Dr ranjith mp antithrombotics in af

JOURNAL REVIEW

Newer Antithrombotics in AF

Dr Ranjith MP
Senior Resident
Department of Cardiology
Government Medical college
Kozhikode

1

Introduction
 Atrial fibrillation is associated with a five-fold risk of
stroke1

 The increase in risk of stroke is similar for paroxysmal,
persistent and permanent AF2

 Strokes associated with AF are usually more severe than
those from other causes, conferring an increased risk of
morbidity, mortality and poor functional outcome1

1. Savelieva et al. Ann Med 2007;39:371–391
2
2. Hart R et al. JACC 2000; 35:183-187

Introduction
 Warfarin -most effective treatment to prevent stroke in patients with AF & it
reduces the risk by about two thirds compared with placebo
Warfarin Control
Better Better

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT
Aggregate

100% 50% 0 -50% -100%
3
Hart R, et al. Ann Intern Med 1999;131:492

Limitations of vitamin K antagonists

 Slow onset and offset of action

 Considerable variability in dose response among
individuals

 Multiple food and drug interactions

 Narrow therapeutic window & considerable risk of
hemorrhage

 Even with careful laboratory monitoring, major bleeding
occurs in 1% to 3% per year
4

Introduction
 Therefore, there is a need for novel approaches to stroke
prevention in AF with new antithrombotic agents

 The Newer Antithrombotics for stroke prevention in AF fall
into two classes:

 Oral direct thrombin inhibitors (e.g. dabigatran)
 Oral direct factor Xa inhibitors (e.g. rivaroxaban, apixaban)

5

Pharmacology of newer Antithrombotics

6

Advantages of direct thrombin inhibitors
over indirect inhibitors

Advantage Mechanism

Better suppression of thrombus Inhibit free and bound
growth thrombin

Retain activity in presence Do not bind PF4 or Vwf
of platelet-rich thrombi

Predictable anticoagulant Do not bind plasma proteins
response

No risk of HIT Do not bind PF4

7

Trials with new agents vs warfarin in AF
(aim INR 2.0-3.0)

8

Ximelagatran
 First oral direct thrombin inhibitor

 As effective as warfarin for prevention of stroke and
systemic embolic events in patients with atrial fibrillation1

 Prolonged administration (35 days) of ximelagratan was
associated with a risk of liver toxicity, which led to
withdrawal of the drug from the market2

1Testa L et al. Expert Opin Drug Saf. 2007;6(4):397-406
2Agnelli G et al. Thromb Res. 2008

N Engl J Med 2009;361:1139-51.
10

The RE-LY Study:
Randomized Evaluation of Long-term anticoagulant therapy
 Dabigatran Compared to Warfarin in 18,113 Patients with AF at Risk of Stroke

Atrial fibrillation
≥ 1 risk factor
Absence of contraindications
951 centers/44 countries

Blinded Event Adjudication

R
Open Blinded

Warfarin Dabigatran Dabigatran
adjusted Etexilate Etexilate
(INR 2.0-3.0) 110 mg BID 150 mg BID
n = 6022 n = 6015 n = 6076
Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

RE-LY: Baseline Characteristics

12

RE-LY: Primary Outcome

13

RE-LY: Summary of Results

14

RE-LY: Stroke or Systemic Embolism
0.05
..

0.04
Cumulative Hazard Rates

Warfarin
Dabigatran 110 mg
0.03

0.02

Dabigatran 150 mg
0.01

0.0

0 0.5 1.0 1.5 2.0 2.5
Years of follow-up
15

RE-LY: Drug Discontinuation

a. Rates of discontinuation at 1 and 2 years were higher with dabigatran
than with warfarin (P < .001). Rates are based on Kaplan-Meier estimates

16

RE−LY Summary
Trial design: Patients with AF were randomized to either dabigatran 110 mg, 150 mg, or
open-label warfarin. Patients were followed for a mean of 2 years.

*Dabigatran 150 mg vs. warfarin; †Dabigatran 110 mg vs. warfarin
Results
(p <0.001*, p = 0.34†) (p = 0.31*, p = 0.03†) • Dabigatran 150 mg superior to warfarin for
stroke/systemic embolism; dabigatran 110 mg
10 10 was non-inferior
• Stroke ↓ in dabigatran 150 mg arm (p < 0.001)
• Major bleeding was higher in warfarin arm
compared with dabigatran 110 mg, but was
%/year

%/year

similar to dabigatran 150 mg
5 5
Conclusions
• Dabigatran 150 mg superior to warfarin
1.53 1.11 1.69 2.71 3.11 3.36 in reducing stroke or systemic
0
embolism, with a similar bleeding
0
profile. The 110 mg dose was non-
Stroke/systemic embolism Major bleeding
inferior for efficacy, associated with
Dabigatran Dabigatran lower bleeding compared with warfarin
110 mg 150 mg

Warfarin
Connolly SJ, et al. N Engl J Med 2009;Aug 30:[Epub]

N Engl J Med 2011;365:883-91.
18

ROCKET AF: Study Design
Risk Factors, at least 2 of:
• CHF
• Hypertension
• Age  75
Atrial Fibrillation • Diabetes
OR
• Stroke, TIA or systemic
embolus

Rivaroxaban Randomize Warfarin
20 mg daily Double Blind / INR target: 2.5
(15 mg for Cr Cl 30-49 ml/min) Double Dummy (2.0-3.0 inclusive)
(N= 14,264)

Monthly Monitoring
Adherence to standard of care guidelines

Primary Endpoint: Stroke or non-CNS Systemic Embolism

MR Patel et al.N Engl J Med 2011;365:883-91.

ROCKET AF: Baseline Demographics
Rivaroxaban Warfarin
(n = 7081) (n = 7090)
CHADS2 Score (mean) 3.48 3.46
2 (%) 13 13
3 (%) 43 44
4 (%) 29 28
5 (%) 13 12
6 (%) 2 2
Prior VKA Use (%) 62 63
Heart Failure (%) 63 62
Hypertension (%) 90 91
Diabetes Mellitus (%) 40 39
Prior Stroke/TIA/Embolism (%) 55 55
Prior Myocardial Infarction (%) 17 18

20

ROCKET AF: Primary Efficacy Outcome
Stroke and non-CNS Embolism

21

ROCKET AF: Primary Safety Outcomes

Rivaroxaban Warfarin HR
Bleeding: Event Rate Event Rate 95% CI P-value
Major and non-major 1.03
14.91 14.52 .442
Clinically Relevant 0.96, 1.11
1.04
Major 3.60 3.45 .576
0.90, 1.20
Non-major Clinically 1.04
11.80 11.37 .345
Relevant 0.96, 1.13


ROCKET AF: Primary Safety Outcomes
Rivaroxaban Warfarin
Event Rate Event Rate HR
or N (Rate) or N (Rate) (95% CI) P-value
Major 3.60 3.45 1.04 (0.90, 1.20) .576
≥ 2 g/dL Hgb drop 2.77 2.26 1.22 (1.03, 1.44) .019
Transfusion (> 2 units) 1.65 1.32 1.25 (1.01, 1.55) .044
Critical organ bleeding 0.82 1.18 0.69 (0.53, 0.91) .007
Bleeding causing death 0.24 0.48 0.50 (0.31, 0.79) .003

Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) .019
Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) .060
Intraventricular 2 (0.02) 4 (0.04)
Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) .051
Subarachnoid 4 (0.04) 1 (0.01)


ROCKET AF- Summary
Trial design: Patients with atrial fibrillation at increased risk for stroke were randomized to
the direct factor Xa inhibitor rivaroxaban 20 mg oral daily (n = 7,131) vs. warfarin with target
INR 2-3 (n = 7,133).

Results
(p for non- • Stroke or non-CNS systemic embolism (per 100
4 inferiority < 0.001) patient-years): 1.7 with rivaroxaban vs. 2.2 with
warfarin (p for noninferiority < 0.001, p for
Per 100 patient-years

superiority = 0.12 by intention to treat analysis, p
for superiority = 0.015 by on-treatment analysis)
2.2
• Major and nonmajor clinically relevant bleeding
1.7
2 (per 100 patient-years): 14.9 vs. 14.5 (p = 0.44)
• Intracranial hemorrhage (per 100 patient-years):
0.5 vs. 0.7 (p = 0.019)

Conclusions
0 • Among AF patients with high stroke
primary
Stroke or non-CNS systemic risk, rivaroxaban was noninferior to
embolism warfarin
Rivaroxaban, Warfarin, • Rivaroxaban was associated with a
20 mg daily INR 2-3
reduced incidence of the primary
outcome without an excess of major
MR Patel et al.N Engl J Med 2011;365:883-91. bleeding or intracranial hemorrhage

ARISTOTLE: Study Design
Risk Factors, at least 1 of:
• CHF
• Hypertension
• Age  75
Atrial Fibrillation • Diabetes
OR
• Stroke, TIA or systemic
embolus

Apixaban 5 mg bd Randomized Warfarin
(2.5-mg for- age≥80, Double Blind INR target: 2.0-3.0
(N= 18,201)
Wt≤60kg 60 kg, or serum
creatinine level of 1.5mg%)

Monthly Monitoring
Adherence to standard of care guidelines

Primary Endpoint: ischemic or hemorrhagic stroke or systemic embolism

Christopher B. G et al.N Engl J Med 2011;365:981-92.

ARISTOTLE : Baseline Characteristics
Apixaban Warfarin
Characteristic
(n=9120) (n=9081)
Age, years, median (25th, 75th %ile) 70 (63, 76) 70 (63, 76)
Women, % 35 35
Region, %
North America 25 25
Latin America 19 19
Europe 40 40
Asia/Pacific 16 16
Warfarin naïve, % 43 43
CHADS score, mean (+/- SD) 2.1 (+/- 1.1) 2.1 (+/- 1.1)
1, % 34 34
2, % 36 36
≥ 3, % 30 30


ARISTOTLE :Baseline Characteristics
Apixaban Warfarin
Characteristic
(n=9120) (n=9081)
Qualifying risk factors, %
Age ≥75 yrs 31 31
Prior stroke, TIA, or SE 19 20
Heart failure or reduced LV EF 35 36
Diabetes 25 25
Hypertension 87 88
Renal function (ClCr ml/min), %
Normal (>80) 41 41
Mild impairment (>50 – 80) 42 42
Moderate impairment (>30 – 50) 15 15
Severe impairment (≤ 30) 1.5 1.5


ARISTOTLE :Primary Outcome
Stroke or systemic embolism


ARISTOTLE :Primary Outcome
Stroke or systemic embolism
Apixaban Warfarin
(N=9120) (N=9081)
Outcome HR (95% CI) P Value
Event Rate Event Rate
(%/yr) (%/yr)
Stroke or systemic embolism* 1.27 1.60 0.79 (0.66, 0.95) 0.011
Stroke 1.19 1.51 0.79 (0.65, 0.95) 0.012
Ischemic or uncertain 0.97 1.05 0.92 (0.74, 1.13) 0.42
Hemorrhagic 0.24 0.47 0.51 (0.35, 0.75) <0.001
Systemic embolism (SE) 0.09 0.10 0.87 (0.44, 1.75) 0.70
All-cause death* 3.52 3.94 0.89 (0.80, 0.998) 0.047
Stroke, SE, or all-cause death 4.49 5.04 0.89 (0.81, 0.98) 0.019
Myocardial infarction 0.53 0.61 0.88 (0.66, 1.17) 0.37


ARISTOTLE :Major Bleeding


ARISTOTLE :Bleeding Outcomes
Apixaban Warfarin
(N=9088) (N=9052)
Outcome HR (95% CI) P Value
Event Rate Event Rate
(%/yr) (%/yr)
Primary safety outcome:
2.13 3.09 0.69 (0.60, 0.80) <0.001
ISTH major bleeding*
Intracranial 0.33 0.80 0.42 (0.30, 0.58) <0.001

Gastrointestinal 0.76 0.86 0.89 (0.70, 1.15) 0.37
Major or clinically relevant
4.07 6.01 0.68 (0.61, 0.75) <0.001
non-major bleeding
GUSTO severe bleeding 0.52 1.13 0.46 (0.35, 0.60) <0.001

TIMI major bleeding 0.96 1.69 0.57 (0.46, 0.70) <0.001

Any bleeding 18.1 25.8 0.71 (0.68, 0.75) <0.001


ARISTOTLE : Conclusion

 Compared with warfarin, apixaban (over 1.8 years)
prevented
 6 Strokes
 15 Major bleeds
 8 Deaths

 Treatment with apixaban as compared to warfarin in patients
with AF & at least one additional risk factor for stroke:
 Reduces stroke and systemic embolism by 21% (p=0.01)
 Reduces major bleeding by 31% (p<0.001)
 Reduces mortality by 11% (p=0.047)


ARISTOTLE : Summary
Trial design: Patients with atrial fibrillation (AF) and at least one additional risk factor for
stroke were randomized to either apixaban 5 mg twice daily or dose-adjusted warfarin
(titrated to a target INR of 2.0-3.0). Patients were followed for a median of 1.8 years.

Results
(p < 0.001)* (p < 0.001)
• Primary efficacy outcome (stroke/systemic embolism)
for apixaban vs. warfarin: 1.27%/year vs. 1.6%/year;
pnoninferiority < 0.001, psuperiority = 0.01
10 10
• All strokes:1.19%/year vs. 1.51%/year, p = 0.01; all-
cause mortality: 3.52%/year vs. 3.94%/year, p = 0.047
• Primary safety outcome (ISTH major bleeding):
% 5 % 5 2.13%/year vs. 3.09%/year, p < 0.001
3.09
2.13
1.27 1.6 Conclusions
0 0 • Landmark trial, demonstrates
superiority of apixaban over warfarin in
Primary efficacy Primary safety
outcome outcome patients with AF for efficacy, with a
significant reduction in bleeding
Apixaban Warfarin
(n = 9,120) • Apixaban is an oral anti-Xa agent that
(n = 9,081)
* For noninferiority
does not require routine blood
Christopher B. G et al.N Engl J Med 2011;365:981- monitoring

AVERROES (Apixaban versus Acetylsalicylic
Acid to Prevent Strokes): Study Design

≈ 1.6 years
Patient characteristics
•Aged 50 years Apixaban 2.5 mg bid
•Atrial fibrillation or 5 mg bid

Randomization
N=5600
•1 additional risk
factor for stroke
•Not suitable for vitamin Aspirin 81-324 mg qd
K antagonist

Primary outcome measures:
• Time to composite outcome of stroke or systemic embolism
• Time to major bleeding

Stuart JC et al.N Engl J Med 2011;364:806-17.

AVERROES: Results (efficacy)
 Apixaban significantly reduced risk of stroke or systemic embolic
events by 54%
 The trial was stopped early as interim analysis showed significant
benefit with apixaban

Primary and secondary end points
Outcomes Apixaban Aspirin (n=2791), Relative risk (95%
(n=2809), % % CI)

Primary end point 1.6 3.6 0.46 (0.33–0.64)

Stroke, embolic event, MI, or vascular 4.1 6.2 0.66 (0.53–0.83)
death

- MI 0.7 0.8 0.85 (0.48–1.50)

- Vascular death 2.5 2.9 0.86 (0.64–1.16)

CV hospitalization 11.8 14.9 0.79 (0.68–0.91)

Total death 3.4 4.4 0.79 (0.62–1.02)


AVERROES: Results (safety)
 The risk of major bleeding increased by a statistically nonsignificant 14%
 There was no increased risk of fatal or intracranial hemorrhage, two particular
concerns with AF patients who receive anticoagulation therapy

Bleeding events
Outcomes Apixaban Aspirin Relative risk
(n=2809), % (n=2791), % (95% CI)

Major bleeding 1.4 1.2 1.14 (0.74–1.75)

Clinical relevant nonmajor 3.0 2.6 1.18 (0.88–1.58)
bleeding

Minor bleeding 5.2 4.1 1.27 (1.01–1.61)

Fatal bleeding 0.1 0.1 0.84 (0.26–2.75)

Intracranial 0.4 0.3 1.09 (0.50–2.39)


Am Heart J 2010:160:635-641.e2.

ENGAGE-AF-TIMI 48; Study Design

AF on ECG < 12 mos
n~16,500
Intended oral A/C
CHADS2 Score > 2 Randomization Strata:
1. CHADS2 2-3 vs 4-6
2. Drug clearance
R

Low Exposure Strategy High Exposure Strategy Active Control
DU-176b 30 mg QD DU-176b 60 mg QD Warfarin
(n=5500) (n=5500) (n=5500)

Median Duration of Followup 24 months
1º EP = Stroke or SEE (Noninferiority Boundary HR 1.38)
2º EP = Stroke or SEE or All-Cause Mortality
Safety EP’s = Major Bleeding, Hepatic Function
Chritian TR et al.Am Heart J 2010:160:635-641.e2.

European Heart Journal doi:10.1093/eht039

Characteristics of Betrixaban
 Orally-active and selective fXa inhibitor
 Oral bioavailability 34%,

 Peak to trough concentration profile 2.5 : 1
 ~20 hour effective half-life

 No dose adjustment expected for renal impairment
 Excreted mostly unchanged through bile with minimal renal
excretion (<5%)

 Antidote in development

 No major drug interactions expected
 Not substrate for CYP450 system
 Substrate for efflux proteins including P-glycoprotein

Stuart JC et al. European Heart Journal. doi:10.1093

EXPLORE-Xa : Study Objectives
Primary Objective
 Safety and tolerability of oral betrixaban at doses of 40,
60 and 80 mg once a day compared with dose-adjusted
warfarin in patients with non-valvular atrial fibrillation
or atrial flutter
 Primary Endpoint
• Time to major and clinically relevant non-major bleeding
 Secondary Endpoints
• Time to any bleeding, death, stroke, MI or systemic embolism

Secondary Objective
 Pharmacokinetics (PK) and pharmacodynamics (PD) of
betrixaban

EXPLORE-Xa: Main Inclusion Criteria
 Male or female, age ≥ 18 years
 AF at the time of enrollment or documented within the
last year
 At least one risk factor for stroke

EXPLORE-Xa: Main Exclusion Criteria

 Need for renal dialysis within one year
 AF due to reversible causes, mechanical prosthetic valve
 SBP > 160 mmHg on repeated measurements
 Active infective endocarditis


EXPLORE-Xa: Patient Disposition & Follow-Up

N=561
Patients Screened

N=53
N=508 Patients Not Randomized
Patients Randomized

N=127 N=127 N=127 N=127
Betrixaban 40 mg Betrixaban 60 mg Betrixaban 80 mg Open-Label Warfarin

N=116 N=115 N=116 N=119
Completed Completed Completed Completed

•Minimum follow-up 3 months; Maximum 12 months;
•Median 4.9 months

EXPLORE-Xa: Baseline Characteristics
All Betrixaban Warfarin Total
N=381 N=127 N=508
Median Age (years) 74 74 74
Age ≥75 years 47.2% 47.2% 47.2%
Male 65.4% 70.1% 66.5%
White 97.4% 99.2% 97.8%
Weight > 90 kg 45.1% 48.8% 46.1%
Country
US 72.4% 73.2% 72.6%
Canada 24.9% 25.2% 25.0%
Germany 2.6% 1.6% 2.3%
Baseline CHADS2 score
0-1 28.1% 29.1% 28.3%
2 39.9% 33.1% 38.2%
3-6 32.0% 37.8% 33.5%
Mean CHADS2 score - - 2.2
Baseline GFR (Cockcroft-Gault)
< 40 mL/min 9.2% 4.7% 8.1%
40-70 mL/min 38.6% 37.8% 38.4%
> 70 mL/min 52.2% 57.5% 53.5%
Concurrent Aspirin Use < 162 mg 38.6% 38.6% 38.6%
No Vitamin K Antagonist Experience 12.6% 14.2% 13.0%

EXPLORE-Xa: Major Bleeding or Clinically
Relevant Non-Major Bleeding


EXPLORE-Xa: Bleeds, strokes & deaths
8
Major+CRNM Strokes Deaths
7
7

6

5 5
5
# of Patients

4

3

2

1 1 1 1 1
1

0
B40 B60 B80 W

EXPLORE-Xa: ALT Elevations (in % of Patients)

Betrixaban Warfarin

>2x ULN 2.4 2.4

>3x ULN 1.8 0.8

>5x ULN 0.5 0.8

>10x ULN 0.3 0.0

Consecutive 0.5 0.8
elevations ≥ 3xULN


EXPLORE-Xa: Type of GI Adverse Events by Treatment

Percentage of patients

Vomiting

Abdominal Pain

Dyspepsia W
B80
Nausea B60
B40
Constipation

Diarrhoea

0 2 4 6 8 10 12


EXPLORE-Xa: Conclusion
 Bleeding was significantly less for betrixaban 40 mg vs.warfarin

 Bleeding at 60 and 80 mg was comparable to warfarin

 The number of strokes were within the range expected for warfarin (0-1 /gp)

 All 3 doses were well tolerated

 D-dimer shows activity across dose spectrum with a trend toward a dose
response

 Compared to well-treated experienced warfarin patients there was a dose
dependent effect on the primary endpoint of major and clinically relevant
non-major bleeding

Summary of recommendations for
antithrombotic agent

 Dabigatran-The FDA has approved the 150 mg b.i.d. dose,
and the 75 mg b.i.d. dose in severe renal impairment,
while the EMA has approvedboth the 110 mg b.i.d. and
150 mg b.i.d. doses

 Rivaroxaban has been approved for stroke prevention in
nonvalvular AF by both the FDA and the EMA

 Apixaban has not yet gained regulatory approval from the
EMA or FDA

Dr ranjith mp antithrombotics in af

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