Atrial Fibrillation and Stroke. Stroke Collaborative 2012

Transcription

1 Atrial Fibrillation and Stroke Stroke Collaborative 2012 Robert Hart, M.D. Stroke Neurology McMaster University Hamilton Health Sciences Hamilton, Ontario

2 Conflict Disclosure Information 2 FINANCIAL DISCLOSURES - Operations/Stroke Advisory/Publication Committees for the AVERROES (apixaban) Bristol Myers-Squibb - Research grant for analysis of intracranial hemorrhages in the RE-LY trial (dabigatran) Boehringer Ingelheim - Consultant for mock-fda advisory panel ROCKET AF (rivaroxaban) Bayer / Johnson & Johnson

3 Why is this man relevant to this lecture?

4 Einthoven (1904) pulsus inaequalis et irregularis (a.k.a. atrial fibrillation)

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6 British Medical Journal 1909; 2: Auricular fibrillation: a common clinical condition. Sir Thomas Lewis

7 The immobility of the auricular walls makes them defenceless against thrombotic deposits, as a horse should be against flies without his cutaneous muscles. Acta Medica Scanda 1948

8 Serial sections of the left atrial appendage were prepared [in AF-patients with embolic stroke] in every case mural thrombus, not obvious to the naked eye, was found in the interstices of the trabeculae carneae. C.M. Fisher. Can Med Assoc J 1953; 69: (b. Waterloo, Ontario)

9 1951 Advertisement for Warfarin

10 Leisure World study Circulation 1968 There was a stronger association of stroke with AF than with other cardiac abnormalities, suggesting that [nonvalvular] AF in the elderly is an important precursor of stroke and should not be regarded lightly.

11 Sir: The Lancet 1972 Letter-to-the-Editor In our cerebrovascular studies, we have been struck by the number of patients in atrial fibrillation who have a severe stroke as the first manifestation of embolism. All patients with chronic atrial fibrillation should be considered for prophylactic anticoagulant therapy to avoid a fate worse than death itself. C.M. Fisher, M.D.

12 Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: The Framingham Study Wolf PA, Dawber TR, Thomas HE et al. Neurology 1978; 28: During 481 person-years of follow-up of idiopathic [nonvalvular] AF, there were 20 instances of stroke This rate of 41.48/1000 person-years was 5.6 times as frequent in men and women of the same age and blood pressure distribution who were free of AF.

13 Frequency of AF in Stroke Patients: Framingham Study Age Group % of Total Strokes % % % % Wolf PA et al. Framingham Study, STROKE 1985

14 Common Causes of Ischemic Stroke Intracranial Atherosclerosis Small Artery Disease Carotid Plaque with Emboli Carotid Stenosis Aortic Arch Plaque Atrial Fibrillation Valve Disease Cardiogenic Emboli Ventricular Thrombi

15 Atrial Fibrillation 16% of brain infarcts Aortic Arch Plaque Carotid Atherosclerosis Other Heart Disease Cerebral Small Artery Disease Left Atrial Thrombi 12% of brain infarcts (3/4ths of AF-associated stroke)

16 Autopsy, Bexar County Hospital (1983) (no thrombi detected by precordial echocardiography)

17 Embolic occlusion of the basilar artery

18 AF and Stroke 1 of every 6 ischemic strokes. About 100,000 patients with AF suffer a stroke yearly in the U.S. Pathogenesis: most due to embolism of left atrial appendage thrombi. By the mid-1980s, the stage was set for randomized trials testing antithrombotic agents for stroke prevention.

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20 Stroke Prevention in Atrial Fibrillation SPAF I (SPAF) Trials (NINDS/NIH) N Years Warfarin vs. placebo ASA vs. placebo SPAF II Warfarin vs. ASA, <75 yrs Warfarin vs. ASA, >75 yrs SPAF III Warfarin vs. ASA + warfarin ASA low-risk cohort

21 30 RCTs of Antithrombotic Rx in Atrial Fibrillation AFASAK I BATAF SPAF I CAFA SPINAF EAFT SPAF II SPAF III SIFA ESPS II AFASAK II Chinese ATAFS PETRO WASPO - 75 UK-TIA - 49 MWNRAF PATAF JNAFESP FFAACS Hiedelberg - 75 SPORTIF II LASAF SPORTIF III SPORTIF V SAFT JAST NASPEAF ACTIVE-W Athens - 45 BAFTA - 973

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25 Metanalysis of 30 Randomized Trials Comparison # trials # pts # strokes* Relative risk reduction Adjusted-dose warfarin vs. control Antiplatelet agents vs. placebo Adjusted-dose warfarin vs. antiplatelet agents 6 2, % (49,74) 8 4, % (6,35) 12 12, % (27,49) *Ischemic strokes and intracranial hemorrhages. Hart RG, Pearce LA, Aguilar MI. Ann Intern Med 2007: 146:

26 Metanalysis of Randomized Trials: Death Comparison Adjusted-dose warfarin vs. control Relative risk reduction in allcause mortality (95%CI) 26% (3,43) Aspirin vs. placebo 14% (-7,31) Adjusted-dose warfarin vs. aspirin 9% (-19,30) Hart RG, Pearce LA, Aguilar MI. Ann Intern Med 2007: 146: 857.

27 Harenberg J. Semin Thromb Hemost. 2009;35: New Oral Anticoagulants Factor Xa Inhibitors and Direct Thrombin Inhibitors Tissue Factor/VIIa X IX VIIIa Va Xa IXa Rivaroxaban Betrixaban Apixaban YM150 Edoxaban II IIa Dabigatran AZD-0837 Fibrinogen Fibrin

28 Phase III Trials of Novel Oral Anticoagulants RE-LY (2009): direct thrombin inhibitor dabigatran 110mg and 150mg twice daily vs. adjusted-dose warfarin (open-label) in 18,113 patients. AVERROES (2011): factor Xa inhibitor apixaban 5mg twice daily vs. aspirin (double-blind) in 5,599 patients. ROCKET AF (2011): factor Xa inhibitor rivaroxaban 20mg daily vs. adjusted-dose warfarin (double-blind) in 14,264 patients. ARISTOTLE (2011): factor Xa inhibitor apixaban 5mg twice daily vs. adjusted-dose warfarin (double-blind) in 18,201 patients

29 Stroke or systemic embolism Stroke or Systemic Embolism Dabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg QD Apixaban 5 mg BID Superiority p-value 0.29 < Ischemic Stroke Dabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg QD Apixaban 5 mg BID HR (95% CI) Comparator better Warfarin better Connolly SJ, et al. NEJM 2009; Alexander J, et al. NEJM 2011; Mahaffey K, et al. NEJM 2011

30 Intracerebral Hemorrhage

31 Anticoagulation in Atrial Fibrillation Pts: Intracranial Bleeding is the Deal-Breaker (Fang MC et al. Am J Med 2007; 120: 700) ~30% of major bleeds on warfarin are intracranial. ATRIA cohort from Kaiser Permanente in late 1990s: 15,370 pt-yrs of warfarin Rx. 72 intracranial bleeds: 76% severe disability or fatal. 98 major extracranial bleeds - 3% severe disability or fatal. 88% of deaths from warfarin-associated bleeding due to intracranial hemorrhage.

32 Recent Oral Anticoagulation Trials: Hemorrhagic Stroke P Value Dabigatran 110 mg BID P <.001 Dabigatran 150 mg BID P <.001 Rivaroxaban 20 mg QD P =.024 Apixaban 5 mg BID P < New Agent Better Connolly SJ, et al. N Engl J Med. 2009;361: Patel MR, et al. N Engl J Med. 2011;365: Granger C, et al. N Eng J Med. 2011;365: HR (95% CI) Warfarin Better

33 Intracranial hemorrhages in the RE-LY RCT (Hart RG, Diener H-C et al. Stroke 2012; 43: ) Warfarin Dabigatran 150 mg Dabigatran 110 mg All intracranial Intracerebral - spontaneous - traumatic 46^ Subdural - spontaneous - traumatic Subarachnoid - spontaneous - traumatic *Intention-to-treat results; on-treatment results similar. Red = p<0.05 vs. warfarin. ^Rate = 0.4%/yr

34 Guidelines 2012 European Society of Cardiology 2012 One of the new OACs, either a DTI or an oral fxa inhibitor should be considered rather than dose-adjusted VKA for most patients (IIaA) AHA/ASA 2012 Warfarin (1A), dabigatran (1B), apixaban (1B) and rivaroxaban (IIaB) are indicated for the prevention of stroke in non-valvular AF Camm AJ, et al. Eur Heart J 2012 (On line) Furie KL, et al. Stroke 2012 (On line)

35 Guidelines 2012 Canadian Cardiovascular Society 2012 we suggest that most patients should receive dabigatran, rivaroxaban or apixaban in preference to warfarin... American College of Chest Physicians 2012 we suggest dabigatran 150 mg bid rather than adjusted-dose VKA therapy (2B). You JJ, et al. Chest 2012; 141: e531s-575s Skanes AC, et al. Can J Cardiol 2012; 28:

36 Stroke risk reductions from randomized trials of antithrombotic agents in atrial fibrillation. Granger C B, Armaganijan L V Circulation 2012;125: Copyright American Heart Association

37 Atrial Fibrillation and Stroke Surprisingly long delay in recognition of stroke risk and developing preventive treatment. 1 of 6 ischemic strokes; most are disabling and embolic. Warfarin with INR 2-3 eliminates the excess risk of stroke with AF (but achieving optimal TTR is difficult). Atrial fibrillation is a common cause of preventable disabling stroke.

38 Atrial fibrillation and Stroke Novel selective oral anticoagulants are at least as efficacious and with reduced risk of intracranial hemorrhage (ICH). Reduced ICH & novel anticoagulants: large, unexpected, consistent, huge importance. Stroke risk stratification identifies who benefit most vs. least from anticoagulation: CHADS 2 traditional, CHA 2 DS 2 -VASc more reliably identifies 10% with very low risk.