- Email: [email protected]
New oral anticoagulants for stroke prevention in atrial fibrillation: Evidence from phase III clinical trials
j o u r n a l o f i n d i a n c o l l e g e o f c a r d i o l o g y 2 ( 2 0 1 2 ) 1 1 2 e1 1 6
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/jicc
Review article
New oral anticoagulants for stroke prevention in atrial fibrillation: Evidence from phase III clinical trials Pushpraj Patel a,*, Nishant Sangole b a b
Department of Cardiology, Krishna Institute of Medical Sciences, Secunderabad, Hyderabad, India Senior Medical Advisor, Medical Affairs Department, Boehringer Ingelheim (I) Pvt. Ltd., Mumbai, India
article info
abstract
Article history:
Atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia. It
Received 26 June 2012
increases both, the risk and severity of strokes and is associated with substantial
Accepted 27 June 2012
morbidity, mortality, decreased quality of life, and related health care cost and care giver
Available online 9 July 2012
burden. Ischemic strokes among patients with AF are commonly caused by cardioemboli, most commonly from within the left atrial appendage. Vitamin K antagonist (VKA),
Keywords:
warfarin has a long history of benefit and has become the gold standard medication for the
Atrial fibrillation
prevention of ischemic stroke in patients with atrial fibrillation. However due to significant
Dabigatran etexilate
underutilization and several limitations of VKA, novel oral anticoagulants are being
Apixaban RE-LY trial
developed. Recently, new oral anticoagulant drugs that act directly by inhibiting activated
ROCKET-AF trial
coagulation factors such as factor X or thrombin have been developed and investigated in
ARISTOTLE trial
phase III clinical trials. Our review focuses on clinical evidence of direct thrombin inhibitor, dabigatran, and FXa inhibitors, rivaroxaban and apixaban in phase III trials for prevention of stroke and systemic embolism in AF. Copyright ª 2012, Indian College of Cardiology. All rights reserved.
1.
Introduction
Atrial fibrillation (AF) is characterized by irregular, disorganized and chaotic electrical activity of the atrium. It is the most common sustained cardiac arrhythmia in clinical practice.1 Non-valvular AF is associated with a 4e5-fold increase in stroke risk across all age groups and is associated with substantial morbidity, mortality, decreased quality of life, and related health care costs.2,3 The primary clinical significance of AF is its role as a potent independent risk factor for ischemic stroke.1,2 Ischemic strokes among patients with AF are commonly caused by cardioemboli, most commonly from within the left atrial
appendage.4,5 In AF, there is loss of organized atrial contraction which is associated with reduced contractility of the left atrial appendage, stasis in the left atrial appendage (LAA), reduced LAA flow velocities and thrombus formation.4,5 The most established therapy for both primary and secondary prevention of stroke and systemic thromboembolism in patients with atrial fibrillation is anticoagulation with the vitamin K antagonist (VKA), warfarin.1 Pooled data from pivotal trials have found that doseadjusted warfarin reduces the risk of stroke by 68%, from an annual risk of 4.5% (placebo) to 1.4% (warfarin).6 A number of randomized clinical studies have also established the value of warfarin in reducing risk of stroke in patients with AF.1,7
* Corresponding author. Flat No. 2, Laxmi Narayana Apartment, Venkata Rao Nagar Colony, Sindhi Colony, Secunderabad 500003, Andhra Pradesh, India. Tel.: þ91 8801806692. E-mail address: [email protected] (P. Patel). 1561-8811/$ e see front matter Copyright ª 2012, Indian College of Cardiology. All rights reserved. http://dx.doi.org/10.1016/j.jicc.2012.06.004
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Vitamin K antagonists (warfarin) has been the gold standard medication for Stroke Prevention in Atrial Fibrillation (SPAF) but has several limitations that include slower onset and offset of action, complex genetic control of their effect with polymorphisms leading to highly variable individual sensitivity and narrow therapeutic window. In addition, metabolism of VKAs is affected by many factors, including diet, drugs, hepatic dysfunction, other co-morbid conditions and alcohol intake. As a result of these limitations, the doseeresponse relationship of VKAs is unpredictable, and therefore frequent coagulation monitoring is required to maintain the international normalized ratio (INR) between 2.0 and 3.0 and dose-adjustment is needed to ensure efficacy of treatment and to minimize the risk of bleeding complications.8,9 These drawbacks have led to an increase interest to develop novel anticoagulant which would be equally efficacious and safe, but will not require routine laboratory monitoring for dose-adjustment. These new oral anticoagulants (OAC) target two distinct stages in the coagulation cascade, directly inhibiting thrombin (factor IIa) or factor Xa (FXa).9,10 Direct thrombin inhibitor, dabigatran, and FXa inhibitors, rivaroxaban and apixaban are new oral anticoagulants two of which have been approved by the USFDA for SPAF and apixaban will be approved by the USFDA on June 28, 2012. All have been compared to well controlled warfarin (INR 2e3) in phase
III trials for prevention of stroke and systemic embolism in AF.9e11
2. Clinical data: evidence of stroke prevention in atrial fibrillation in phase III trials (Table 1) 2.1.
Dabigatran etexilate
The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial12,13 compared dabigatran etexilate with warfarin for stroke prevention in AF patients. In RE-LY trial,12,13 18,113 patients with non-valvular atrial fibrillation at risk of stroke were randomized in an unblinded fashion to either warfarin with a goal INR of 2.0e3.0, or dabigatran. Patients in the dabigatran group were then randomized in a blinded fashion to receive either 110 mg twice a day or 150 mg twice a day. Patients were followed for a median of 2 years for the primary composite outcome of all stroke (ischemic or hemorrhagic) or systemic embolism. At study end, dabigatran etexilate 110 mg twice a day was non-inferior to warfarin with respect to the primary end point of all stroke (ischemic or hemorrhagic) or systemic embolism, with event rates of 1.54% and 1.71% per year, respectively (non-inferiority
Table 1 e Comparison of phase III clinical trials of stroke prevention in AF (new oral anticoagulants). Phase III clinical trial Drugs AF patients
Design
Primary end point Conclusion
RE-LY Dabigatran (110 mg/150 mg twice daily) Warfarin (INR 2e3) 18,113 patients one risk factor 50% VKA naive CHADS2: 0e1 CHADS2: 2 CHADS2: 3 Open-label warfarin
ROCKET-AF Rivaroxaban (20 mg once a day) Warfarin (INR 2e3) 14,264 patients moderate/high risk CHADS2: 2 CHADS2: 3
ARISTOTLE Apixaban (5 mg twice daily) Warfarin (INR 2e3) 18,201 patients one risk factor Both VKA naive/non-naı¨ve
Randomized, double-blind, dummy design with sham INR
Randomized, double-blind, dummy design with sham INRs Composite: stroke/systemic embolism Composite: stroke/systemic Composite: stroke/systemic embolism embolism -Dabigatran 150 mg twice daily is superior to -Rivaroxaban 20 (or 15) mg -Apixaban 5 (or 2.5) mg warfarin and is associated with lower rates once a day is non-inferior to warfarin twice daily is superior of stroke and systemic embolism, but similar in patients with moderate-to-high to warfarin and is rates of major hemorrhage. risk of stroke. associated with less -Dabigatran 110 mg twice daily is equally -There is no difference in rates bleeding and lower effective and non-inferior to warfarin of major and clinically relevant mortality. with lower rates of major bleeding. nonmajor bleeding between -Apixaban 5 (or 2.5) mg -Dabigatran 110 and 150 mg twice daily treatments. twice daily is associated are associated with lower rates of intracranial -Intracranial haemorrhages occurs with a lower rate of haemorrhages than warfarin. less frequently with rivaroxaban intracranial -TTR: 64.4% (mean). than warfarin. haemorrhages than -All-cause mortality: 12% (P ¼ 0.051). -TTR: 55% (mean). warfarin. There were 3 arms in this study compared -TTR: 62.2% (mean). to ARISTOTLE and hence the sample size All-cause mortality: is lesser in each arm. This could explain 11% better (P ¼ 0.047). the fact that significance was very narrowly missed.
CHADS2 e Congestive cardiac failure, hypertension, age, diabetes, past h/o stroke or transient ischemic attacks; TTR e Time in therapeutic range; INR e International normalized ratio.
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P < 0.001) and in addition, a 35% reduction in risk (two step Hochberg procedure) was observed with dabigatran etexilate 150 mg twice a day (P < 0.001 for superiority, P < 0.001 for noninferiority). Dabigatran etexilate 150 mg twice a day was superior to warfarin for preventing stroke of all types, ischemic (25%) or hemorrhagic (74%) stroke, disabling or fatal stroke, and death (15%) from vascular causes.12,13 The rate of major hemorrhage was significantly lower with dabigatran etexilate 110 mg twice a day compared with warfarin (3.57% per year, P ¼ 0.003), whereas the rate of major hemorrhage with dabigatran etexilate, 150 mg bid (3.32% per year) was non-inferior to warfarin. Rate of intracerebral hemorrhage (ICH) was lower with either dose of dabigatran etexilate than with warfarin, and a reduction of all-cause mortality with dabigatran etexilate, 150 mg bid (3.64% per year and 4.13% per year, respectively) was marginally significant compared to warfarin (P ¼ 0.051). Dabigatran 150 mg twice a day was superior to warfarin in life-threatening bleeding (20%), and total bleeding (9%).12,13 Two new oral factor Xa inhibitors, rivaroxaban and apixaban have been extensively studied in phase III clinical trials as alternatives to warfarin for stroke prevention in high-risk patients with AF.
2.2.
Rivaroxaban
Rivaroxaban was compared with warfarin in patients with high-risk AF in ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).14,15 This trial was a double-blind, double-dummy multi-center randomized control trial. The trial evaluated rivaroxaban once daily versus warfarin to maintain INR of 2.0e3.0 in 14,264 patients with non-valvular atrial fibrillation at moderate-to-high risk for stroke (CHADS2 [congestive cardiac failure, hypertension, age, diabetes, past h/o stroke or transient ischemic attacks] score of 2 or greater). In ROCKET-AF trial,14,15 it was found that rivaroxaban was non-inferior to warfarin for primary efficacy end point,
a composite of stroke and systemic embolism, which occurred in 1.7% and 2.2% of patients on treatment with rivaroxaban and warfarin group (hazard ratio in the rivaroxaban group, 0.79; 95% CI, 0.66e0.96; P < 0.001 for non-inferiority). However, in the intention-to-treat analysis rivaroxaban was not superior to warfarin with events occurring in 2.1% and 2.4% of patients (hazard ratio, 0.88; 95% CI, 0.74e1.03; P ¼ 0.12). The rates of primary safety end point, a composite of major and clinically relevant nonmajor bleeding events, was similar between rivaroxaban and warfarin groups (P ¼ 0.44). However there was significant reduction in intracranial hemorrhage (0.5% vs. 0.7%, P ¼ 0.02) and fatal bleeding (0.2% vs. 0.5%, P ¼ 0.003) in the rivaroxaban group.14,15 Thus ROCKET-AF trial demonstrated that rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolism in AF, but unlike dabigatran, rivaroxaban did not decrease the risk of ischemic stroke.
2.3.
Apixaban
Apixaban has been compared to aspirin in the study AVERROES16,17 (Apixaban versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment). It was a randomized double-blind study involving 5599 patients with a mean CHADS2 score of 2.0 and compared twice daily dose of 5 mg apixaban with 81e324 mg aspirin. The trial was terminated early due to the clear benefit of apixaban over aspirin in reduction of strokes (hazard ratio ¼ 0.45; 95% CI ¼ 0.32e0.62; P < 0.001).16,17 Apixaban has recently been compared to warfarin in the ARISTOTLE trial18 (Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation). This trial involved 18,201 patients with a mean CHADS2 of 2.1 and a median duration of 1.8 years of follow-up. Patients were randomized to a twice daily dose of apixaban (5 mg) or warfarin titrated to an INR of 2.0e3.0. Apixaban was found non-inferior but also superior to warfarin for the prevention of stroke and systemic embolism (hazard ratio ¼ 0.79; CI, 0.66e0.95; P < 0.001 for non-inferiority;
Table 2 e Overview of phase III clinical trials of newer anticoagulants in VTE and ACS. Newer oral anticoagulant Dabigatran
Rivaroxaban
Apixaban
Deep vein thrombosis prevention RE-NOVATE RE-MODEL RE-MOBILIZE RE-MEDY (secondary prevention), RE-SONATE RECORD I RECORD II RECORD III RECORD IV MAGELLAN EINSTEIN e Ext (secondary prevention) ADVANCE 1 ADVANCE 2 ADVANCE 3 ADOPT AMPLIFY-Ext
Deep vein thrombosis treatment
Acute coronary syndromes
RE-COVER RECOVER II
RE-DEEM
EINSTEIN-DVT EINSTEIN-PE
ATLAS TIMI 46
AMPLIFY
APPRAISE
j o u r n a l o f i n d i a n c o l l e g e o f c a r d i o l o g y 2 ( 2 0 1 2 ) 1 1 2 e1 1 6
P ¼ 0.01 for superiority) while also demonstrating a decreased risk of bleeding (hazard ratio ¼ 0.69, 95% CI, 0.60e0.80; P < 0.001). Importantly, the rate of intracranial hemorrhage was significantly lower for apixaban (0.24 vs. 0.47% per year for warfarin, P < 0.001), and overall mortality was also reduced (hazard ratio ¼ 0.89; 95% CI, 0.80e0.99; P ¼ 0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35e0.75; P < 0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74e1.13; P ¼ 0.42).18 The difference of reduction in ischemic strokes in AF with apixaban was not significant. Thus apixaban was superior in comparison with warfarin, reduced stroke and systemic embolism by 21% (P ¼ 0.01), resulted in 31% less bleeding (P < 0.001), and resulted in 11% lower mortality (P ¼ 0.047).18
3.
Other potential frontiers
Besides stroke prevention in AF direct thrombin inhibitor, dabigatran, and FXa inhibitors, rivaroxaban and apixaban newer oral anticoagulants have been studied extensively and held promise in the treatment and prevention of various thrombo-embolic disorders. Recently, several phase III clinical trials (Table 2) have added to the growing evidence that VKAs will most likely be replaced by several novel anticoagulants which will improve substantially the management of venous thrombo-embolism (VTE) prophylaxis and treatment, and acute coronary syndromes (ACS).19
4.
Conclusion
Warfarin has been the treatment of choice to reduce the risk of stroke among moderate-risk and high-risk patients with AF. However, warfarin therapy is significantly underutilized and has several limitations. The net clinical benefit of oral anticoagulant treatment is directly proportional to baseline stroke risk and inversely proportional to bleeding risk. RE-LY trial in conjunction with the ROCKET-AF and ARISTOTLE trial suggests that dabigatran, rivaroxaban and apixaban are at least as safe and efficacious as warfarin in the prevention of stroke and systemic embolism in non-valvular atrial fibrillation. Dabigatran, rivaroxaban and apixaban in comparison with warfarin, all significantly reduced the risk of primary efficacy end point; which included hemorrhagic and ischemic stroke. Out of these three drugs, only dabigatran at a dose of 150 mg twice daily significantly reduced the risk of ischemic stroke as compared with well controlled warfarin. Going forward, we would have options of newer OACs to choose for SPAF. Clinician’s need to tailor the therapy while choosing the right anticoagulant for SPAF. However, without head to head clinical trials, conclusion regarding superiority among the three new oral anticoagulants cannot be drawn, but RE-LY, ROCKET-AF and ARISTOTLE trials demonstrated the potential of these new oral anticoagulants to replace VKAs (warfarin) in future for prevention of stroke and
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systemic embolism in non-valvular atrial fibrillation. Thus newer oral anticoagulant agents (dabigatran, rivaroxaban and apixaban) are going to revolutionize the treatment of stroke prevention in AF, VTE prophylaxis and treatment, and ACS as evident from promising phase III clinical trials.
Conflicts of interest Dr. Nishant Sangole is employed as senior medical advisor (medical affairs division) of Boehringer Ingelheim India Pvt. Ltd.
references
1. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):e531See575S. 2. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22(8):983e988. 3. Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke. 2005;36(6):1115e1119. 4. Medi C, Hankey GJ, Freedman SB. Stroke risk and antithrombotic strategies in atrial fibrillation. Stroke. 2010;41:2705e2713. 5. Hart RG, Halperin JL. Atrial fibrillation and stroke: concepts and controversies. Stroke. 2001;32:803e808. 6. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;154:1449e1457. 7. Testai FD, Aiyagari V. Dabigatran and other oral antithrombotic agents for the prevention of stroke in patients with atrial fibrillation. Res Rep Clin Cardiol. 2011;2:71e81. Available from: http://www.dovepress.com/getfile.php? fileID¼10376. 8. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest. 2008;133:160Se198S. 9. Eriksson BI, Quinlan DJ, Eikelboom JW. Novel oral factor Xa and thrombin inhibitors in the management of thromboembolism. Annu Rev Med. 2011;62:41e57. 10. Weitz JI. Factor Xa and thrombin as targets for new oral anticoagulants. Thromb Res. 2011;127(suppl 2):S5eS12. 11. Hochlt T, Huber K. New anticoagulants for the prevention of stroke in atrial fibrillation. Fundam Clin Pharmacol. 2012;26:47e53. 12. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139e1151. 13. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363:1875e1876. 14. ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factorXa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010;159:340e347.
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15. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883e891. 16. Eikelboom JW, O’Donnell M, Yusuf S, et al. Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. Am Heart J. 2010;159:348e353. e341.
17. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364:806e817. 18. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981e992. 19. Steffel J, Braunwald E. Novel oral anticoagulants: focus on stroke prevention and treatment of venous thromboembolism. Eur Heart J. 2011;32(16):1968e1976.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/jicc
Review article
New oral anticoagulants for stroke prevention in atrial fibrillation: Evidence from phase III clinical trials Pushpraj Patel a,*, Nishant Sangole b a b
Department of Cardiology, Krishna Institute of Medical Sciences, Secunderabad, Hyderabad, India Senior Medical Advisor, Medical Affairs Department, Boehringer Ingelheim (I) Pvt. Ltd., Mumbai, India
article info
abstract
Article history:
Atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia. It
Received 26 June 2012
increases both, the risk and severity of strokes and is associated with substantial
Accepted 27 June 2012
morbidity, mortality, decreased quality of life, and related health care cost and care giver
Available online 9 July 2012
burden. Ischemic strokes among patients with AF are commonly caused by cardioemboli, most commonly from within the left atrial appendage. Vitamin K antagonist (VKA),
Keywords:
warfarin has a long history of benefit and has become the gold standard medication for the
Atrial fibrillation
prevention of ischemic stroke in patients with atrial fibrillation. However due to significant
Dabigatran etexilate
underutilization and several limitations of VKA, novel oral anticoagulants are being
Apixaban RE-LY trial
developed. Recently, new oral anticoagulant drugs that act directly by inhibiting activated
ROCKET-AF trial
coagulation factors such as factor X or thrombin have been developed and investigated in
ARISTOTLE trial
phase III clinical trials. Our review focuses on clinical evidence of direct thrombin inhibitor, dabigatran, and FXa inhibitors, rivaroxaban and apixaban in phase III trials for prevention of stroke and systemic embolism in AF. Copyright ª 2012, Indian College of Cardiology. All rights reserved.
1.
Introduction
Atrial fibrillation (AF) is characterized by irregular, disorganized and chaotic electrical activity of the atrium. It is the most common sustained cardiac arrhythmia in clinical practice.1 Non-valvular AF is associated with a 4e5-fold increase in stroke risk across all age groups and is associated with substantial morbidity, mortality, decreased quality of life, and related health care costs.2,3 The primary clinical significance of AF is its role as a potent independent risk factor for ischemic stroke.1,2 Ischemic strokes among patients with AF are commonly caused by cardioemboli, most commonly from within the left atrial
appendage.4,5 In AF, there is loss of organized atrial contraction which is associated with reduced contractility of the left atrial appendage, stasis in the left atrial appendage (LAA), reduced LAA flow velocities and thrombus formation.4,5 The most established therapy for both primary and secondary prevention of stroke and systemic thromboembolism in patients with atrial fibrillation is anticoagulation with the vitamin K antagonist (VKA), warfarin.1 Pooled data from pivotal trials have found that doseadjusted warfarin reduces the risk of stroke by 68%, from an annual risk of 4.5% (placebo) to 1.4% (warfarin).6 A number of randomized clinical studies have also established the value of warfarin in reducing risk of stroke in patients with AF.1,7
* Corresponding author. Flat No. 2, Laxmi Narayana Apartment, Venkata Rao Nagar Colony, Sindhi Colony, Secunderabad 500003, Andhra Pradesh, India. Tel.: þ91 8801806692. E-mail address: [email protected] (P. Patel). 1561-8811/$ e see front matter Copyright ª 2012, Indian College of Cardiology. All rights reserved. http://dx.doi.org/10.1016/j.jicc.2012.06.004
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Vitamin K antagonists (warfarin) has been the gold standard medication for Stroke Prevention in Atrial Fibrillation (SPAF) but has several limitations that include slower onset and offset of action, complex genetic control of their effect with polymorphisms leading to highly variable individual sensitivity and narrow therapeutic window. In addition, metabolism of VKAs is affected by many factors, including diet, drugs, hepatic dysfunction, other co-morbid conditions and alcohol intake. As a result of these limitations, the doseeresponse relationship of VKAs is unpredictable, and therefore frequent coagulation monitoring is required to maintain the international normalized ratio (INR) between 2.0 and 3.0 and dose-adjustment is needed to ensure efficacy of treatment and to minimize the risk of bleeding complications.8,9 These drawbacks have led to an increase interest to develop novel anticoagulant which would be equally efficacious and safe, but will not require routine laboratory monitoring for dose-adjustment. These new oral anticoagulants (OAC) target two distinct stages in the coagulation cascade, directly inhibiting thrombin (factor IIa) or factor Xa (FXa).9,10 Direct thrombin inhibitor, dabigatran, and FXa inhibitors, rivaroxaban and apixaban are new oral anticoagulants two of which have been approved by the USFDA for SPAF and apixaban will be approved by the USFDA on June 28, 2012. All have been compared to well controlled warfarin (INR 2e3) in phase
III trials for prevention of stroke and systemic embolism in AF.9e11
2. Clinical data: evidence of stroke prevention in atrial fibrillation in phase III trials (Table 1) 2.1.
Dabigatran etexilate
The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial12,13 compared dabigatran etexilate with warfarin for stroke prevention in AF patients. In RE-LY trial,12,13 18,113 patients with non-valvular atrial fibrillation at risk of stroke were randomized in an unblinded fashion to either warfarin with a goal INR of 2.0e3.0, or dabigatran. Patients in the dabigatran group were then randomized in a blinded fashion to receive either 110 mg twice a day or 150 mg twice a day. Patients were followed for a median of 2 years for the primary composite outcome of all stroke (ischemic or hemorrhagic) or systemic embolism. At study end, dabigatran etexilate 110 mg twice a day was non-inferior to warfarin with respect to the primary end point of all stroke (ischemic or hemorrhagic) or systemic embolism, with event rates of 1.54% and 1.71% per year, respectively (non-inferiority
Table 1 e Comparison of phase III clinical trials of stroke prevention in AF (new oral anticoagulants). Phase III clinical trial Drugs AF patients
Design
Primary end point Conclusion
RE-LY Dabigatran (110 mg/150 mg twice daily) Warfarin (INR 2e3) 18,113 patients one risk factor 50% VKA naive CHADS2: 0e1 CHADS2: 2 CHADS2: 3 Open-label warfarin
ROCKET-AF Rivaroxaban (20 mg once a day) Warfarin (INR 2e3) 14,264 patients moderate/high risk CHADS2: 2 CHADS2: 3
ARISTOTLE Apixaban (5 mg twice daily) Warfarin (INR 2e3) 18,201 patients one risk factor Both VKA naive/non-naı¨ve
Randomized, double-blind, dummy design with sham INR
Randomized, double-blind, dummy design with sham INRs Composite: stroke/systemic embolism Composite: stroke/systemic Composite: stroke/systemic embolism embolism -Dabigatran 150 mg twice daily is superior to -Rivaroxaban 20 (or 15) mg -Apixaban 5 (or 2.5) mg warfarin and is associated with lower rates once a day is non-inferior to warfarin twice daily is superior of stroke and systemic embolism, but similar in patients with moderate-to-high to warfarin and is rates of major hemorrhage. risk of stroke. associated with less -Dabigatran 110 mg twice daily is equally -There is no difference in rates bleeding and lower effective and non-inferior to warfarin of major and clinically relevant mortality. with lower rates of major bleeding. nonmajor bleeding between -Apixaban 5 (or 2.5) mg -Dabigatran 110 and 150 mg twice daily treatments. twice daily is associated are associated with lower rates of intracranial -Intracranial haemorrhages occurs with a lower rate of haemorrhages than warfarin. less frequently with rivaroxaban intracranial -TTR: 64.4% (mean). than warfarin. haemorrhages than -All-cause mortality: 12% (P ¼ 0.051). -TTR: 55% (mean). warfarin. There were 3 arms in this study compared -TTR: 62.2% (mean). to ARISTOTLE and hence the sample size All-cause mortality: is lesser in each arm. This could explain 11% better (P ¼ 0.047). the fact that significance was very narrowly missed.
CHADS2 e Congestive cardiac failure, hypertension, age, diabetes, past h/o stroke or transient ischemic attacks; TTR e Time in therapeutic range; INR e International normalized ratio.
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P < 0.001) and in addition, a 35% reduction in risk (two step Hochberg procedure) was observed with dabigatran etexilate 150 mg twice a day (P < 0.001 for superiority, P < 0.001 for noninferiority). Dabigatran etexilate 150 mg twice a day was superior to warfarin for preventing stroke of all types, ischemic (25%) or hemorrhagic (74%) stroke, disabling or fatal stroke, and death (15%) from vascular causes.12,13 The rate of major hemorrhage was significantly lower with dabigatran etexilate 110 mg twice a day compared with warfarin (3.57% per year, P ¼ 0.003), whereas the rate of major hemorrhage with dabigatran etexilate, 150 mg bid (3.32% per year) was non-inferior to warfarin. Rate of intracerebral hemorrhage (ICH) was lower with either dose of dabigatran etexilate than with warfarin, and a reduction of all-cause mortality with dabigatran etexilate, 150 mg bid (3.64% per year and 4.13% per year, respectively) was marginally significant compared to warfarin (P ¼ 0.051). Dabigatran 150 mg twice a day was superior to warfarin in life-threatening bleeding (20%), and total bleeding (9%).12,13 Two new oral factor Xa inhibitors, rivaroxaban and apixaban have been extensively studied in phase III clinical trials as alternatives to warfarin for stroke prevention in high-risk patients with AF.
2.2.
Rivaroxaban
Rivaroxaban was compared with warfarin in patients with high-risk AF in ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).14,15 This trial was a double-blind, double-dummy multi-center randomized control trial. The trial evaluated rivaroxaban once daily versus warfarin to maintain INR of 2.0e3.0 in 14,264 patients with non-valvular atrial fibrillation at moderate-to-high risk for stroke (CHADS2 [congestive cardiac failure, hypertension, age, diabetes, past h/o stroke or transient ischemic attacks] score of 2 or greater). In ROCKET-AF trial,14,15 it was found that rivaroxaban was non-inferior to warfarin for primary efficacy end point,
a composite of stroke and systemic embolism, which occurred in 1.7% and 2.2% of patients on treatment with rivaroxaban and warfarin group (hazard ratio in the rivaroxaban group, 0.79; 95% CI, 0.66e0.96; P < 0.001 for non-inferiority). However, in the intention-to-treat analysis rivaroxaban was not superior to warfarin with events occurring in 2.1% and 2.4% of patients (hazard ratio, 0.88; 95% CI, 0.74e1.03; P ¼ 0.12). The rates of primary safety end point, a composite of major and clinically relevant nonmajor bleeding events, was similar between rivaroxaban and warfarin groups (P ¼ 0.44). However there was significant reduction in intracranial hemorrhage (0.5% vs. 0.7%, P ¼ 0.02) and fatal bleeding (0.2% vs. 0.5%, P ¼ 0.003) in the rivaroxaban group.14,15 Thus ROCKET-AF trial demonstrated that rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolism in AF, but unlike dabigatran, rivaroxaban did not decrease the risk of ischemic stroke.
2.3.
Apixaban
Apixaban has been compared to aspirin in the study AVERROES16,17 (Apixaban versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment). It was a randomized double-blind study involving 5599 patients with a mean CHADS2 score of 2.0 and compared twice daily dose of 5 mg apixaban with 81e324 mg aspirin. The trial was terminated early due to the clear benefit of apixaban over aspirin in reduction of strokes (hazard ratio ¼ 0.45; 95% CI ¼ 0.32e0.62; P < 0.001).16,17 Apixaban has recently been compared to warfarin in the ARISTOTLE trial18 (Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation). This trial involved 18,201 patients with a mean CHADS2 of 2.1 and a median duration of 1.8 years of follow-up. Patients were randomized to a twice daily dose of apixaban (5 mg) or warfarin titrated to an INR of 2.0e3.0. Apixaban was found non-inferior but also superior to warfarin for the prevention of stroke and systemic embolism (hazard ratio ¼ 0.79; CI, 0.66e0.95; P < 0.001 for non-inferiority;
Table 2 e Overview of phase III clinical trials of newer anticoagulants in VTE and ACS. Newer oral anticoagulant Dabigatran
Rivaroxaban
Apixaban
Deep vein thrombosis prevention RE-NOVATE RE-MODEL RE-MOBILIZE RE-MEDY (secondary prevention), RE-SONATE RECORD I RECORD II RECORD III RECORD IV MAGELLAN EINSTEIN e Ext (secondary prevention) ADVANCE 1 ADVANCE 2 ADVANCE 3 ADOPT AMPLIFY-Ext
Deep vein thrombosis treatment
Acute coronary syndromes
RE-COVER RECOVER II
RE-DEEM
EINSTEIN-DVT EINSTEIN-PE
ATLAS TIMI 46
AMPLIFY
APPRAISE
j o u r n a l o f i n d i a n c o l l e g e o f c a r d i o l o g y 2 ( 2 0 1 2 ) 1 1 2 e1 1 6
P ¼ 0.01 for superiority) while also demonstrating a decreased risk of bleeding (hazard ratio ¼ 0.69, 95% CI, 0.60e0.80; P < 0.001). Importantly, the rate of intracranial hemorrhage was significantly lower for apixaban (0.24 vs. 0.47% per year for warfarin, P < 0.001), and overall mortality was also reduced (hazard ratio ¼ 0.89; 95% CI, 0.80e0.99; P ¼ 0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35e0.75; P < 0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74e1.13; P ¼ 0.42).18 The difference of reduction in ischemic strokes in AF with apixaban was not significant. Thus apixaban was superior in comparison with warfarin, reduced stroke and systemic embolism by 21% (P ¼ 0.01), resulted in 31% less bleeding (P < 0.001), and resulted in 11% lower mortality (P ¼ 0.047).18
3.
Other potential frontiers
Besides stroke prevention in AF direct thrombin inhibitor, dabigatran, and FXa inhibitors, rivaroxaban and apixaban newer oral anticoagulants have been studied extensively and held promise in the treatment and prevention of various thrombo-embolic disorders. Recently, several phase III clinical trials (Table 2) have added to the growing evidence that VKAs will most likely be replaced by several novel anticoagulants which will improve substantially the management of venous thrombo-embolism (VTE) prophylaxis and treatment, and acute coronary syndromes (ACS).19
4.
Conclusion
Warfarin has been the treatment of choice to reduce the risk of stroke among moderate-risk and high-risk patients with AF. However, warfarin therapy is significantly underutilized and has several limitations. The net clinical benefit of oral anticoagulant treatment is directly proportional to baseline stroke risk and inversely proportional to bleeding risk. RE-LY trial in conjunction with the ROCKET-AF and ARISTOTLE trial suggests that dabigatran, rivaroxaban and apixaban are at least as safe and efficacious as warfarin in the prevention of stroke and systemic embolism in non-valvular atrial fibrillation. Dabigatran, rivaroxaban and apixaban in comparison with warfarin, all significantly reduced the risk of primary efficacy end point; which included hemorrhagic and ischemic stroke. Out of these three drugs, only dabigatran at a dose of 150 mg twice daily significantly reduced the risk of ischemic stroke as compared with well controlled warfarin. Going forward, we would have options of newer OACs to choose for SPAF. Clinician’s need to tailor the therapy while choosing the right anticoagulant for SPAF. However, without head to head clinical trials, conclusion regarding superiority among the three new oral anticoagulants cannot be drawn, but RE-LY, ROCKET-AF and ARISTOTLE trials demonstrated the potential of these new oral anticoagulants to replace VKAs (warfarin) in future for prevention of stroke and
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systemic embolism in non-valvular atrial fibrillation. Thus newer oral anticoagulant agents (dabigatran, rivaroxaban and apixaban) are going to revolutionize the treatment of stroke prevention in AF, VTE prophylaxis and treatment, and ACS as evident from promising phase III clinical trials.
Conflicts of interest Dr. Nishant Sangole is employed as senior medical advisor (medical affairs division) of Boehringer Ingelheim India Pvt. Ltd.
references
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