The New Oral Anticoagulants: Handle with Care Philip C. Comp, M.D., Ph.D. October 18, 2013
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The New Oral Anticoagulants: Handle with Care Philip C. Comp, M.D., Ph.D. October 18, 2013 Speaker for dabigatran (Pradaxa®) and rivaroxaban (Xarelto®) Anticoagulant Quiz β’ Which commonly used anticoagulant does not require laboratory monitoring? β’ Which anticoagulant has no antidote? β’ The dose of which anticoagulant depends on renal function? (Enoxaparin, Lovenox®) Edoxaban The New Oral Anticoagulants Dabigatran (Pradaxa®) Rivaroxaban (Xarelto®) Inhibits thrombin Twice a day Atrial fibrillation Inhibits factor Xa Once a day Atrial fibrillation; DVT/PE treatment; Reduction in risk of DVT/PE (after 6 mn Tx); Hip/Knee prophylaxis; Apixaban (Eliquis®) Inhibits factor Xa Twice a day Atrial fibrillation Canine Model of Blood Coagulation Factor IX Factor X PROTHROMBIN Canine Model of Blood Coagulation Effect of Warfarin Factor IXa Factor Xa THROMBIN Canine Model of Blood Coagulation Oral Anti-Xa Factor IXa Factor Xa THROMBIN Canine Model of Blood Coagulation Oral Anti-thrombin Factor IXa Factor Xa rivaroxaban apixaban THROMBIN ππππ’π πππ«ππ§ There is no free lunch The effectiveness of an anticoagulant must be weighed against the risk of bleeding Bleeding Thrombosis Apixaban, Dabigatran and Rivaroxaban β’ β’ β’ β’ β’ β’ Oral Short half-lives Renal clearance No INRs No food interactions Few drug interactions Prevention of Stroke-Apixaban Number needed to treat/1.8 years: 167 Granger et al. NEJM 3654: 981-92, 2011 Atrial Fibrillation- Dabigatran 35% RRR ! Number needed to treat/ 2 years: 88 Connolly et al. NEJM 361, 2009 Atrial Fibrillation- Rivaroxaban Number needed to treat/1.6 years: 135 C Patel et al. NEJM 365: 883-91, 2011 CHADS2 Scores 0-1 33% 2 35% 3-6 33% ESTIMATE 5% risk/year In a non-treated group Number needed to treat NT 88 v. warfarin STROKE Atrial Fibrillation- Dabigatran Warfarin Dabigatran Modified from Connolly et al. NEJM 361, 2009 Percentage of AF patients with stroke per year No treatment ~ 5.0% Warfarin 1.6% Dabigatran 1.0% 100 strokes occur 68% of strokes gone; 32 occur 3.4% 0.6% 80% of strokes gone; 20 occur Modified from Connolly et al. NEJM 361, 2009 STROKE = Ischemic Stroke and Hemorrhagic Stroke* *Subdural hematomas, epidural hematomas, subarachnoid hematomas and intracerebral hemorrhage Stroke rates (percent/year) All Stroke Hemorrhagic Stroke Dabigatran/ 1.44/1.57 Warfarin 0.10/0.38 Time INR in 2-3 range 64 Rivaroxaban/ 2.61/3.12 0.5/0.7 55 0.24/0.47 62 Warfarin (as treated) Apixaban/ 1.19/1.51 Warfarin Bleeding and death rates (percent/year) Major Bleeding Dabigatran/ 3.11/3.36 Warfarin Death Rivaroxaban/ 3.60/3.40 1.90/2.20 Warfarin (as treated) Apixaban/ 2.13/3.09 Warfarin 3.64 /4.13 3.52/3.94 Bleeding Event Rate (%/year) Apixaban Warfarin Dabigatran Warfarin Rivaroxaban Warfarin Intracranial Gastrointestinal 0.33 0.80 0.76 0.86 0.30 0.74 1.51 1.02 0.77 1.18 3.15 2.16 N Engl J Med 2011;365:981-92 N Engl J Med 2009;361:1139-51. N Engl J Med 2011;365:883-91. NNT with dabigatran for 1 year to prevent one adverse event compared to warfarin NNT Stroke or systemic embolus Intracranial bleeding 172 Major bleeding 154 Life-threatening bleeding 286 227 Nature Reviews Cardiology 7, 10-11 (January 2010) Can atrial fibrillation studies be directly compared? Mean Age and CHADS2 Score Apixaban 70y 2.1 ± 1.1 Rivaroxaban 73y 3.5 ± 0.94 Dabigatran 72y 2.1 ± 1.1 Direct comparison of strokes and bleeding between studies is difficult. CHF Hypertension Age > 75 Diabetes Prior stroke 1 1 1 1 2 New oral agents in atrial fibrillation Apixaban superior to warfarin Rivaroxaban not inferior to warfarin Dabigatran superior to warfarin Davis, N Engl J Med 2012;366:1914-22. No food interactions Compare to WARFARIN AND FOOD Dietitians CHLOROPHOBIA (fear of the color green) Green Tea Green Tea 333 liters of green tea contain 1 mg vitamin K Iceberg Lettuce New anticoagulants have short half- lives (9-17 hours) Forgetfulness 30% Other priorities 16% Decision to omit doses 11% Lack of information 9% Osterberg l et al. NEJM 353: 487-97 2005 1,800,000 patients prescribed a statin: Patients filled prescriptions for a mean of 11.4 medications/3 month 10% of patients filled prescriptions for 23 or more medications. 10% had prescriptions written by 4 or more prescribers. Choudhry NK The Implications of Therapeutic Complexity on Adherence to Cardiovascular Medications. Archives of Internal Medicine 171:814-822, 2011 Retrospective Study of Medication Prescription in Oklahoma City, n=3 β’ 64 year old man: 14 medications daily; 31 pills β’ 61 year old woman: 15 medications; 39 pills β’ 90 year old man: 15 medications; 27 pills Drugs donβt work in patients who donβt take them C. Everett Koop, M.D. 1916-2013 Typical Clinical Trial Patient Who is the ideal patient? β’ Does not like INRs β’ Reliable β’ Well insured Who will have a bleed? β’ Frail (<60 kg) β’ Reduced creatinine clearance β’ Over 80 years of age Harper. Bleeding Risk with Dabigatran in the Frail Elderly N Engl J Med 2012; 366:864-866 Proper prescriber behavior β’ At each visit β Are your taking drug X? β’ At every visit β Why are you taking drug X? β’ At each visit β Are you taking X every day? KIDNEY FUNCTION IS IMPORTANT! CHECK THE CREATININE CLEARANCE What is the effect of no more INRs? No more anticoagulation clinics and fewer office visits. Will that reduce compliance? BOUNCING BEN in a BAD candidate! 5 INR 4 3 2 1 0 2-Aug 2-Sep 2-Oct 2-Nov Who to switch from warfarin β’ Not a cure for the bouncing INR β’ Stroke risk: Least benefit to well controlled warfarin patients β’ Fewer potential drug interactions in polypharmacy patients? Warfarin > new anticoagulant Patients angst: Miss INRs Miss food restrictions If bleeding occurs Little data available a. Factor VIIa b. Factor VIII Inhibitor Bypassing Activity (FEIBA) c. Hydration Fresh frozen plasma and Vitamin K are not the way to go! Everyone is developing an antidote Oral anticoagulant inhibits factor Xa Inhibitor Xa Everyone is developing an antidote A recombinant antidote (DU-176b) Xa Surgery while on medication Dabigatran (100% renal) Rivaroxaban (65% renal clearance) Apixaban (25% renal clearance) When to stop the medication preoperatively depends on the medication and renal function. Look it up! What is the cost per day* Dabigatran = $9.50 Rivaroxaban= $9.46 Apixaban = $9.40 *Sam's Club, Northwest Highway, OKC 10/10/13 Advising patients β’ Explain they are taking lots of medications β stroke preventers critical β’ Avoid friendly little black dogs and get someone else to clean the gutters! Summary of New Anticoagulants β’ Marginally better than warfarin for atrial fibrillation β’ No food interactions; few drug interactions β’ No need for INRs β’ Short-half life β take regularly β’ Check creatinine clearance yearly