Anticoagulation: A Changing Landscape. Kelly Matsuda Pharm.D. July 16, Kelly Matsuda Pharm.D. July 16, 2011

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1 Anticoagulation: A Changing Landscape Kelly Matsuda Pharm.D. July 16, 2011 Kelly Matsuda Pharm.D. July 16, 2011

2 Objectives Review epidemiology of stroke/tia and atrial fibrillation. Review of warfarin and in Stroke and atrial fibrillation. Published Clinical Data with the new and agents studied in atrial fibrillation.

3 Atrial Fibrillation: A Risk Factor for Vascular Events RISK FACTORS: THROMBOSIS Hypertension Hyperlipidemia Age Diabetes Mellitus Smoking Atherosclerosis/Atherothrombosis MI AF CHF CHF Stroke, MI, Vascular Death Wolf PA et al. Arch Intern Med 1987; 147: Leckey R et al. Can J Cardiol 2000; 16:

4 Prevalence, percent AF Prevalence: Age and Gender Prevalence of AF increases with age; men > women JAMA 2001; 285: 2370 Age, years

5 The Percentage of Strokes Attributable to AF Increases with Age Framingham Study 30 % AF prevalence Strokes attributable to AF Age Range (years) Wolf et al. Stroke 1991; 22:

6 Mortality Rates in AF Double the overall age and gender matched population No reduction in past two decades Mortality 9-fold higher during 1 st 4 months after diagnosis Miyasaka Y, et al. JACC 2007; 49:

7 Blood Flow in Atrial Fibrillation Disturbed Flow (left atrium) Stroke Risk

8 Intrinsic Pathway HMW Kininogen Pre-kallikren Kallikren Extrinsic Pathway Tissue Injury XII XI XIIa XIa Tissue Factor IX IXa VII VIIa VIII VIIIa Tenase IXa VIIa Ca ++ VIIa Tissue Factor Ca ++ X Xa X

9 Common Pathway Prothrombinase Xa Va Ca ++ Prothrombin Thrombin Fibrinogen Fibrin

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12 Properties of an Ideal anticoagulant Properties Orally active Rapid onset of action No food drug interaction or drug drug interactions Predictable anticoagulant effect Extra renal clearance Rapid offset of action Safe antidote Benefits Ease of administration Obviates need for overlap with parenteral anticoagulant Simplified dosing No routine anticoagulation monitoring Safe in patients with renal insufficiency Simplifies management in case of bleed or intervention Useful in case of major bleed Favorable net clinical benefit risk Treatment benefit outweighs risk

13 WARFarin trivia outbreak1920s cattle bled from minor procedure or spontaneously Dr. Schofield, cattle ingesting moldy silage made from sweet clover. repeat experiment in rabbits, one with damaged clover and one with undamaged clover, nothing happened to undamaged group, damaged group died Dr. Rodrick demonstrated it was lack of functioning prothrombin 1933 U Wisconsin- -Dr. Link and students (campbell and stahmann) 4-hydroxy-coumarin later named dicoumarol. Dicoumarol is plant product of coumarin from spoiled sweet clover 1948 Dr link went on to develop rodenticides which coumarin was used in a potent form. WARF stems from Wisconsin Alumi Research Foundation, the ARIN is a link with coumarin. Widely used anticoagulant today

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15 Antithrombotic Therapy for Atrial Fibrillation ACC/AHA/ESC Guidelines 2006 Risk Category No risk factors CHADS 2 = 0 One moderate risk factor CHADS 2 = 1 Any high risk factor or >1 moderate risk factor CHADS 2 >2 or mitral stenosis Prosthetic valve Recommended Therapy Aspirin, mg qd Aspirin, mg/d or Warfarin Warfarin (INR , target 2.5) Warfarin (INR , target 3.0) Fuster V, et al. Eur Heart J 2006;27:1979.

16 Sites of Antithrombotic Action Fondaparinux Rivaroxaban Apixaban endoxaban Heparin LMWHs AT AT AT Bivalirudin Hirudin Argatroban Dabitgatran Tissue factor Plasma clotting cascade Factor Xa Prothrombin Thrombin (IIa) Fibrinogen Aspirin Platelet activation Platelet aggregation Fibrin Collagen Thromboxane A 2 ADP Clopidogrel Prasugrel Eptifibatide Abciximab Tirofiban (GPB) Fibrinolytics Thrombus

17 Why do we need another warfarin management lecture? Warfarin therapy is: Highly effective Complex to manage Underutilized When utilized, managed poorly but effective solutions have evolved.

18 Conventional Anticoagulants properties Warfarin UFH LMWH fondaparinux Mode of Action Vitamin K antagonist Indirect factor IIa and Xa inhibitor Indirect factor Xa and minor IIa inhibitor Indirect Xa inhibitor Bioavailability 100 % 100% 100% 100% Peak action ( t max) 4-5 days Iv: immediate Sq: min Sq 2-4 hours enox Sq 2.9 hours dalt Sq 4 hours tinz Sq 2-4 hours Elimination half life ( t 1/2) ) hours hours 3-4 hours hours Route of elimination Multiple Reticulendothel ial system > 80% renal 100% renal Involvement of CYP Yes No No No J Douketis, Curr pharma design 2010:16:3426 UFH=unfractionated heparin, LMWH= low molecular weight heparin ( enox=enoxaparin, dalt=dalteparin,nz=tinz=tinzaparin

19 Properties Fondaparinux Argatroban lepirudin Mode of action Conventional anticoagulants Xa IIa IIa Bioavailability 100% 100% 100% Peak action 2-4 hours 1-3 hours Elimination half life (t 1/2 ) Route of elimination Involvement of CYP hours hours 1 hour 100% renal 100% hepatic 100% no Minor cyp majority thru hydroxylation aromatization no

20 Problems with Warfarin 1. Delayed onset/offset 2. Unpredictable dose response 3. Narrow therapeutic index 4. Drug-drug, drug-food interactions 5. Problematic monitoring 6. High bleeding rate 7. Slow reversibility

21 Risk of Intracranial Hemorrhage in Outpatients Adapted from: Hylek EM, Singer DE, Ann Int Med 1994;120: Hylek, et al, studied the risk of intracranial hemorrhage in outpatients treated with warfarin. They determined that an intensity of anticoagulation expressed as a prothrombin time ratio (PTR) above 2.0 (roughly corresponding to an INR of 3.7 to 4.3) resulted in an increase in the risk of bleeding.

22 Lowest Effective Intensity for Warfarin Therapy for Stroke Prevention in Atrial Fibrillation INR below 2.0 results in a higher risk of stroke Hylek EM, et al. NEJM 1996;335:

23 Odds Ratio Therapeutic Range for Warfarin INR Values at Stroke or ICH Stroke Intracranial Hemorrhage INR Fuster et al. J Am Coll Cardiol. 2001;38:

24 Anticoagulation in Atrial Fibrillation Stroke Risk Reductions Warfarin Better Control Better AFASAK SPAF BAATAF CAFA SPINAF EAFT Aggregate 100% 50% 0-50% -100% Hart R, et al. Ann Intern Med 2007;146:857.

25 Anticoagulation in Atrial Fibrillation The Standard of Care for Stroke Prevention Warfarin Better Control Better AFASAK SPAF BAATAF Unblinded Unblinded Unblinded CAFA Terminated early SPINAF EAFT Double-blind; Men only 2 o prevention; Unblinded Aggregate 100% 50% 0-50% -100% Hart R, et al. Ann Intern Med 2007;146:857.

26 J Douketis, Curr pharma design 2010:16:3426 New Anticoagulants Properties Dabigatran Rivaroxaban Apixaban Mode of action Direct factor IIA (thrombin inhibitor) Direct factor Xa inhibitor Bioavailability 6.5% 80% 80% Direct factor Xa inhibitor Peak action 1-3 hours 1-3 hours 1-3 hours Elimination half life (t ½) Route of elimination Involvement of CYP hours 9-15 hours 9-14 hours 100% renal 65% renal 25% renal Minor Minor Minor

27 Sites of Antithrombotic Action for Thrombin inhibitors Fondaparinux Rivaroxaban Apixaban endoxaban Heparin LMWHs AT AT AT Bivalirudin Hirudin Argatroban Dabitgatran Tissue factor Plasma clotting cascade Factor Xa Prothrombin Thrombin (IIa) Fibrinogen Aspirin Platelet activation Platelet aggregation Fibrin Collagen Thromboxane A 2 ADP Clopidogrel Prasugrel Eptifibatide Abciximab Tirofiban (GPB) Fibrinolytics Thrombus

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29 Baseline Characteristics Characteristic Dabigatran 110 mg Dabigatran 150 mg Warfarin Randomized Mean age (years) Male (%) CHADS2 score (mean) 0-1 (%) 2 (%) 3+ (%) Prior stroke/tia (%) Prior MI (%) CHF (%) Baseline ASA (%) Warfarin Naïve (%)

30 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 = HR (95% CI) Warfarin better Dabigatran better

31 1 0 Outcome: Superiority Analysis D 110mg D 150mg warfarin D 110mg vs. Warfarin D 150mg vs. Warfarin Annual rate Annual rate Annual rate RR 95% CI P* RR 95% CI P Stroke or systemic Embolism 1.5 % 1.1 % 1.7 % <0.001 Stroke 1.4 % 1.0 % 1.6 % <0.001

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33 Cumulative Hazard Rates Hemorrhagic Stroke 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

34 Bleeding D 110mg D 150mg warfarin D 110mg vs. Warfarin D 150mg vs. Warfarin Annual rate Annual rate Annual rate RR 95% CI p RR 95% CI p Total 14.6% 16.4% 18.2% < Major 2.7 % 3.1 % 3.4 % Life- Threatening major 1.2 % 1.5 % 1.8 % < Gastrointestinal Major 1.1 % 1.5 % 1.0 % <0.001

35 MI, Death and Net clinical Benefit D 110mg D 150mg warfarin D 110mg vs. Warfarin D 150mg vs. Warfarin Annual rate Annual rate Annual rate RR 95% CI p RR 95% CI p MI 0.7% 0.7 % 0.5 % Death 3.8 % 3.6 % 4.1 % Net Clinical Benefit 7.1 % 6.9 % 7.6 % Net Clinical Benefit includes vascular events, death and major bleed

36 Stopping Rates Permanent Discontinuation Dabigatran150 Dabigatran110 Warfarin Years of Follow-up

37 Cumulative Risk ALT or AST >3x ULN Warfarin Dabigatran150 Dabigatran Years of Follow-up

38 Common Adverse Events Adverse events occurring in >5% of any group Dabigatran 110 mg % Dabigatran 150 mg % Warfarin Dyspepsia * Dyspnea Dizziness Peripheral edema Fatigue Cough Chest pain Arthralgia Back pain Nasopharyngitis Diarrhea Atrial fibrillation Urinary tract infection Upper respiratory tract infection *Occurred more commonly on dabigatran p<0.001 %

39 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

40 Sites of Antithrombotic Action for Thrombin inhibitors Fondaparinux Rivaroxaban Apixaban endoxaban Heparin LMWHs AT AT AT Bivalirudin Hirudin Argatroban Dabitgatran Tissue factor Plasma clotting cascade Factor Xa Prothrombin Thrombin (IIa) Fibrinogen Aspirin Platelet activation Platelet aggregation Fibrin Collagen Thromboxane A 2 ADP Clopidogrel Prasugrel Eptifibatide Abciximab Tirofiban (GPB) Fibrinolytics Thrombus

41 Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB on behalf of the ROCKET AF Investigators

42 Study Design Atrial Fibrillation Risk Factors CHF Hypertension At least 2 or Age 75 3 required* Diabetes OR Stroke, TIA or Systemic embolus Rivaroxaban 20 mg daily 15 mg for Cr Cl ml/min Randomize Double Blind / Double Dummy (n ~ 14,000) Warfarin INR target ( inclusive) Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-cns Systemic Embolism * Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

43 Statistical Methodologies Sample Size Warfarin event rate ~2.3 Type 1 error 0.05 (2-sided) 405 events; >95% power ~14,000 patients Superiority Non-inferiority Inferiority Rivaroxaban Better Primary Efficacy Evaluation: Stroke or non-cns Embolism Non-Inferiority: Protocol Compliant on treatment Superiority: On Treatment and then by Intention-to-Treat Primary Safety Evaluation: Major or non-major Clinically Relevant Bleeding Warfarin Better

44 Baseline Demographics Rivaroxaban (N=7081) Warfarin (N=7090) Age (years) 73 (65, 78) 73 (65, 78) Female (%) Race (%) White Black Asian Region (%) North America Latin America Asia-Pacific Central Europe Western Europe Creatinine Clearance (ml/min) (%) 30 - < > 80 Values are median (IQR) Based on Intention-to-Treat Population

45 Baseline Demographics CHADS 2 Score (mean) 2 (%) 3 (%) 4 (%) 5 (%) 6 (%) Rivaroxaban (N=7081) Warfarin (N=7090) Prior VKA Use (%) Congestive Heart Failure (%) Hypertension (%) Diabetes Mellitus (%) Prior Stroke/TIA/Embolism (%) Prior Myocardial Infarction (%) Based on Intention-to-Treat Population

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

47 Primary Efficacy Outcome Stroke and non-cns Embolism On Treatment N= 14,143 Rivaroxaban Warfarin Event Event Rate Rate HR (95% CI) 0.79 (0.65,0.95) P-value ITT N= 14, (0.74,1.03) Rivaroxaban better Warfarin better Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations

48 Key Secondary Efficacy Outcomes Rivaroxaban Warfarin Vascular Death, Stroke, Embolism Stroke Type Hemorrhagic Ischemic Unknown Type Event Rate Event Rate HR (95% CI) P-value (0.74, 0.99) (0.37, 0.93) 0.94 (0.75, 1.17) 0.65 (0.25, 1.67) Non-CNS Embolism (0.09, 0.61) Myocardial Infarction (0.63, 1.06) All Cause Mortality Vascular Non-vascular Unknown Cause (0.70, 1.02) 0.89 (0.73, 1.10) 0.63 (0.36, 1.08) 0.75 (0.40, 1.41) Event Rates are per 100 patient-years Based on Safety on Treatment Population

49 Major >2 g/dl Hgb drop Transfusion (> 2 units) Critical organ bleeding Bleeding causing death Primary Safety Outcomes Rivaroxaban Event Rate or N (Rate) Warfarin Event Rate or N (Rate) HR (95% CI) 1.04 (0.90, 1.20) 1.22 (1.03, 1.44) 1.25 (1.01, 1.55) 0.69 (0.53, 0.91) 0.50 (0.31, 0.79) P- value Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) Intraventricular 2 (0.02) 4 (0.04) Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) Subarachnoid 4 (0.04) 1 (0.01) Event Rates are per 100 patient-years Based on Safety on Treatment Population

50 Adverse Events and Liver Enzyme Data Any Adverse Event Any Serious Adverse Event AE leading to study drug discontinuation Epistaxis Peripheral edema Dizziness Nasopharyngitis Cardiac failure Bronchitis Dyspnea Diarrhea ALT Elevation >3 x ULN >5 x ULN >3 x ULN and T Bili > 2 x ULN Values are N (%) Based on Safety Population Rivaroxaban (N=7111) Warfarin (N=7125)

51 Efficacy: Summary Rivaroxaban was non-inferior to warfarin for prevention of stroke and non-cns embolism. Rivaroxaban was superior to warfarin while patients were taking study drug. By intention-to-treat, rivaroxaban was non-inferior to warfarin but did not achieve superiority. Safety: Similar rates of bleeding and adverse events. Less ICH and fatal bleeding with rivaroxaban. Conclusion: Rivaroxaban is a proven alternative to warfarin for moderate or high risk patients with AF.

52 Sites of Antithrombotic Action for Thrombin inhibitors Fondaparinux Rivaroxaban Apixaban endoxaban Heparin LMWHs AT AT AT Bivalirudin Hirudin Argatroban Dabitgatran Tissue factor Plasma clotting cascade Factor Xa Prothrombin Thrombin (IIa) Fibrinogen Aspirin Platelet activation Platelet aggregation Fibrin Collagen Thromboxane A 2 ADP Clopidogrel Prasugrel Eptifibatide Abciximab Tirofiban (GPB) Fibrinolytics Thrombus

53 AVERROES Design 36 countries, 522 centres AF and 1 risk factor and demonstrated or expected unsuitable for VKA Apixiban 5 mg bid 2.5 mg bid in selected patients R 5600 patients Double Blind ASA mg / d

54 Baseline Characteristics Characteristics Apixaban ASA AVERROES Age ( mean and SD) 70± 10 years 70± 10 years Male ( years) CHADS2 score (mean and SD) ± ± 1.1 Prior stroke/tia 14% 13% Diabetes 19% 20% Hypertension 86% 87% CHF 40% 38% Baseline ASA 76% 74% Unsuitable for VKA VKA used and discontinued VKA expected unsuitable 39% 61% 40% 60%

55 Apixaban vs. Aspirin: The AVERROES Trial Primary and Secondary Endpoints Outcomes Apixaban (n=2809) Aspirin (n=2791) Relative risk (95% CI) Stroke or systemic embolism ( ) Stroke, embolism, MI, or vascular death ( ) MI ( ) Vascular death ( ) Cardiovascular hospitalization ( ) Total death ( ) Connolly S. European Society of Cardiology, Stockholm, August 31, 2010

56 Apixaban vs. Aspirin: The AVERROES Trial Bleeding Events Outcomes Apixaba n (n=2809 ) Aspirin (n=2791) Relative risk (95% CI) Major bleeding ( ) Fatal bleeding ( ) Intracranial ( ) Clinical relevant non-major bleeding ( ) Minor bleeding ( ) Connolly S. European Society of Cardiology, Stockholm, August 31, 2010

57 What about other trials? Apixaban ARISTOTLE trial Edoxaban ENGAGE trial

58 Challenges with New Oral Anticoagulants will Costs be high who will pay? How will we assess compliance? How will we treat bleeds?

59 Challenges for New Anticoagulants New oral anticoagulants are poised to replace warfarin for stroke prevention in AF Dabigatran is the first, but others will soon follow How the new agents compare with each other remains to be determined

60 ESC AF Guidelines: September, 2010

61 Europace (2010) 12, doi: /europace/euq350, p. 16 ESC AF Guidelines: September, 2010 New ESC Guidelines for AF OACs, such as a VKA, should be adjusted to an intensity range of INR (target 2.5). New OAC drugs [DTIs and factor Xa inhibitors] which may be viable alternatives to a VKA, may ultimately be considered. Where oral anticoagulation is appropriate therapy, dabigatran may be considered, as an alternative to adjusted dose VKA therapy... dabigatran 150 mg b.i.d. may be considered, in view of the improved efficacy in the prevention of stroke and systemic embolism (but lower rates of intracranial haemorrhage and similar rates of major bleeding events, when compared with warfarin)