Novel Anticoagulants for Stroke Prevention in Atrial Fibrillation. Cardiology Update 2014 William C. Finneran III, MD FACC Cardiology Associates

Transcription

1 Novel Anticoagulants for Stroke Prevention in Atrial Fibrillation Cardiology Update 2014 William C. Finneran III, MD FACC Cardiology Associates

2 Lunch!

3 Disclosure Statement The Reading Hospital and Medical Center Speakers Bureau Medtronic Speakers Bureau Boehringer-Ingelheim Speakers Bureau St. Jude Medical Speakers Bureau Pfizer Speakers Bureau Bristol-Myers Squibb Speakers Bureau

4 Objectives Identify atrial fibrillation as a major cause of thromboembolic stroke Discuss CHADS2/CHADSVASC score for risk assessment Old antithrombotic and antiplatelet agents New anticoagulation agents to prevent stroke Dabigatran Rivaroxaban Apixaban Edoxaban awaiting FDA approval How best to treat my patient?

5 Figure 2. Prevalence of AF in 2 American epidemiological studies. Committee Members et al. Circulation 2001;104: Copyright American Heart Association

6 Figure 3. Relative risk of stroke and mortality in patients with AF compared with patients without AF. Source data are from the Framingham Heart Study (11), Regional Heart Study (8), Whitehall study (8), and Manitoba study (18). Committee Members et al. Circulation 2001;104: Copyright American Heart Association

7 What s with the speaker s nose? Talked back to his wife? Again? Rough Friday night? Again? Bad Irish genes?

8

9 Stroke Risk per annum with CHADS % 1 2.8% 2 4.0% 3 5.9% 4 8.5% % %

10 Stroke Risk per annum with CHA2DS2-VASc 0 0% 1 1.3% 2 2.2% 3 3.2% 4 4.0% 5 6.7% 6 9.8% 7 9.6% 8 6.7% %

11 There s an App for that! AnticoagEvaluator American College of Cardiology

12 Figure 6. Antithrombotic therapy for prevention of stroke (ischemic and hemorrhagic) in patients with nonvalvular AF: adjusted-dose warfarin compared with placebo. Committee Members et al. Circulation 2001;104: Copyright American Heart Association

13 Figure 7. Adjusted odds ratios for ischemic stroke and intracranial bleeding in relation to intensity of anticoagulation in randomized trials of antithrombotic therapy for patients with AF. The data are from Hylek et al (203,207 ). Committee Members et al. Circulation 2001;104: Copyright American Heart Association

14 Figure 8. Antithrombotic therapy for prevention of stroke (ischemic and hemorrhagic) in patients with nonvalvular AF: warfarin compared with aspirin and aspirin compared with placebo. Committee Members et al. Circulation 2001;104: Copyright American Heart Association

15 Figure 1. Patterns of atrial fibrillation. 1, episodes that generally last less than or equal to 7 days (most less than 24 h); 2, usually more than 7 days; 3, cardioversion failed or not attempted; and 4, either paroxysmal or persistent AF may be recurrent. Committee Members et al. Circulation 2001;104: Copyright American Heart Association

16 Atrial Fibrillation and Stroke AF responsible for 1/6 of all strokes Warfarin reduces stroke in AF by 64% significant increase in intracranial and other hemorrhage Difficult to use Only 50% of eligible patients receive warfarin An alternative treatment is needed RE-LY Investigators

17 Advantages of New Anticoagulation Agents No requirement for INR monitoring Less dietary and drug interactions Equal or lower rate of ischemic stroke or major bleeding compared to warfarin

18

19 Mechanism of action of new agents Cios D, Fanikos J Circulation 2012;125:e542-e544 Copyright American Heart Association

20 Randomized Evaluation of Longterm anticoagulant therapy Dabigatran Compared to Warfarin in 18,113 Patients with Atrial Fibrillation at Risk of Stroke

21 Original Article Dabigatran versus Warfarin in Patients with Atrial Fibrillation Stuart J. Connolly, M.D., Michael D. Ezekowitz, M.B., Ch.B., D.Phil., Salim Yusuf, F.R.C.P.C., D.Phil., John Eikelboom, M.D., Jonas Oldgren, M.D., Ph.D., Amit Parekh, M.D., Janice Pogue, M.Sc., Paul A. Reilly, Ph.D., Ellison Themeles, B.A., Jeanne Varrone, M.D., Susan Wang, Ph.D., Marco Alings, M.D., Ph.D., Denis Xavier, M.D., Jun Zhu, M.D., Rafael Diaz, M.D., Basil S. Lewis, M.D., Harald Darius, M.D., Hans- Christoph Diener, M.D., Ph.D., Campbell D. Joyner, M.D., Lars Wallentin, M.D., Ph.D., and the RE-LY Steering Committee and Investigators N Engl J Med Volume 361(12): September 17, 2009

22 Study Overview In a large, randomized trial, two doses of the direct thrombin inhibitor dabigatran were compared with warfarin in patients who had atrial fibrillation and were at risk for stroke At 2 years, the 110-mg dose of dabigatran was found to be noninferior, and the 150-mg dose superior, to warfarin with respect to the primary outcome of stroke or systemic embolism

23 Dabigatran Dabigatran Etexilate, a pro-drug, is rapidly converted to dabigatran 6.5% bioavailability, 80% excreted by kidney Half-life of hours Phase 2 data identified 110 mg BID and 150 mg BID as viable doses

24 Trial Execution Performed December 2005-March 2009 Median Follow up 2.0 years Follow up 99.9% complete Mean TTR = 64% (patients on warfarin)

25 Stroke or Systemic Embolism Dabigatran 110 vs. Warfarin Non-inferiority p-value <0.001 Superiority p-value 0.34 Dabigatran 150 vs. Warfarin <0.001 <0.001 Margin = Dabigatran better HR (95% CI) Warfarin better

26 Ischemic/Unspecified Stroke Cumulative Hazard Rates D 110 mg vs. Warfarin RR = % CI = P = 0.35 D 150 mg vs. Warfarin RR = % CI = P = 0.03 Dabigatran110 Warfarin Dabigatran Years of Follow-up

27 Hemorrhagic Stroke Cumulative Hazard Rates D 110 mg vs. Warfarin RR = % CI = P <0.001 D 150 mg vs. Warfarin RR = % CI = P <0.001 Warfarin Dabigatran110 Dabigatran Years of Follow-up

28 Conclusions Dabigatran 150 mg significantly reduced stoke compared to warfarin with similar risk of major bleeding Dabigatran 110 mg had a similar rate of stroke as warfarin with significantly reduced major bleeding Both doses markedly reduced intra-cerebral, lifethreatening and total bleeding Dabigatran had no major toxicity, but did increase dyspepsia and GI bleeding

29 Dabigatran Oral direct thrombin inhibitor Reduction of risk of stroke and systemic embolism in patients with NVAF No direct reversal agent

30 Dabigatran Dosing 150 mg orally twice a day Cr Clearance > mg orally twice a day Cr Clearance If Cr Clearance < 15 not indicated Cr Clearance determined by Cockroft-Gault equation

31 Mechanism of action of rivaroxaban (Xarelto). Cios D, Fanikos J Circulation 2012;125:e542-e544 Copyright American Heart Association

32 Original Article Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation Manesh R. Patel, M.D., Kenneth W. Mahaffey, M.D., Jyotsna Garg, M.S., Guohua Pan, Ph.D., Daniel E. Singer, M.D., Werner Hacke, M.D., Ph.D., Günter Breithardt, M.D., Jonathan L. Halperin, M.D., Graeme J. Hankey, M.D., Jonathan P. Piccini, M.D., Richard C. Becker, M.D., Christopher C. Nessel, M.D., John F. Paolini, M.D., Ph.D., Scott D. Berkowitz, M.D., Keith A.A. Fox, M.B., Ch.B., Robert M. Califf, M.D., and the ROCKET AF Steering Committee, for the ROCKET AF Investigators N Engl J Med Volume 365(10): September 8, 2011

33 Study Overview In this trial, 14,264 patients with atrial fibrillation were randomly assigned to receive either rivaroxaban or warfarin. In a per-protocol, as-treated analysis, rivaroxaban was noninferior to warfarin with respect to the primary end point of stroke or systemic embolism.

34 Primary Efficacy Outcome Stroke and non-cns Embolism Cumulative event rate (%) Event Rate Rivaroxaban Warfarin Warfarin Rivaroxaban HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 No. at risk: Rivaroxaban Warfarin Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population Days from Randomization

35 Conclusions In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group.

36 Rivaroxaban Oral factor Xa inhibitor Reduction of risk of stroke and systemic embolism in patients with NVAF No direct antidote? Prothrombin complex concentrate

37 Rivaroxaban Dosing 20 mg orally once a day Cr Clearance > 50 ml/min 15 mg orally once a day Cr Clearance 15 ml/min to 50 ml/min Avoid with Cr Clearance < 15 ml/min

38 Original Article Apixaban versus Warfarin in Patients with Atrial Fibrillation Christopher B. Granger, M.D., John H. Alexander, M.D., M.H.S., John J.V. McMurray, M.D., Renato D. Lopes, M.D., Ph.D., Elaine M. Hylek, M.D., M.P.H., Michael Hanna, M.D., Hussein R. Al-Khalidi, Ph.D., Jack Ansell, M.D., Dan Atar, M.D., Alvaro Avezum, M.D., Ph.D., M. Cecilia Bahit, M.D., Rafael Diaz, M.D., J. Donald Easton, M.D., Justin A. Ezekowitz, M.B., B.Ch., Greg Flaker, M.D., David Garcia, M.D., Margarida Geraldes, Ph.D., Bernard J. Gersh, M.D., Sergey Golitsyn, M.D., Ph.D., Shinya Goto, M.D., Antonio G. Hermosillo, M.D., Stefan H. Hohnloser, M.D., John Horowitz, M.D., Puneet Mohan, M.D., Ph.D., Petr Jansky, M.D., Basil S. Lewis, M.D., Jose Luis Lopez-Sendon, M.D., Prem Pais, M.D., Alexander Parkhomenko, M.D., Freek W.A. Verheugt, M.D., Ph.D., Jun Zhu, M.D., Lars Wallentin, M.D., Ph.D., for the ARISTOTLE Committees and Investigators N Engl J Med Volume 365(11): September 15, 2011

39 Study Overview The oral direct factor Xa inhibitor, apixaban, was compared with warfarin in atrial fibrillation. Apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and lowered mortality.

40 Kaplan Meier Curves for the Primary Efficacy and Safety Outcomes. Granger CB et al. N Engl J Med 2011;365:

41 Conclusions In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.

42 Apixaban Dosing 5 mg twice a day 2.5 mg twice a day (> = 2 of the following) > = 80 years of age Weight < = 80 Kg Serum Cr > = 1.5 mg/dl Patients with end-stage CKD on stable hemodialysis 5 mg twice a day Reduction to 2.5 mg twice a day for either age > 80 or body weight < = 60 kg

43

44 AHA/ASA Science Advisory Recommendations October 2012 Prevention of 1 st and recurrent stroke Warfarin Class I Dabigatran Class I Rivaroxaban Class IIa Apixaban Class I Stroke, published online August 2, 2012

45 2014 ACC/AHA/HRS Recommendations (Class. Level of Evidence) CHA2DS2-VASc Score 0 Reasonable to omit antithrombotic therapy (IIa,B) CHA2DS2-VASc Score 1 No antithrombotic therapy or treatment with an oral anticoagulant or aspirin may be considered (IIb,C) CHA2DS2-VASc Score >= 2 Oral anticoagulants recommended Warfarin (I,A) Novel anticoagulants Dabigatran, Rivaroxaban, Apixaban (I,B)

46

47 Timing After Acute Stroke Warfarin Small or moderate sized infarct start post 24hrs Large infarct, hemorrhagic transformation, uncontrolled hypertension start post 2 weeks Dabigatran RE-LY Trial excluded stroke within 14 days or severe stroke within 6 months before screening Rivaroxaban ROCKET-AF excluded severe stroke within 3 months, any stroke within 14 days ROCKET-AF excluded TIA within 3 days

48 Case Study # 1 78 year old female presents to your office on Friday afternoon at 4:55 PM Complains of palpitations EKG shows atrial fibrillation Hypertension BP 152/78 Diabetes Mellitus No history of CHF No history of prior stroke or TIA

49 Case Study # 1 CHADS2 Score 3 HTN, age > 75, DM Annual risk of stroke without anticoagulation (warfarin) 5.9% CHA2DS2-VASc Score 5 HTN, age > 75, DM, female Annual risk of stroke 6.7%

50 Warfarin Dabigatran Rivaroxaban Apixaban Case Study # 1 Treatment Options?

51 Case Study # 2 66 year old male with hx of bicuspid aortic valve, severe AS Status post mechanical AVR Seen in office follow up 1 month post-op Patient says he hates warfarin wants new drug he saw on TV Can you switch to new anticoagulant?

52 Case Study # 2 RE-ALIGN Trial Results Evaluation of long term safety of the use of Dabigatran in patients with a bileaflet mechanical heart valve 252 patients, years old Study stopped December 2012 Tx with Dabigatran resulted in a higher number of thromboembolic and bleeding events compared to warfarin Published NEJM 9/1/2013

53 Case Study # 2 RE-ALIGN Trial Results Advise patient to stay on warfarin Mechanical heart valves induce coagulation activation and thrombin generation by exposure of blood to the artificial surfaces and sewing ring Atrial fibrillation low blood flow, stasis, endothelial dysfunction Warfarin also inhibits synthesis of Factor IX, Dabigatran exclusively inhibits thrombin Fran Van Der Werf, MD PhD, lead investigator of RE-ALIGN

54 What about Cardioversion with the new anticoagulants?

55 What about Cardioversion with the new anticoagulants? Post-hoc analysis of ROCKET AF Incidence of electrical CV, pharmacologic CV, AF ablation 143 pts. ECV, 142 pts. PCV, 79 AF ablation No long term differences in stroke rates following CV or AF ablation Similar outcomes with rivaroxaban or warfarin Piccini, et al., J Am Coll Cardiol 2013; 61(19):

56 What about Cardioversion with the new anticoagulants? Cardioversion in RE-LY Trial 1983 Cardioversions in 1270 pts. Frequencies of stroke and major bleeding on dabigatran 110 mg and 150 mg within 30 days of CV was low c/w warfarin (0.8%, 0.3%, and 0.6%) Comparable to warfarin with/without TEE guidance Dabigatran reasonable alternative to warfarin for CV Nagarakanti et. al., Circulation. 2011; 123:

57 Dabigatran Versus Warfarin in Patients With Atrial FibrillationClinical Perspective Circulation Volume 123(2): January 18, 2011 Copyright American Heart Association

58 Time of primary outcome events after cardioversion. Nagarakanti R et al. Circulation 2011;123: Copyright American Heart Association

59

60 Ten Points to Remember for the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation Summary Prepared by Aman Chugh, MD

61 Point 1 In assessing risk of stroke in a patient with nonvalvular AF, the writing committee recommends (Class I) the usage of the CHA 2 DS 2 -VASc (C=congestive heart failure; H=hypertension; A 2 =age 75 years [doubled]; D=diabetes mellitus; S 2 =stroke, transient ischemic attack, or thromboembolism (doubled); V=vascular disease; A=age years; Sc=sex category, i.e., female gender) score, as opposed to the CHADS 2 score.

62 Point 2 For nonvalvular AF patients with a history of stroke or transient ischemic attack, or a CHA 2 DS 2 -VASc score 2, oral anticoagulation is recommended (Class I). Options for oral anticoagulation include warfarin, dabigatran, rivaroxaban, and apixaban.

63 Point 3 For patients with nonvalvular AF and a CHA 2 DS 2 -VASc score of 0, it is reasonable to omit antithrombotic therapy (Class IIa).

64 Point 4 The following options may be considered with a patient with nonvalvular AF and a CHA 2 DS 2 - VASc score of 1: no antithrombotic therapy, oral anticoagulation, or aspirin (Class IIb).

65 Point 5 None of the new novel oral anticoagulants (dabigatran, rivaroxaban, or apixaban) are recommended to be used in patients with AF and a mechanical or bioprosthetic heart valve (Class III harm).

66 Point 6 As in the earlier guidelines, the committee recommends against the use of certain antiarrhythmic medications (flecainide, propafenone, dofetilide, and sotalol) in patients with severe left ventricular hypertrophy (LVH). In the current guidelines, severe LVH is now defined as wall thickness exceeding 1.5 cm.

67 Point 7 Oral anticoagulation should be prescribed to patients with hypertrophic cardiomyopathy and AF irrespective of the CHA 2 DS 2 -VASc score (Class I).

68 Point 8 A randomized trial suggested that a lenient (<110 bpm) rate control strategy was as effective as a strict strategy (<80 bpm) in patients with persistent/permanent AF. However, the writing committee still advocates for the latter (Class IIa), as the results of this single trial were not thought to be definitive.

69 Point 9 Catheter ablation is useful in patients with symptomatic, paroxysmal AF who have not responded to or tolerated antiarrhythmic medications (Class I).

70 Point 10 Catheter ablation is also reasonable in selected patients with symptomatic, paroxysmal AF prior to a trial of medical therapy, provided that it can be performed at an experienced center (Class IIa).

71 Questions?