New Oral Anticoagulants

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1 New Oral Anticoagulants Tracy Minichiello, MD Associate Professor of Medicine Chief, San FranciscoVA Anticoagulation and Thrombosis Services What percentage of time do patients on warfarin spend in therapeutic range? A. 55% B. 65% C. 75% D. 85% 54% 39% 7% 0% A. B. C. D. New Oral Anticoagulants New Oral Anticoagulants Warfarin Only oral anticoagulant for 50 years Need for frequent monitoring Myriad of drug interactions Interaction with alcohol Requirement for dietary stasis Sporadic changes in level for no reason New Agents No lab testing required Few drug interactions Activity independent of vitamin k no food drug interactions More predictable dose effect Ansell, J. Hematology Copyright 2010 American Society of Hematology. Copyright restrictions may apply. 1

2 New Oral Antithrombotics Oral agents (Pradax) Rivaroxaban (Xarelto) Apixaban (n/a) status Approved US Approved in? nonvalvular AFIB eur/canada 2008 MOA DTI antixa antixa Ortho Trials: VTE RE-MOBILIZE: NOT noninferior to enoxaparin 30mg bid (VTE/mortality) RECORD 1-4: superior to enox 40mg daily & enox 30mg bid ADVANCE: NOT noninferior to enox 30mg bid-sample size Bleed Same Same Lower Renal metabolism 80% 30-60% 25% New Oral Antithrombotics Oral agents Drug Interaction CYP3A4* Drug Interaction pgp inhibitors** (Pradaxa) Rivaroxaban (Xarelto) Apixaban (n/a) -- Yes -- Emycin, ketoconazole rifampin Yes Yes -- rifampin Antidote None None none monitoring ECT, TT, PTT Anti Xa Anti Xa RE-LY- DABIGATRAN v WARFARIN FOR STROKE PREVENTION IN AFIB RE-LY-Exclusion Criteria History of heart valve disorder Recent stroke Reversible causes of AF Active liver disease (LFT elevations >2x ULN) Concomitant therapy with P-gp inducers CrCl <30 ml/min or on dialysis Connolly SJ et al. NEJM

3 RE-LY-Exclusion Criteria Major surgery or GI ulcer within 1 month History of intracranial,intraocular, spinal, retroperitoneal, intra-articular bleeding GI bleed within 1 year Hemorrhagic disorder or bleeding diathesis Fibrinolytic agent within 48 hours Uncontrolled hypertension Anemia or thrombocytopenia RE-LY-Exclusion Criteria Hemorrhagic disorder or bleeding diathesis Fibrinolytic agent within 48 hours Uncontrolled hypertension SBP>180 mm Hg and/or DBP>100 mm Hg) Anemia or thrombocytopenia RE-LY-Analysis MI in AFIB trials Warfarin vs. Non Warfarin Anticoagulant CONS Adherence Dyspepsia &dosing Age major bleed > 80yo risk GI bleed Rule of 50 (<50kg, CrCl <50ml/min) 2/3 CHADS2 2 PROS Lower stroke rate Lower hemorrhagic stroke risk Lower risk of life threatening bleeding and intracranial bleeding Lip, GY Amer J Med

4 ANALYSIS OF RELY TRIAL- <57% 65-72% 57-65% >72% -Patient Selection Patients with non valvular afib Poorly controlled INR Increased risk ICH Difficulty with INR testing? < 80 years old, CrCl >30 ml/min, no CAD??concomitant antiplatelet therapy Wallentin, L Lancet 2010 Re-Cover: vs Warfarin in VTE: Cumulative Risk of Recurrent VTE or Related Death Re-Cover: vs Warfarin in VTE Cumulative Risk of Bleeding Shulman, s et al NEJM 2009 Shulman, s et al NEJM

5 EINSTEIN-Rivaroxan in Symptomatic VTE AVERROES-Apixaban v ASA in AFIB Vte rates 2.1% rivoroxan 3% warfarin Cumulative stroke risk 3.7% v 1.6% If hx stroke 8.3% v 2.5% The EINSTEIN Investigators. N Engl J Med 2010;363: Connolly SJ et al NEJM 2011 Vte rates 1.3% rivoroxan 7.1% placebo VTE by 82% Minor bleed 5.4% v 1.2% Connolly SJ et al. N Engl J Med 2011;364: Connolly SJ et al NEJM 2011 Major bleeding 1.2% v 1.4% More minor bleeding with apixaban Current Concerns Only oral anticoagulant for 50 years No lab testing monitoring Activity independent of vitamin k Predictable dose effect Lack of long term data Cannot measure anticoagulant effect/ monitor adherence Cannot reverse easily with vitamin k?safety in compromised organ function 5

6 :Prescribing Info Indicated for stroke prevention in non-valvular AFIB 150 mg po twice daily; 75 mg po twice daily if CrCL < ml/min. ECT is a better marker of anticoagulant activity than aptt, (PT)/INR, or thrombin time If ECT is not available, the aptt test provides an approximation of anticoagulant activity Prescribing Info: Overdose Dabigtran is dialyzable. 60% of drug may be removed over 2-3 hours Consider FFP, PCC, Factor V, platelet transfusion if on antiplatelet drug Prescribing Information: Converting from warfarin When converting from warfarin to dabigatran discontinue warfarin and start dabigatran when INR < 2.0 Prescribing Information: Converting to warfarin For CrCl >50 ml/min, start warfarin 3 days before discontinuing PRADAXA. For CrCl ml/min, start warfarin 2 days before discontinuing PRADAXA. For CrCl ml/min, start warfarin 1 day before discontinuing PRADAXA. For CrCl <15 ml/min, no recommendations can be made 6

7 Prescribing Information: converting to/from parenteral AC For patients on parenteral anticoagulant, start dabigatran 0 to 2 hours before the next dose of the parenteral drug was to have been given or when IV heparin discontinued For patients currently taking dabigatran, wait 12 hours (CrCl 30 ml/min) or 24 hours (CrCl <30 ml/min) after the last dose of dabigatran before initiating treatment with a parenteral anticoagulant Prescribing Information: Surgery & Interventions Discontinue dabigatran 1 to 2 days (CrCl 50 ml/min) or 3 to 5 days (CrCl <50 ml/min) before invasive or surgical procedures Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port 7