Anticoagulation: A Changing Landscape Kelly Matsuda Pharm.D. July 16, 2011 Kelly Matsuda Pharm.D. July 16, 2011
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.
Atrial Fibrillation: A Risk Factor for Vascular Events RISK FACTORS: THROMBOSIS • Hypertension • Hyperlipidemia • Age • Diabetes Mellitus • Smoking Atherosclerosis/Atherothrombosis Atherosclerosis/Atherothrombosis MI MI AF CHF AF CHF Stroke, MI, Vascular Death Wolf PA et al. Arch Intern Med 1987; 147: 1561-1564 Leckey R et al. Can J Cardiol 2000; 16: 481-485
AF Prevalence: Age and Gender Prevalence of AF increases with age; men > women Prevalence, percent Age, years JAMA 2001; 285: 2370
The Percentage of Strokes Attributable to AF Increases with Age Framingham Study 30 20 AF prevalence % Strokes attributable to AF 10 0 50 – 59 60 – 69 70 – 79 80 – 89 Age Range (years) Wolf et al. Stroke 1991; 22: 983-988
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: 986-992
Blood Flow in Atrial Fibrillation Disturbed Flow (left atrium) Stroke Risk
Intrinsic Pathway Extrinsic Pathway HMW Kininogen Tissue Injury Pre-kallikren Kallikren XII XIIa Tissue Factor XI XIa VII VIIa IX IXa Tenase VIII VIIIa VIIa IXa Tissue Factor VIIa Ca ++ Ca ++ X Xa X
Common Pathway Prothrombinase Xa Va Ca ++ Prothrombin Thrombin Fibrinogen Fibrin
Properties of an Ideal anticoagulant Properties Benefits Orally active Ease of administration Rapid onset of action Obviates need for overlap with parenteral anticoagulant No food drug interaction or drug Simplified dosing drug interactions Predictable anticoagulant effect No routine anticoagulation monitoring Extra renal clearance Safe in patients with renal insufficiency Rapid offset of action Simplifies management in case of bleed or intervention Safe antidote Useful in case of major bleed Favorable net clinical benefit risk Treatment benefit outweighs risk
WARFarin trivia outbreak1920s cattle bled from minor procedure or spontaneously 1921 -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 1929- 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
Antithrombotic Therapy for Atrial Fibrillation ACC/AHA/ESC Guidelines 2006 Recommended Therapy Risk Category No risk factors Aspirin , 81-325 mg qd CHADS 2 = 0 Aspirin , 81-325 mg/d or One moderate risk factor CHADS 2 = 1 Warfarin Any high risk factor or >1 moderate risk factor Warfarin CHADS 2 >2 (INR 2.0-3.0, target 2.5) or mitral stenosis Warfarin Prosthetic valve (INR 2.5-3.5, target 3.0) Fuster V , et al. Eur Heart J 2006;27:1979.
Sites of Antithrombotic Action Tissue factor Collagen Fondaparinux Aspirin Rivaroxaban Apixaban Plasma clotting ADP endoxaban cascade Thromboxane A 2 Clopidogrel AT Prasugrel Prothrombin Heparin AT Factor Platelet activation LMWHs Xa AT Eptifibatide Abciximab Tirofiban Thrombin (IIa) Platelet aggregation (GPB) Bivalirudin Hirudin Argatroban Fibrin Fibrinogen Dabitgatran Thrombus Fibrinolytics
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.
Conventional Anticoagulants properties Warfarin UFH LMWH fondaparinux Mode of Action Vitamin K Indirect factor Indirect factor Indirect Xa inhibitor antagonist IIa and Xa Xa and minor inhibitor IIa inhibitor Bioavailability 100 % 100% 100% 100% Peak action 4-5 days Iv: immediate Sq 2-4 hours Sq 2-4 hours enox ( t max) Sq: 20-60 min Sq 2.9 hours dalt Sq 4 hours tinz Elimination half 36- 42 hours 1-1.5 hours 3-4 hours 17-21 hours life ( t 1/2) ) Route of Multiple Reticulendothel > 80% renal 100% renal elimination ial system Involvement of Yes No No No CYP J Douketis, Curr pharma design 2010:16:3426 UFH=unfractionated heparin, LMWH= low molecular weight heparin ( enox=enoxaparin, dalt=dalteparin,nz=tinz=tinzaparin
Conventional anticoagulants Properties Fondaparinux Argatroban lepirudin Mode of Xa IIa IIa action Bioavailability 100% 100% 100% Peak action 2-4 hours 1-3 hours Elimination 17-21 hours 0.5- 1 hours 1 hour half life (t 1/2 ) Route of 100% renal 100% hepatic 100% elimination Involvement no Minor cyp no of CYP majority thru hydroxylation aromatization
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
Risk of Intracranial Hemorrhage in Outpatients Adapted from: Hylek EM, Singer DE, Ann Int Med 1994;120:897-902 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.
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;335:540-546.
Therapeutic Range for Warfarin INR Values at Stroke or ICH 15.0 Stroke Intracranial Hemorrhage Odds Ratio 10.0 5.0 1.0 0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 INR Fuster et al. J Am Coll Cardiol . 2001;38:1231-1266.
Anticoagulation in Atrial Fibrillation Stroke Risk Reductions Control Warfarin Better Better AFASAK SPAF BAATAF CAFA SPINAF EAFT Aggregate - 100% 50% 100% - 50% 0 Hart R, et al. Ann Intern Med 2007;146:857.
Anticoagulation in Atrial Fibrillation The Standard of Care for Stroke Prevention Warfarin Control Better Better Unblinded AFASAK Unblinded SPAF Unblinded BAATAF Terminated early CAFA Double-blind; Men only SPINAF 2 o prevention; Unblinded EAFT Aggregate -100% 50% 100% -50% 0 Hart R, et al. Ann Intern Med 2007;146:857.
New Anticoagulants Properties Dabigatran Rivaroxaban Apixaban Mode of action Direct factor IIA Direct factor Xa Direct factor Xa (thrombin inhibitor inhibitor inhibitor) Bioavailability 6.5% 80% 80% Peak action 1-3 hours 1-3 hours 1-3 hours Elimination half 14-17 hours 9-15 hours 9-14 hours life (t ½) Route of 100% renal 65% renal 25% renal elimination Involvement of Minor Minor Minor CYP J Douketis, Curr pharma design 2010:16:3426
Sites of Antithrombotic Action for Thrombin inhibitors Tissue factor Collagen Fondaparinux Aspirin Rivaroxaban Apixaban Plasma clotting ADP endoxaban cascade Thromboxane A 2 Clopidogrel AT Prasugrel Prothrombin Heparin AT Factor Platelet activation LMWHs Xa AT Eptifibatide Abciximab Tirofiban Thrombin (IIa) Platelet aggregation (GPB) Bivalirudin Hirudin Argatroban Fibrin Fibrinogen Dabitgatran Thrombus Fibrinolytics
Baseline Characteristics Characteristic Dabigatran 110 Dabigatran 150 Warfarin mg mg Randomized 6015 6076 6022 Mean age (years) 71.4 71.5 71.6 Male (%) 64.3 63.2 63.3 CHADS2 score 2.1 2.2 2.1 (mean) 0-1 (%) 32.6 32.2 30.9 2 (%) 34.7 35.2 37.0 3+ (%) 32.7 32.6 32.1 Prior stroke/TIA (%) 19.9 20.3 19.8 Prior MI (%) 16.8 16.9 16.1 CHF (%) 32.2 31.8 31.9 Baseline ASA (%) 40.0 38.7 40.6 Warfarin Naïve (%) 49.9 49.8 51.4
Stroke or Systemic Embolism Superiority Non-inferiority p-value p-value Dabigatran 110 vs. Warfarin <0.001 0.34 <0.001 <0.001 Dabigatran 150 vs. Warfarin Margin = 1.46 0.50 0.75 1.00 1.25 1.50 HR (95% CI) Warfarin better Dabigatran better
1 0 Outcome: Superiority Analysis D 110mg vs. D 150mg vs. D 110mg D 150mg warfarin Warfarin Warfarin RR RR Annual Annual Annual P* P rate rate rate 95% CI 95% CI Stroke or 0.91 0.66 systemic 1.5 % 1.1 % 1.7 % 0.34 0.53-0.82 <0.001 0.74-1.11 Embolism 0.92 0.64 Stroke 1.4 % 1.0 % 1.6 % 0.41 0.51-0.81 <0.001 0.74-1.13
Hemorrhagic Stroke 0.04 D 110 mg vs. D 150 mg vs. Warfarin Warfarin RR = 0.31 RR =0.26 95% CI =0.17-0.56 95% CI =0.14-0.49 0.03 Cumulative Hazard Rates P <0.001 P <0.001 0.02 Warfarin 0.01 Dabigatran110 0.0 Dabigatran150 0 0.5 1.0 1.5 2.0 2.5 Years of Follow-up
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