing back Mylan’s generic introduction even further, the company
said in its lawsuit. In addition, Mylan
claims that Ranbaxy may have violated
FDA rules in submitting its application,
making it ineligible for the 6-month, exclusive-rights period for atorvastatin.
Medicine Has Economic Power
Office-based physicians contributed $1.4
trillion in economic activity in 2009 and
supported 4 million jobs nationwide, according to a report from the American
Medical Association. The report, prepared by the Lewin Group, calculates the
state-by-state impact of the 638,000 office-based physicians in the United
PRACTICE TRENDS
States. In total, they provided $833 billion
in wages and benefits and generated $63
billion in state and local tax revenues in
2009, the report said. On average, each
office-based physician supported $2.2
million in economic output and 6.2 jobs,
including his or her own.
Medical Boards Fail on Discipline
State medical boards failed to discipline
more than half of doctors who either
lost their clinical privileges or had them
restricted by the hospitals where they
worked, according to a report from advocacy group Public Citizen. In all,
Concomitant use of REVATIO with ritonavir and other potent CYP3A inhibitors is not
recommended [see Warnings and Precautions].
Alpha-blockers
Use caution when co-administering alpha-blockers with REVATIO because of additive blood
pressure-lowering effects [see Warnings and Precautions].
In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker
doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign
prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations,
mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg,
9/5 mmHg, and 8/4 mmHg, respectively, were observed. Mean additional reductions of
standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were also
observed. There were infrequent reports of patients who experienced symptomatic postural
hypotension. These reports included dizziness and light-headedness, but not syncope.
Amlodipine
When sildenafil 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to
ADVERSE EVENTS
Placebo
Revatio 20 mg TID
Placebohypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg
%
Epoprostenol
Epoprostenol
Subtracted
systolic and 7 mmHg diastolic.
(n=70)
(n=69)
57
23
Headache
34
Pregnancy
25
14
Edema^
13
Pregnancy Category B
16
14
Dyspepsia
2
No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits
17
11
Pain in extremity
6
dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m2 basis, 32and 68-times, respectively, the recommended human dose (RHD) of 20 mg TID. In a rat pre- and
25
7
Diarrhea
18
postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent
25
7
Nausea
18
to 5-times the RHD on a mg/m2 basis).There are, however, no adequate and well-controlled
9
7
Nasal congestion
2
studies of sildenafil in pregnant women. Because animal reproduction studies are not always
încludes peripheral edema
predictive of human response, this drug should be used during pregnancy only if clearly needed.
REVATIO Injection
Labor and Delivery
REVATIO injection was studied in a 66-patient, placebo-controlled study at doses targeting
The safety and efficacy of REVATIO during labor and delivery has not been studied.
plasma concentrations between 10 and 500 ng/mL (up to 8 times the exposure of the
Nursing Mothers
recommended dose). Adverse events in PAH patients were similar to those seen with oral tablets. It is not known if sildenafil or its metabolites are excreted in human breast milk. Because
Postmarketing Experience
many drugs are excreted in human milk, caution should be exercised when REVATIO is
The following adverse reactions have been identified during postapproval use of sildenafil
administered to a nursing woman.
(marketed for both PAH and erectile dysfunction). Because these reactions are reported
Pediatric Use
voluntarily from a population of uncertain size, it is not always possible to reliably estimate
Safety and effectiveness of sildenafil in pediatric pulmonary hypertension patients have not
their frequency or establish a causal relationship to drug exposure.
been established.
Cardiovascular Events
Geriatric Use
In postmarketing experience with sildenafil at doses indicated for erectile dysfunction,
Clinical studies of REVATIO did not include sufficient numbers of subjects aged 65 and over
serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction,
to determine whether they respond differently from younger subjects. Other reported clinical
sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient
experience has not identified differences in responses between the elderly and younger patients.
ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency
hemorrhages have been reported in temporal association with the use of the drug. Most, but
of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
not all, of these patients had preexisting cardiovascular risk factors. Many of these events
Hepatic Impairment
were reported to occur during or shortly after sexual activity, and a few were reported to
occur shortly after the use of sildenafil without sexual activity. Others were reported to have No dose adjustment for mild to moderate impairment is required. Severe impairment
has not been studied.
occurred hours to days after use concurrent with sexual activity. It is not possible to
Renal Impairment
determine whether these events are related directly to sildenafil, to sexual activity, to the
patient’s underlying cardiovascular disease, or to a combination of these or other factors.
No dose adjustment is required (including severe impairment CLcr < 30 mL/min).
Decreases in and Loss of Vision
OVERDOSAGE
When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy
In studies with healthy volunteers of single doses up to 800 mg, adverse events were
(NAION), a cause of decreased vision including permanent loss of vision, has been
similar to those seen at lower doses but rates and severities were increased.
reported postmarketing in temporal association with the use of phosphodiesterase type 5
In cases of overdose, standard supportive measures should be adopted as required.
(PDE5) inhibitors, including sildenafil. Most, but not all, of these patients had underlying
Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma
anatomic or vascular risk factors for developing NAION, including but not necessarily
proteins and it is not eliminated in the urine.
limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension,
NONCLINICAL TOXICOLOGY
coronary artery disease, hyperlipidemia and smoking. It is not possible to determine
Carcinogenesis, Mutagenesis, Impairment of Fertility
whether these events are related directly to the use of PDE5 inhibitors, to the patient’s
Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day,
underlying vascular risk factors or anatomical defects, to a combination of these factors,
a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite
or to other factors [see Warnings and Precautions].
33 and 37 times, for male and female rats respectively, the human exposure at the RHD of
Loss of Hearing
20 mg TID. Sildenafil was not carcinogenic when administered to male and female mice for up
Cases of sudden decrease or loss of hearing have been reported postmarketing in
to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day,
temporal association with the use of PDE5 inhibitors, including REVATIO. In some of the
a dose equivalent to the RHD on a mg/m2 basis. Sildenafil was negative in in vitro bacterial and
cases, medical conditions and other factors were reported that may have also played a role
in the otologic adverse events. In many cases, medical follow-up information was limited. It Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and
is not possible to determine whether these reported events are related directly to the use of in vivo mouse micronucleus assays to detect clastogenicity.
There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day,
REVATIO, to the patient’s underlying risk factors for hearing loss, a combination of these
a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major
factors, or to other factors [see Warnings and Precautions].
metabolite of 19 and 38 times for males and females, respectively, the human exposure at
Other Events
the RHD of 20 mg TID.
The following list includes other adverse events that have been identified during
PATIENT COUNSELING INFORMATION
postmarketing use of REVATIO. The list does not include adverse events that are reported
• Inform patients of contraindication of REVATIO with regular and/or intermittent use of
from clinical trials and that are listed elsewhere in this section. These events have been
organic nitrates.
chosen for inclusion either due to their seriousness, reporting frequency, lack of clear
• Inform patients that sildenafil is also marketed as VIAGRA for erectile dysfunction.
alternative causation, or a combination of these factors. Because these reactions were
Advise patients taking REVATIO not to take VIAGRA or other PDE5 inhibitors.
reported voluntarily from a population of uncertain size, it is not possible to reliably
• Advise patients to seek immediate medical attention in the event of a sudden loss of
estimate their frequency or establish a causal relationship to drug exposure.
vision in one or both eyes while taking REVATIO. Such an event may be a sign of NAION.
Nervous system: Seizure, seizure recurrence
• Advise patients to seek prompt medical attention in the event of sudden decrease or loss of
DRUG INTERACTIONS
hearing while taking REVATIO. These events may be accompanied by tinnitus and dizziness.
Nitrates
RX only
Concomitant use of REVATIO with nitrates in any form is contraindicated
Revised: March 2011
[see Contraindications].
RVU00253/275540-01
© 2011 Pfizer Inc
All rights reserved.
Printed in USA/March 2011
Ritonavir and other Potent CYP3A Inhibitors
At doses higher than the recommended 20 mg TID, there was a greater incidence of some
adverse events including flushing, diarrhea, myalgia and visual disturbances. Visual
disturbances were identified as mild and transient, and were predominately colortinge to
vision, but also increased sensitivity to light or blurred vision.
The incidence of retinal hemorrhage at the recommended sildenafil 20 mg TID dose was
1.4% versus 0% placebo and for all sildenafil doses studied was 1.9% versus 0% placebo.
The incidence of eye hemorrhage at both the recommended dose and at all doses studied
was 1.4% for sildenafil versus 1.4% for placebo. The patients experiencing these events had
risk factors for hemorrhage including concurrent anticoagulant therapy.
In a placebo-controlled fixed dose titration study of REVATIO (starting with recommended
dose of 20 mg TID and increased to 40 mg TID and then 80 mg TID) as an adjunct to
intravenous epoprostenol in pulmonary arterial hypertension, the adverse events that were
reported were more frequent than in the placebo arm (>6% difference) are shown in Table 2.
Table 2. REVATIO-Epoprostenol Adverse Events More Frequent (> 6%) than Placebo
39
10,672 physicians were listed in the National Practitioner Data Bank as having
restricted or revoked clinical privileges,
yet 5,887 (55%) of them did not see any
licensing action from their states, the
group reported. Of those escaping licensing actions, 1,119 had been otherwise disciplined for incompetence, negligence, or malpractice, and 605 were
disciplined for substandard care, the report said. Hospital boards had identified
220 of the otherwise-unsanctioned doctors as “an immediate threat to health or
safety,” according to Public Citizen.
–Alicia Ault
Did you know
REVATIO samples are
just a phone call away?
Order REVATIO Starter
Samples by phone
Contact the REVATIO Sample Fulfillment
Program by calling 1-866-833-9559
Important Safety Information
Do not use REVATIO in patients taking organic nitrates in any form, either regularly
or intermittently. Consistent with its known effects on the nitric oxide/cGMP
pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates.
Before starting REVATIO, physicians should carefully consider whether their patients
with underlying conditions could be adversely affected by the mild and transient
vasodilatory effects of REVATIO on blood pressure. Pulmonary vasodilators may
significantly worsen the cardiovascular status of patients with pulmonary venoocclusive disease (PVOD) and administration of REVATIO to these patients is not
recommended. Should signs of pulmonary edema occur when sildenafil is
administered, the possibility of associated PVOD should be considered.
Caution is advised when PDE5 inhibitors, such as REVATIO, are administered with
α-blockers as both are vasodilators with blood pressure lowering effects.
In PAH patients, the concomitant use of vitamin K antagonists and REVATIO resulted
in a greater incidence of reports of bleeding (primarily epistaxis) versus placebo.
The incidence of epistaxis was higher in patients with PAH secondary to CTD
(sildenafil 13%, placebo 0%) than in PPH patients (sildenafil 3%, placebo 2%).
Co-administration of REVATIO with potent CYP3A4 inhibitors, eg, ketoconazole,
itraconazole, and ritonavir, is not recommended as serum concentrations of
sildenafil substantially increase. Co-administration of REVATIO with CYP3A4
inducers, including bosentan; and more potent inducers such as barbiturates,
carbamazepine, phenytoin, efavirenz, nevirapine, rifampin, and rifabutin, may
alter plasma levels of either or both medications. Dosage adjustment may
be necessary.
Non-arteritic anterior ischemic optic neuropathy (NAION) has been reported
post-marketing in temporal association with the use of PDE5 inhibitors for the
treatment of erectile dysfunction, including sildenafil.
It is not possible to determine if these events are related to PDE5 inhibitors or
to other factors. Physicians should advise patients to seek immediate medical
attention in the event of sudden loss of vision while taking PDE5 inhibitors,
including REVATIO.
Sudden decrease or loss of hearing has been reported in temporal association
with the intake of PDE5 inhibitors, including REVATIO. It is not possible to
determine whether these events are related directly to the use of PDE5 inhibitors
or to other factors. Physicians should advise patients to seek prompt medical
attention in the event of sudden decrease or loss of hearing while taking PDE5
inhibitors, including REVATIO.
REVATIO should be used with caution in patients with anatomical deformation of the
penis or patients who have conditions which may predispose them to priapism.
The effectiveness of REVATIO in pulmonary hypertension (PH) secondary to sickle
cell anemia has not been established. In a small, prematurely terminated study of
patients with PH secondary to sickle cell disease, vaso-occlusive crises requiring
hospitalization were more commonly reported by patients who received REVATIO
than by those randomized to placebo.
REVATIO contains sildenafil, the same active ingredient found in VIAGRA®.
Combinations of REVATIO with VIAGRA or other PDE5 inhibitors have not been
studied. Patients taking REVATIO should not take VIAGRA or other PDE5 inhibitors.
Patients with the following characteristics did not participate in the preapproval
clinical trial: patients who have suffered a myocardial infarction, stroke, or lifethreatening arrhythmia within the last 6 months, unstable angina, hypertension
(BP >170/110), retinitis pigmentosa, or patients on bosentan. The safety of REVATIO
is unknown in patients with bleeding disorders and patients with active peptic
ulceration. In these patients, physicians should prescribe REVATIO with caution.
The most common side effects of REVATIO (placebo-subtracted) were epistaxis
(8%), headache (7%), dyspepsia (6%), flushing (6%), and insomnia (6%). Adverse
events of REVATIO injection were similar to those seen with oral tablets.
The most common side effects of REVATIO (placebo-subtracted) as an adjunct to
intravenous epoprostenol were headache (23%), edema (14%), dyspepsia (14%),
pain in extremity (11%), diarrhea (7%), nausea (7%), and nasal congestion (7%).
Indication
REVATIO is indicated for the treatment of pulmonary arterial hypertension (PAH)
(WHO Group I) to improve exercise ability and delay clinical worsening. Delay in
clinical worsening was demonstrated when REVATIO was added to background
epoprostenol therapy. Studies establishing effectiveness included predominantly
patients with NYHA Functional Class II-III symptoms and etiologies of primary
pulmonary hypertension (71%) or pulmonary hypertension associated with
connective tissue disease (25%). The efficacy of REVATIO has not been adequately
evaluated in patients taking bosentan concurrently.
Please see Brief Summary of Prescribing Information on the following pages.
RVU00243A
© 2011 Pfizer Inc.
All rights reserved.
www.REVATIO.com
Printed in USA/March 2011
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TAVR Effective in Older, High-Risk Patients

Transcription

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