dr ranjith mp antithrombotics in af

JOURNAL REVIEW

Newer Antithrombotics in AF

1

Dr Ranjith MP Senior Resident

Department of Cardiology Government Medical college

Kozhikode

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

2 1. Savelieva et al. Ann Med 2007;39:371–391 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

3 Hart R, et al. Ann Intern Med 1999;131:492

Warfarin Better

Control Better

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

100% 50% 0 -50% -100%

Aggregate

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

7

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

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

10

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

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

R

Warfarin adjusted

(INR 2.0-3.0) n = 6022

Dabigatran Etexilate

110 mg BID n = 6015

Dabigatran Etexilate

150 mg BID n = 6076

Blinded Event Adjudication

Open Blinded

Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

RE-LY: Baseline Characteristics

12 Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

RE-LY: Primary Outcome


RE-LY: Summary of Results


RE-LY: Stroke or Systemic Embolism

15

..

Cu

mu

lati

ve H

azar

d R

ate

s

0.0

0.01

0.02

0.03

0.04

0.05

0 0.5 1.0 1.5 2.0 2.5

Years of follow-up

Dabigatran 110 mg

Dabigatran 150 mg

Warfarin

Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

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

RE−LY Summary

• Dabigatran 150 mg superior to warfarin for

stroke/systemic embolism; dabigatran 110 mg

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

similar to dabigatran 150 mg

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.

Results

Conclusions

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

Stroke/systemic embolism

• Dabigatran 150 mg superior to warfarin

in reducing stroke or systemic

embolism, with a similar bleeding

profile. The 110 mg dose was non-

inferior for efficacy, associated with

lower bleeding compared with warfarin

0

5

%/y

ea

r

1.53 1.11 2.71 3.11

5

10

Major bleeding

10

1.69

Dabigatran

110 mg

Dabigatran

150 mg

Warfarin

0

%/y

ea

r

3.36

(p <0.001*, p = 0.34†) (p = 0.31*, p = 0.03†)

*Dabigatran 150 mg vs. warfarin; †Dabigatran 110 mg vs. warfarin

18

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

ROCKET AF: Study Design

Rivaroxaban 20 mg daily

(15 mg for Cr Cl 30-49 ml/min)

Warfarin INR target: 2.5

(2.0-3.0 inclusive)

Primary Endpoint: Stroke or non-CNS Systemic Embolism

Atrial Fibrillation

Randomize Double Blind /

Double Dummy (N= 14,264)

Monthly Monitoring Adherence to standard of care guidelines

Risk Factors, at least 2 of: • CHF • Hypertension • Age 75 • Diabetes

OR • Stroke, TIA or systemic

embolus

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

ROCKET AF: Baseline Demographics

20

Rivaroxaban (n = 7081)

Warfarin (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


ROCKET AF: Primary Efficacy Outcome

Stroke and non-CNS Embolism

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

ROCKET AF: Primary Safety Outcomes

Bleeding:

Rivaroxaban Warfarin HR 95% CI P-value Event Rate Event Rate

Major and non-major Clinically Relevant

14.91 14.52 1.03

0.96, 1.11 .442

Major 3.60 3.45 1.04

0.90, 1.20 .576

Non-major Clinically Relevant

11.80 11.37 1.04

0.96, 1.13 .345


Rivaroxaban Warfarin

HR (95% CI) P-value

Event Rate or N (Rate)

Event Rate or N (Rate)

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: Primary Safety Outcomes


0

2

4

primary

ROCKET AF- Summary

• Stroke or non-CNS systemic embolism (per 100

patient-years): 1.7 with rivaroxaban vs. 2.2 with

warfarin (p for noninferiority < 0.001, p for

superiority = 0.12 by intention to treat analysis, p

for superiority = 0.015 by on-treatment analysis)

• Major and nonmajor clinically relevant bleeding

(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)

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

Conclusions

• Among AF patients with high stroke

risk, rivaroxaban was noninferior to

warfarin

• Rivaroxaban was associated with a

reduced incidence of the primary

outcome without an excess of major

bleeding or intracranial hemorrhage

(p for non-

inferiority < 0.001)

Rivaroxaban,

20 mg daily

Pe

r 1

00

pa

tie

nt-

ye

ars

1.7

2.2

Stroke or non-CNS systemic

embolism

Warfarin,

INR 2-3


N Engl J Med 2011;365:981-92.

ARISTOTLE: Study Design

Apixaban 5 mg bd

(2.5-mg for- age≥80, Wt≤60kg 60 kg, or serum creatinine level of 1.5mg%)

Warfarin INR target: 2.0-3.0

Primary Endpoint: ischemic or hemorrhagic stroke or systemic embolism

Atrial Fibrillation

Randomized Double Blind (N= 18,201)

Monthly Monitoring Adherence to standard of care guidelines

Risk Factors, at least 1 of: • CHF • Hypertension • Age 75 • Diabetes

OR • Stroke, TIA or systemic

embolus

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

ARISTOTLE : Baseline Characteristics


Characteristic Apixaban (n=9120)

Warfarin (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


Characteristic Apixaban (n=9120)

Warfarin (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


Outcome

Apixaban (N=9120)

Warfarin (N=9081)

HR (95% CI) P Value Event Rate

(%/yr) Event Rate

(%/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

Outcome

Apixaban (N=9088)

Warfarin (N=9052)

HR (95% CI) P Value Event Rate

(%/yr) Event Rate

(%/yr)

Primary safety outcome: ISTH major bleeding*

2.13 3.09 0.69 (0.60, 0.80) <0.001

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 non-major bleeding

4.07 6.01 0.68 (0.61, 0.75) <0.001

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

• Primary efficacy outcome (stroke/systemic embolism)

for apixaban vs. warfarin: 1.27%/year vs. 1.6%/year;

pnoninferiority < 0.001, psuperiority = 0.01

• 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):

2.13%/year vs. 3.09%/year, p < 0.001

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

Conclusions

(p < 0.001)*

Apixaban

(n = 9,120)

Primary efficacy

outcome

• Landmark trial, demonstrates

superiority of apixaban over warfarin in

patients with AF for efficacy, with a

significant reduction in bleeding

• Apixaban is an oral anti-Xa agent that

does not require routine blood

monitoring

0

5

10

1.27 1.6

(p < 0.001)

2.13 3.09

5

Primary safety

outcome

Warfarin

(n = 9,081)

0

10

% %

* For noninferiority

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

92.

N Engl J Med 2011;364:806-17.

AVERROES (Apixaban versus Acetylsalicylic

Acid to Prevent Strokes): Study Design

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

Apixaban 2.5 mg bid or 5 mg bid

Aspirin 81-324 mg qd

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

Patient characteristics

•Aged 50 years

•Atrial fibrillation

•1 additional risk factor for stroke

•Not suitable for vitamin K antagonist

≈ 1.6 years

Ran

do

miz

atio

n

N=5600

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

(n=2809), %

Aspirin (n=2791),

%

Relative risk (95%

CI)

Primary end point 1.6 3.6 0.46 (0.33–0.64)

Stroke, embolic event, MI, or vascular

death

4.1 6.2 0.66 (0.53–0.83)

- 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

(n=2809), %

Aspirin

(n=2791), %

Relative risk

(95% CI)

Major bleeding 1.4 1.2 1.14 (0.74–1.75)

Clinical relevant nonmajor

bleeding

3.0 2.6 1.18 (0.88–1.58)

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

Low Exposure Strategy

DU-176b 30 mg QD

(n=5500)

Active Control

Warfarin

(n=5500)

High Exposure Strategy

DU-176b 60 mg QD

(n=5500)

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

AF on ECG < 12 mos

Intended oral A/C

CHADS2 Score > 2

R

Randomization Strata:

1. CHADS2 2-3 vs 4-6

2. Drug clearance

Median Duration of Followup 24 months

n~16,500

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

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: Main Exclusion Criteria

EXPLORE-Xa: Patient Disposition & Follow-Up


N=561 Patients Screened

N=508 Patients Randomized

N=53 Patients Not Randomized

N=127 Betrixaban 40 mg



N=127 Open-Label Warfarin

N=116 Completed

N=115 Completed

N=116 Completed

N=119 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


1

5 5

7

1 1 1 1

0

1

2

3

4

5

6

7

8

B40 B60 B80 W

# o

f P

atie

nts

Major+CRNM Strokes Deaths

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

elevations ≥ 3xULN

0.5 0.8

EXPLORE-Xa: Type of GI Adverse Events by Treatment


0 2 4 6 8 10 12

Diarrhoea

Constipation

Nausea

Dyspepsia

Abdominal Pain

Vomiting

Percentage of patients

W

B80

B60

B40

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

THANK YOU

dr ranjith mp antithrombotics in af

Documents

n engl j med

af patients

introduction warfarin

oral daily n

non stroke

ann med

stroke prevention

high stroke primary