New Anticoagulation Options for Stroke Prevention in Atrial Fibrillation. Joy Wahawisan, Pharm.D., BCPS April 25, 2012

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1 New Anticoagulation Options for Stroke Prevention in Atrial Fibrillation Joy Wahawisan, Pharm.D., BCPS April 25, 2012

2 Stroke in Atrial Fibrillation % Stroke 1991;22:983. Age Range (years)

3 CHADS 2 Risk Score Risk Factor Score (points) CHF 1 Hypertension 1 Age 75 1 Diabetes Mellitus 1 Stroke or TIA 2 JAMA 2001;285(22): CHADS 2 Score Adjusted Stroke Rate (%/year)

4 ACC/AHA/ESC Guidelines on Antithrombotic Therapy No risk factors CHADS 2 = 0 Risk Factor Recommended Therapy Aspirin mg One moderate risk factor CHADS 2 = 1 Aspirin mg or warfarin (INR 2 3, target 2.5) Any high risk factor, or more than one moderate risk factor CHADS 2 = 2 + Warfarin (INR 2 3, target 2.5) JACC 2011;57(2): Eur Heart J 2010;. Circulation 2006;114:e257-e354.

5 Efficacy and Safety of Warfarin Ischemic Stroke Odds Ratio 1 INR Ann Intern Med 2004;141: NEJM 1996;335:540-6.

6 Warfarin: Mechanism of Action Intrinsic Pathway exposed collagen Extrinsic Pathway vessel injury IX IXa X VII VIIa Prothrombin (II) Xa Thrombin (IIa) Fibrinogen Fibrin Cross linked fibrin clot

7 Limitations of Warfarin Delayed onset/offset Multiple food and drug interactions Genetic variability (VKORC1, CYP 2C9) Variability in metabolism requiring dosage adjustments Requires frequent monitoring of INR due to narrow therapeutic index

8 Good things about warfarin Oral, once daily dosing No renal adjustment needed Antidotes available (vitamin K, FFP, PCC)

9 Updates to the AF Guidelines, 2011 New recommendation (Class IIb): The addition of clopidogrel to aspirin might be considered in patients in whom warfarin is considered unsuitable Based upon ACTIVE-A and ACTIVE-W trials J Am Coll Cardiol 2011;57:

10 ACTIVE-A & ACTIVE-W ACTIVE-W Clopidogrel+ASA vs. warfarin for stroke prevention 5.6% clopidogrel+asa vs. 3.93% warfarin annual risk Similar bleeding risk ACTIVE-A Clopidogrel+ASA vs. ASA for stroke prevention in those unsuitable for warfarin 6.8% clopidogrel+asa vs 7.6% ASA annual risk of major vascular events 2.4% clopidogrel+asa vs 3.3% ASA annual risk for stroke More major bleeding with dual therapy 2% vs. 1.3%/year ACTIVE-W Lancet 2006;367: ACTIVE-A NEJM 2009;360:

11 Anticoagulant Development 2010 FDA approved dabigatran (Pradaxa ) for stroke prevention in AF 1954 Warfarin approved by FDA 2003 Ximelagatran (Exanta ) halted by FDA due to liver damage (SPORTIF III, V) 2011 Rivaroxaban (Xarelto ) FDA approved for stroke prevention in AF

12 Anticoagulant Development, Aug Results from ARISTOTLE presented at ESC proving apixaban superior over warfarin for stroke prevention in AF Spring 2012 Many reports published concerning safety of dabigatran July 2011 Rivaroxaban FDA approved for ortho prophylaxis Nov 2011 Rivaroxaban FDA approved for stroke prevention in AF June 2012 FDA expected to make decision regarding apixaban approval

13 New anticoagulant options Dabigatran (Pradaxa ) Approved Oct 2010 for stroke prevention in AF Rivaroxaban (Xarelto ) Approved 2011 for stroke prevention in AF and prophylaxis of hip/knee replacement surgery Apixaban (Eliquis ) Major phase 3 clinical trial recently published in NEJM showing superiority to warfarin for stroke prevention in AF

14 Dabigatran Oral direct thrombin inhibitor Rapid onset of action Dabigatran Xa Prothrombin (II) Thrombin (IIa) Fibrinogen Fibrin Cross linked fibrin clot

15 Pros Rapid onset of action Predictable and consistent anticoagulant effects Low potential for drug-drug interactions No drug-food interactions No requirement for routine coagulation monitoring Cons Renally eliminated no clinical trial data on patients with renal impairment (only PK data) Not good for GI patient population Currently expensive - $9/day (cash) (S&W tier 2, prior auth required - $25/month) No antidote No test for patient compliance

16 Open-label RCT RE-LY, 2009 Dabigatran 150 mg PO BID vs. warfarin (INR target 2 3) TTR: 64% Characteristic Dabi 150 mg BID Warfarin Mean age NEJM 2009;361(12): Mean CHADS 2 score 0 1 (%) 2 (%) 3 + (%)

17 Results from RE-LY Superior in efficacy Yearly stroke rate: 1.11% dabi vs. 1.69% warfarin Similar bleeding profile Major bleeding/year: 3.11% dabi vs. 3.36% warfarin (RR 0.93; 95% CI ; p=0.31) Less intracranial bleeding 0.3%/year dabigatran vs. 0.74%/year warfarin No difference in mortality (p=0.051) NEJM 2009;361(12):

18 Post-marketing issues that have come up with dabigatran GI bleeding RE-LY: 1.51% dabigatran vs. 1.02% warfarin (RR 1.5, 95% CI ; P<0.001) Especially in elderly? ISMP report of 505 cases of serious bleeding in first quarter of 2011 (median age of patients = 80 years) New Zealand 78 cases of bleeding: 4 major factors 1. Prescriber error 2. Impaired renal function 3. Advanced age > Complications from lack of reversal agent NEJM 2012;366(9): ISMP. < Accessed March 26, 2012.

19 ...but how does that compare with warfarin? Of an estimated 99,628 cases of emergency hospitalizations per year in adults > 65 due to adverse drug events......warfarin accounted for 33.3% N = 32,877 cases/year in adults > 65 NEJM 2011;365(21):

20 CHEST 2012 Guidelines on Antithrombotic Therapy in Atrial Fibrillation Recommendation : For patients with AF, including those with paroxysmal AF, [with a CHADS2 score of 1 or above], we suggest dabigatran 150 mg twice daily rather than adjusted-dose vitamin K antagonist therapy (Grade 2B). CHEST 2012;141(2)(Suppl):e531S-e575S.

21 Rivaroxaban (Xarelto ) Direct, competitive, oral factor Xa inhibitor Once daily dosing Adjust for CrCl < 50 ml/min (15 mg) Xa Prothrombin (II) Thrombin (IIa) Fibrinogen Fibrin Cross linked fibrin clot

22 ROCKET-AF, 2011 Double blind, double dummy Rivaroxaban 20 mg PO daily vs. warfarin TTR = 57.8% Characteristic Riv 20 mg daily Warfarin Mean age NEJM 2011;365: Mean CHADS 2 score 0 1 (%) 2 (%) 3 + (%)

23 Results from ROCKET-AF Non-inferior in efficacy Yearly stroke rate: 1.7% riv vs. 2.2% warfarin (p<0.001 for non-inferiority) Similar bleeding profile Major bleeding/year:14.9% riv vs. 14.5% warfarin (HR 1.03; 95% CI ; P = 0.44) Less intracranial bleeding 0.5% rivaroxaban vs. 0.7% warfarin (P=0.02) No difference in mortality (P=0.07) NEJM 2011;365:

24 Primary Efficacy Outcomes by Quartile TTR Rivaroxaban Events (%) Warfarin Events (%) HR (95% CI) % ( ) % ( ) % ( ) % ( ) Time in therapeutic range not a surrogate marker for anticoagulation benefit

25 Is there a reversal agent for rivaroxaban? Most likely: prothrombin complex concentrate (PCC) Healthy volunteers received rivaroxaban or dabigatran daily until therapeutic, then followed by PCC 50 IU/kg Immediate, complete reversal of rivaroxaban as measured by prothrombin time (15.8 sec to 12.8 sec baseline) Effect was sustained for 24 hours No effect on dabigatran treated patients Circulation 2011;124:

26 Apixaban (Eliquis ) Direct, competitive, oral factor Xa inhibitor Twice daily dosing NOT yet FDA approved Xa Prothrombin (II) Thrombin (IIa) Fibrinogen Fibrin Cross linked fibrin clot

27 ARISTOTLE, 2011 Double blind, double dummy Apixaban 5 mg PO BID vs. warfarin TTR = 62.2% Characteristic Apix 5 mg BID Warfarin Mean age NEJM 2011;365: Mean CHADS 2 score 0 1 (%) 2 (%) 3 + (%)

28 Results from ARISTOTLE Superior in efficacy Yearly stroke rate: 1.27% apixaban vs. 1.6% warfarin (p=0.01 for superiority) Causes less bleeding Major bleeding/year: 2.13% apix vs. 3.09% warfarin (HR 0.69; P<0.001) Less intracranial bleeding 0.33% apixaban vs. 0.8% warfarin (HR 0.42; P<0.001) Lower mortality 3.52% apixaban vs. 3.94% warfarin (HR 0.89; P=0.047) NEJM 2011;365:

29 RE-LY ROCKET-AF ARISTOTLE Efficacy: stroke or systemic emboli (%) Dabigatran 150 mg bid Warfarin Rivaroxaban 20 mg daily Warfarin Apixaban 5 mg bid Warfarin Superior Non-inferior Superior Safety: Intracranial bleeding (%) Overall mortality No difference No difference Mean CHADS

30 Future directions Very elderly More data needed for kidney dysfunction All renally eliminated Dose reductions based upon PK data Poor medication adherence? Rebound effect noted with rivaroxaban Half life 5 9 hours should it be BID??

31 What do they all have in common? High cost will be a barrier All are equal or better than warfarin All have similar or better safety profiles than warfarin All decrease hemorrhagic strokes All are renally excreted

32 Who should be switched? Patients with a high bleeding risk on warfarin Those unable to achieve a high TTR Patients who do not want warfarin due to diet or medication interactions Those who do not want to monitor