Atrial Fibrillation - Royal Columbian Hospital

Atrial Fibrillation: Review on its Management and Update on Newer Oral Anticoagulants
Benjamin Leung, BSc, MD, FRCPC
Royal Columbian Hospital
Cardiologist, UBC Clinical Instructor
March 26, 2014
UBC Emergency Residents Academic Half Day
Disclosures
NONE
OBJECTIVE
• Review of the prevalence of AF and its risk of stroke
• Brief overview of rate vs rhythm control
• Review of risk calculators for stroke in AF and risk predictors of bleeding
• Review of newer oral anticoagulants in stroke prevention compared to warfarin
CASE
65 M Retired Accountant
•PMedHx: Hypertension, Dyslipidemia
•Meds: HCTZ 25 mg od
•Routine GP visit, incidentally found to have an irregular heart rhythm. •ECG confirms Atrial Fibrillation at HR of 86 bpm
•Patient asymptomatic
•Management??
Atrial Fibrillation (AF)
is Common Among Canadians
ƒ Currently, it is estimated that 350,000 Canadians have atrial fibrillation1
ƒ Atrial fibrillation affects approximately: ƒ 3% of Canadians over the age of 451
ƒ 6% over the age of 651
ƒ 10% over the age of 802,3
ƒ The lifetime risk of atrial fibrillation is 1 in 4 after the age of 404,5
1. Heart and Stroke Foundation. Atrial fibrillation. Available at http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics.htm. 2. Go AS, et al. JAMA. 2001;285:2370–5.
3. Heeringa J, et al. Eur Heart J. 2006;27:949–53.
4. Lloyd‐Jones DM, et al. Circulation. 2002;106:3068‐72.
5. Lloyd‐Jones DM, et al. Circulation. 2004;110:1042‐6.
5
ETIOLOGY
•
•
•
•
•
Changes in atrial myocardium physiology
Multiple wavelets theory
Atrial inflammation and fibrosis
Atrial Enlargement
“AF begets AF”
Disease Associations
Most Common Associations
Patterns of AF
Classification
• First detected
• Paroxysmal
‐ recurrent AF ( > 2 episodes) that terminate spontaneous in less than
7 days
• Persistent
‐ fails to terminate spontaneously after 7 days.
• Permanent
‐ Persistent AF with decision made to no longer choose a rhythm
control strategy
Work‐Up
• Rule out secondary causes
• Most often though…..
– TSH
– Echocardiogram
– Screen for sleep apnea and hypertension
Overview of AF Management
Management Strategy of Atrial Fibrillation
For every patient with atrial fibrillation, there are two principle goals of therapy:
1)Control symptoms
2)Prevention of stroke and complications
Management of new onset AF in ER
Rate Control Agents in ER
Pharmacological Cardioversion in ER
Indications for Urgent Cardioversion
• Refractory to initial medical treatment with evidence of hypotension, ischemia, end‐organ hypoperfusion
• Evidence of pre‐excitation syndrome
Oh no……WTF!!
Rate vs Rhythm Control Strategy
• Decision to choose rate vs rhythm control strategy depends on several factors
• Ultimately the goal is symptom relief depending on the patient
• Many trials comparing rate vs rhythm control (including AFFIRM and RACE) did not show significant differences in hard outcomes such as mortality
• However, these trials had relatively short follow‐up and older population (Average age of AFFIRM was 69 years old and 3.5 year follow‐up)
Rate vs Rhythm Control Strategy
Antiarrhythmic Medications
in Normal LV function
Antiarrhythmic Medications in Abnormal LV function
What’s the target HR for atrial fibrillation rate control?
AF is a Major Risk Factor for Stroke
ƒ There are about 50 000 new strokes in Canada each year1, 2
ƒ Atrial fibrillation causes 1 of every 5 strokes3
ƒ After age 60, atrial fibrillation causes 1 in 4 strokes4
1. Canadian Stroke Network 2010;
2. Mittman N et al. BURST study 2009. 3. Heart and Stroke Foundation. Atrial fibrillation. Available at http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics.htm; 4. Gladstone DJ, et al. Stroke. 2009;40:235‐40.
24
How Much AF is Needed Before The Risk of Stroke Increases?
ƒ TRENDS :
AF duration ≥ 5.5 hours doubles thromboembolic risk1
ƒ ASSERT :
Atrial tachyarrhythmias (episodes of atrial rate >190 beats per
minute for more than 6 minutes) were found in 10.1% (by 3 months)
and an additional 24.5% (at 2.5 years) of patients with hypertension,
no history of AF, and recently implanted pacemakers or
defibrillators2
• Subclinical atrial tachyarrythmias identified by 3 months were
associated with a 2.5-fold increase in the risk for subsequent ischemic
stroke and systemic embolism2
ƒ ACTIVE W :
Substudy showed risk of stroke is equivalent in patients with permanent or paroxysmal AF3
1. Glotzer TV, et al. Circ Arrhythm Electrophysiol. 2009 Oct;2(5):474‐80.
2. Healey J, et al. N Engl J Med. 2012;366:120‐9. 3. Hohnloser SH, et al. JACC. 2007;50:2156–61.
4. Skanes AC, et al. Can J Cardiol. 2012;28:125‐36.
25
Outcome of Strokes in AF Patients
Outcome of first ischemic stroke in patients admitted with AF (n=597)1
Patients (%)
60
40
20
2
0
Fatal
Disabling
AF strokes are more severe, disabling and fatal relative to non‐AF strokes.3
1. Gladstone DJ, et al. Stroke. 2009;40:235‐40.
2. Images courtesy of www.strokecenter.org, Albers G, Stanford Stroke Center, Stanford School of Medicine and Kelley RE, Minagar A. South Med J. 2003;96(4):343‐9.
3. Canadian Stroke Strategy. Canadian Best Practice Recommendations for Stroke Care Update 2010. 26
How do You Reduce the Risk of Stroke?
Stroke Risk Reduction with Warfarin
7
64% 6
relative risk reduction
Stroke (%/year)
5
38% relative risk reduction
4
3
2
1
Placebo
Warfarin
ASA
Warfarin
0
Warfarin vs Placebo
Warfarin vs ASA
6 trials
n=2900
8 trials
n=3647
Hart RG, et al. Ann Intern Med. 2007;147(8):590‐91.
27
Relative Risk Reduction of Stroke in Atrial Fibrillation: Warfarin Compared with Placebo
STUDY, Year (Reference)
Adjusted‐dose warfarin
compared with placebo or control
Relative Risk Reduction (95% CI)
AFASAK I, 1989 (2); 1990 (3)
SPAF I, 1991 (5)
BAATAF, 1990 (4)
CAFA, 1991 (6)
SPINAF, 1992 (7)
EAFT, 1993 (8)
All trials (n=6)
100%
Hart RG et al. Ann Intern Med 2007;146:857‐67.
50%
‐50%
‐100%
Favors Warfarin
Favors Placebo or Control
28
Relative Risk Reduction of Stroke in Atrial Fibrillation: Warfarin Compared with Antiplatelet
STUDY, Year (Reference)
Relative Risk Reduction (95% CI)
AFASAK I, 1989 (2); 1990 (3)
AFASAK II, 1998 (14)
Chinese ATAFS, 2006 (30)
EAFT, 1993 (8)
PATAF, 1999 (16)
SPAF II, 1994 (10)
Age ≤ 75 y
Age > 75 y
Aspirin trials (n = 8)*
SIFA, 1997 (12)
ACTIVE‐W, 2006 (28)
NASPEAF, 2004 (25)
All antiplatelet trials (n = 11)
100%
50%
Favors Warfarin
Hart RG, et al. Ann Intern Med. 2007;147(8):590‐91.
0%
‐50%
‐100%
Favors Antiplatelet
29
Warfarin has been a great drug in reducing ischemic stroke in patients with AF
In 1000 patients with nonvalvular AF who are treated with warfarin for 1 year:
31 less ischemic strokes for 1 increase in major bleed
Every AF Patient Should be Stratified for Stroke Risk : CHADS2
Always use a predictive stroke risk index such as CHADS2
RISK FACTOR
SCORE
Congestive Heart Failure
1
Hypertension*
1
Age ≥75 years
1
Diabetes Mellitus
1
Stroke or TIA
2
*History of hypertension, even well controlled hypertension, is considered an independent risk factor for stroke Cairns JA, et al. Can J Cardiol. 2011;27:74‐90. Skanes AC, et al. Can J Cardiol. 2012;28:125‐36
Gage et al, JAMA 2001;285(22):2864‐70.
31
CHADS2VASC Score Calculator
Congestive Heart Failure
Hypertension
Age: < 65 (0), 65‐75 (1), >75 (2)
Diabetes
Vascular Disease
Stroke (2)
Female
HAS‐BLED SCORE
CCS Guidelines Recommend Oral Anticoagulant (OAC) Therapy in Almost All AF Patients Adjusted Stroke Rate (%/year)
18.2%
20
15
12.5%
8.5%
10
5
1.9%
2.8%
4.0%
5.9%
0
0
1
2
3
4
5
6
CHADS2 Score
OAC is recommended in these patients
% of AF patients: 7% 27% 30% 19% 13% 4% 0.3%
If CHADS2 score = 0, OAC is recommended only in patients with increasing stroke risk, meaning ≥ 65 yrs, or combination of female sex or vascular disease. Cairns JA, et al. Can J Cardiol. 2011;27:74‐90.
Gage BF, et al. JAMA. 2001;285:2864‐70.
Skanes AC, et al. Can J Cardiol. 2012;28:125‐36.
34
CCS 2012 Updated Recommendations : Anticoagulation for Stroke Prevention in AF Patients
Assess Thromboembolic Risk (CHADS2)
CHADS2 = 0
CHADS2 = 1
CHADS2 ≥ 2
Increasing stroke risk
No anti‐
thrombotic
No additional risk factors for stroke
ASA
Either female sex or vascular disease
OAC*
Age ≥ 65 yrs or combination female sex and vascular disease
OAC*
OAC*
*Aspirin is a reasonable alternative in some as indicated by risk‐benefit
When OAC therapy is indicated, most patients should receive dabigatran, or rivaroxaban, or apixaban (once approved), in preference to warfarin. Skanes AC, et al. Can J Cardiol. 2012;28:125‐36. 35
Warfarin has limitations……
•
•
•
•
•
Slow onset
Genetic variation in metabolism of the drug
Food and drug interactions
Narrow therapeutic window
Frequent monitoring and blood tests
Anticoagulation is Underutilized
in High‐risk AF Patients
Preadmission treatment in patients with known AF
who were admitted with acute ischemic stroke and were classified as high risk for systemic emboli according to published guidelines (n=597)
Dual antiplatelet therapy
2%
No antithrombotics
29%
30%
Warfarin subtherapeutic
10%
Single antiplatelet agent
Gladstone DJ, et al. Stroke. 2009;40:235‐40.
29%
Warfarin therapeutic
In addition, only 18% of AF patients who had a previous stroke had a therapeutic INR of warfarin at the time of stroke 37
Oral Anticoagulants: New Agents
ƒ Warfarin (vitamin K antagonist) has traditionally been used as the anticoagulant of choice for stroke prevention. ƒ Recently, three new oral anticoagulants have been studied in clinical trials for stroke prevention in AF patients:
AGENT
CLASS
APPROVAL STATUS IN CANADA FOR STROKE PREVENTION IN AF
Dabigatran
Direct thrombin inhibitor
Pharmacare Special Auth
Rivaroxaban
Factor Xa inhibitor
Pharmacare Special Auth
Apixaban
Factor Xa inhibitor
Not Pharmacare
Pradax (dabigatran etexilate) Product Monograph. Boehringer Ingelheim Canada Ltd. June 13, 2011; Xarelto (rivaroxaban) Product Monograph. Bayer Canada Inc. January 11, 2012; Eliquis (apixaban) Summary of Product Characteristics. Bristol‐Myers Squibb/Pfizer EEIG, United Kingdom. May 18, 2011.
38
RE‐LY, ROCKET‐AF, ARISTOTLE
Dosing and Patient Demographics
RE‐LY
Dabigatran 110mg
RE‐LY
Dabigatran 150mg
ROCKET‐AF
Rivaroxaban
20mg
ARISTOTLE
Apixaban
5mg
Open‐label*
Open‐label*
Double‐blind
Double‐blind
BID
BID
OD
BID
Congestive heart failure
32.2%
31.8%
63%
35.5%
Hypertension
78.8%
78.9%
90%
87.3%
71.4 71.5
73
70 Diabetes
23.4%
23.1%
40%
25%
Stroke/ Transient ischemic attack/Systemic embolism (prior)
19.9%
20.3%
55%
19.2%
2.1
2.2
3.5
2.1
Design Frequency
Age (median, years)
CHADS2 Score (mean)
* vs. warfarin; dabigatran dose was blinded.
Pradax (dabigatran etexilate) Product Monograph. Boehringer Ingelheim Canada Ltd. June 13, 2011;
Xarelto (rivaroxaban) Product Monograph. Bayer Canada Inc. January 11, 2012;
Eliquis (apixaban) Summary of Product Characteristics. Bristol‐Myers Squibb/Pfizer EEIG, United Kingdom. May 18, 2011; Connolly SJ, et al; for the RE‐LY Steering Committee and Investigators. N Engl J Med. 2009;361(12):1139‐51; Connolly SJ, et al; for the RE‐LY Investigators. N Engl J Med. 2011;363(19):1875‐6 (updated); Patel MR, et al; and the ROCKET AF Steering Committee for the ROCKET AF Investigators. N Engl J Med. 2011;365(10):883‐91; Granger SJ, et al; for the ARISTOTLE Committees and Investigators. N Engl J Med. 2011;365(11):981‐92.
39
Dabigatran: RE‐LY
18,113 patients with ≥ 1 risk factor (mean CHADS2 score: 2.1)
Stroke or Systemic Embolism
%/yr
3.5
0.05
Major Hemorrhage
p=0.003 (sup)
RRR 20%
p=0.32 (sup)
RRR 7%
3.0
3.32%
0.04
Warfarin
0.03
3. 57%
2.5
Dabigatran
2.87%
2.0
110 mg
1.5
0.02
Dabigatran
1.0
150 mg
0.01
34% RRR for 150 mg
p<0.001 NI
0.00
0.5
0
0
6
12
18
Months
24
30
Connolly SJ et al. N Engl J Med 2009;361:1139‐51.
Connolly SJ et al; N Engl J Med 2011;363(19):1875‐6. (updated) Dabigatran Dabigatran
110 mg BID 150 mg BID
Warfarin
40
Rivaroxaban: ROCKET‐AF
14,264 patients with ≥ 2 risk factors
(mean CHADS2: 3.5) Stroke or Systemic Embolism
Cumulative Event Rate (%)
6
5
%/yr
4
Warfarin
3
Major Hemorrhage
3.6%
3.4%
4
2.4%/yr
3
Rivaroxaban
2
2.1%/yr
2
p<0.001 for non‐inferiority 1
P=0.58
1
21% RRR
0
0
0
120 240
360 480 600
720 840
Rivaroxaban
Warfarin
Days since randomization
Patel MR et al, NEJM 2011. 365(10):883‐91.
41
Apixaban: ARISTOTLE
18,201 patients with ≥ 1 risk factor
(mean CHADS2 2.1) Stroke or Systemic Embolism
%/yr
4
Cumulative Event Rate (%)
4
Major Hemorrhage
Warfarin
3
3
3.09%
1.60%/yr
2
Apixaban
1.27%/yr
1
P=0.01 2
2.13%
p<0.001
1
21% RRR
0
0
0
6
12
18
24
30
Apixaban
Warfarin
Months
Granger et al. N Engl J Med 2011
42
New Anticoagulants vs Warfarin
All‐Cause Mortality
The new OAC agents are consistently associated with a numerically lower risk for all‐cause mortality compared to warfarin.†
Relative Risk (95% CI)
TRIAL OAC Agent
Dabigatran 150mg b.i.d.
RE‐LY Dabigatran 110mg b.i.d.
ROCKET‐AF
.
Rivaroxaban 20mg o.d.
ARISTOTLE
Apixaban* 5mg b.i.d.
0.5
†
Not intended as cross‐trial comparison
*Not approved in Canada
for stroke prevention in AF patients
New Anticoagulant
Better
1
2
Warfarin
Better
Data obtained from intention‐to‐treat analysis
Connolly SJ, et al; for the RE‐LY Steering Committee and Investigators. N Engl J Med. 2009;361:1139‐51;
Patel MR, et al; and the ROCKET AF Steering Committee for the ROCKET AF Investigators. N Engl J Med. 2011;365:883‐91;
Granger CB, et al; for the ARISTOTLE Committees and Investigators. N Engl J Med. 2011; 365:981‐92.
43
NOACs vs. Warfarin: All Stroke
NOACs vs. Warfarin: Hemorrhagic Stroke
NOACs vs. Warfarin: Ischemic Stroke
NOACs vs Warfarin: Major Bleeding
Challenges of new oral anticoagulants
•
•
•
•
•
No test to measure anticoagulation effect
No confirmation of adherence
No antidotes
No information on long term side effects
No head to head comparison studies
How do we choose with new oral anticoagulant to use?
Choosing which newer oral anticoagulant to use………
• Advantages and disadvantages of each newer oral anticoagulant
• There is a role for each new oral anticoagulant depending on patient characteristics and scenarios
• Ultimately which newer oral anticoagulant to use should be a discussion with the patient about the pros and cons of each agent Emergency Management of Bleeding with NOAC
ER Management of Bleeding
• Withold anticoagulation therapy and other drugs that impaire hemostasis
• Control bleeding
• Supportive treatment with IV fluids, appropriate blood products
• Activated charcoal if NOAC taken within 2 hours
• Nonspecific prohemostatic agents can be considered
– FEIBA 50‐100 U/kg
– Prothrombin Complex Concentrate 50 U/kg
– Recombinant factor VIIa 120 U/kg
– Dialysis in extreme cases with dabigatran only
How to Switch from Warfarin
DABIGATRAN
APIXIBAN
RIVAROXABAN
Discontinue warfarin
and start dabigatran once Discontinue warfarin
and start rivaroxaban once
INR < 2.0
INR ≤ 2.5
1. Pradax (dabigatran etexilate) Product Monograph. Boehringer Ingelheim Canada Ltd. June 13, 2011.
2. Xarelto (rivaroxaban) Product Monograph. Bayer Canada Inc. January 11, 2012.
53
Left Atrial Appendage Closure
Key Learnings ƒ Atrial fibrillation is a major risk factor for stroke, and AF strokes are more severe, disabling and fatal relative to non‐AF stroke. ƒ Patients should be stratified for stroke risk using the CHADS2 and CHA2DS2‐VASc scoring systems; bleeding risk is calculated using the HAS‐BLED scoring system, although it has limitations.
ƒ The new oral anticoagulants include dabigatran, rivaroxaban and apixaban, although only dabigatran and rivaroxaban are currently approved in Canada for the atrial fibrillation indication.
ƒ The new OACs provide benefits, including no need for INR monitoring, lower risk of stroke or systemic embolism, intracranial hemorrhage, major bleeding, and all‐cause mortality compared to warfarin. ƒ Renal function should be evaluated prior to administration of new OACs. Patients with renal impairment should be monitored carefully with the new OACs, and dosing should be modified according to creatinine clearance values. Thanks for your Attention