New Oral Anticoagulants: A Review Babak Moini, MD Veterans Affairs Hospital Noon Lecture Series Acknowledgment: Some of the slides were borrowed from Amanda Miller Phar.D. Case1 68 male with hx of DM, CHF and prior ischemic CVA admitted for new afib. He has a hx of non-compliance. CHADs2: 4. Which anticoagulant to send him home with? Oral Anticoagulants Available in US Coumadin warfarin Pradaxa® dabigatran Xarelto® rivaroxaban Eliquis® apixaban 1954 2010 2011 2012 Mechanism of Action Mechanism of Action Medication Coumadin (warfarin) Vitamin K Antagonist Pradaxa (dabigatran) Direct Thrombin Inhibitor Xarelto (rivaroxaban) Factor Xa Inhibitor Eliquis (apixaban) Factor Xa Inhibitor rivaroxaban apixaban dabigatran http://www.healio.com/~/media/Images/News/Online/Orthopedics/2009/12_December/01/79_fig_400_307_ 57368.gif Pharmacology: Coumadin Dabigatran Rivaroxaban Apixaban Bioavailability 100% 60-100% 50% Protein bound 99% 90-95% 80-85% Metabolism CYP Conjugation CYP CYP Half Life 40hrs 12-17hrs 5-9hrs 12hrs Onset of action 72hrs 1-2hrs 2-4hrs 2-4hrs Elimination Liver Renal Renal Renal Indications: Coumadin Dabigatrn Afib (RELY) DVT/PE Not yet. (RECOVER) Post TKA/THA DVT prophylaxis + Rivaroxaban (ROCKETAF) Apixaban (Aristotle) + (AVERROES) (EINSTEIN) (RECORD 1-3) + (ADVANCE) Not yet approved: Rivaroxaban for prophylaxis of DVT in medically ill patients (MAGELLAN). Rivaroxaban vs Enoxaparin. NI < 30 days, superior at 35 days. Usual Dosing (A fib) Warfarin • Once daily, titrate to INR 2-3 Dabigatran • 150 mg BID • 75 mg BID (CrCl 15-30 ml/min) Rivaroxaban • 20 mg daily • 15 mg daily (CrCl 15-50 ml/min) Apixaban • 5 mg BID • 2.5 mg BID if any 2 of the following: age > 80, wt < 60kg, SCr > 1.5 Usual Dosing (VTE) Only FDA-approved agent = rivaroxaban VTE Prophylaxis (knee/hip surgery) 10mg once daily (up to 35 days) No renal dose (CrCl < 30 ml/min avoid) VTE Treatment: 15 mg BID x 3 weeks then 20mg daily No renal dose (CrCl < 30 ml/min avoid) Perioperative Recommendations Dabigatran • Hold 1-2 days before procedure • CrCl < 50 hold 3-5 days • Low bleed risk hold 1 day Rivaroxaban • CrCl < 30/ low risk hold 2 days • High bleed risk hold 2 days • CrCl < 30/ high risk hold 4 days Apixaban • Low bleed risk hold x 1 day • High bleed risk hold x 2 days Dabigatran PI, Blood 2012;119:3016-23 Major Side Effects: Bleeding: varied definition in each study. GI ICH Major (drop in Hgb by 2, life threatening). Dabigatran: Pills are made in acidic content, hence has 20% rate of GI side effects. ? Observed increase risk of GI bleeding. Monitoring Levels: Coumadin: INR New Oral anticoagulants: no standardized studies. No accurate quantitative measures. Dabigatran: ECT, Thrombin clotting time Rivaroxaban: special anti-Xa activity Abixaban special anti-Xa activity Drug-Drug Interactions: No where as severe as with Warfarin. Dabigatran: P-glycoprotein, pro-drug. Needs acidic environment, avoid co-administration with PPI. Rivaroxaban: CYP-450 and P-glycoprotein. Caution with dual inhibitors (Ketoconazole, Itroconazole, Clarithromycin). No dose adjustments needed. Abixaban: CYP3A4 and P-glycoprotein. Decrease dose to 2.5mg bid in dual inhibitors. Switching To/From Warfarin Medication Recommendations for Conversion Stop warfarin, initiate dabigatran when INR < 2 Dabigatran Initiate warfarin 3 days before D/C dabigatran Stop warfarin, initiate rivaroxaban when INR < 2-3 Rivaroxaban Initiate warfarin with bridging 24 hours after D/C rivaroxaban Stop warfarin, initiate apixaban when INR < 2 Apixaban Initiate warfarin with bridging when next apixaban dose is due. Treatment of Bleeding: No evidence based guidelines. Remember that unlike Coumadin, the new OAC will continuously bind to factor Xa or thrombin, hence making FFP less useful. Current available Rx for life threatening active bleeding: based on case reports. Factor VII PCC: 3 and 4 factor concentrates. HD: only for Dabigatran. Large volume of distribution. Charcoal Gonsalves Et al. Mayo Clinic Proc. 5-2013 Trials vs Warfarin for A Fib RE-LY DAB vs WAR ROCKET-AF RIV vs WAR ARISTOTLE APIX vs WAR Dabigatran Rivaroxaban Apixaban Open-label, blind outcomes, noninferiority Double-blind, noninferiority Double-blind, noninferiority n = 18,113 n = 14,264 n = 18,201 Randomization D 150mg BID D 110mg BID W (INR 2-3) R 20mg daily* W (INR 2-3) A 5mg BID* W (INR 2-3) Inclusion Criteria Nonvalvular AF with increased stroke risk Nonvalvular AF with prior stroke or >2 risk factors Nonvalvular AF with >1 risk factor for stroke Exclusion CrCl < 30 CrCl < 30 CrCl < 25 Comparator Design Sample size * Dose reductions for renal impairment Trials vs Warfarin for A fib RE-LY DAB vs WAR ROCKET-AF RIV vs WAR ARISTOTLE APIX vs WAR Average age (yrs) 71 73 70 Mean CHADS2 2.1 3.5 2.1 0-1 32% 0% 34% 2 36% 13% 36% 3-6 32% 87% 30% Prior TIA/stroke 20% 55% 19% TTR (INR @ goal) 64% 55% 62% Median follow-up 2 yrs 1.9 yrs 1.8 yrs Primary endpoint Stroke (ischemic, hemorrhagic) + systemic embolism Major Findings: RELY Dabigatran 110mg NI to Warfarin (1.53% vs 1.69%). Dabigatran 150mg superior to Warfarin ONLY if compared with sub-optimal INR subgroup (1.11 % vs 1.69%). Major bleeding less with 110mg (2.71 vs 3.11%). ROCKET-AF Rivaroxaban NI to Warfarin (2.1% vs 2.4%) Less ICH or fatal bleeding (0.4% vs 0.8% ) ARISTOTLE: Abixaban Superior to Warfarin (1.27% vs 1.6% ) Less Major bleeding (1.4% vs 2.1% ) Key Safety Endpoints (% per year) RE-LY ROCKET AF ARISTOTLE D110 D150 WAR RIV WAR APIX WAR 1o bleeding endpoint* 2.71 3.11 3.36 14.9 14.5 2.13 3.09 Major bleed 2.71 3.11 3.36 5.55 5.42 2.13 3.09 GI bleeding 1.12 1.51 1.02 3.2 2.2 0.76 0.86 Intracranial hemorrhage 0.23 0.3 0.74 0.5 0.7 0.33 0.8 *: Primary safety endpoint: o RE-LY major hemorrhage o ROCKET-AF major + non-major clinically relevant bleeding o ARISTOTLE ISTH (Int Soc Thromosis & Hemostasis) major bleeding Figure 3 Forest plot for (A) major bleeding, (B) intracranial bleeding, and (C) gastrointestinal bleeding, new oral anticoagulants (NOA) versus warfarin in patients with AF. http://dx.doi.org/10.1016/j.amjcard.2012.03.049 Quick Review of EvidenceBased Medicine: I A: Systemic review of multiple RCTs / multiple RTCs B: High quality single RTC II: A: Systemic review of cohort studies B: High quality cohort studie(s) III: Systemic review of Case/Control studies / Case Control studies IV Case reports IV Expert opinion Anticoagulation Recommendations (AF) Risk/CHADS2 CHEST 2012 AHA/ASA No therapy > antithrombotic therapy (2B) Low Risk CHADS2 = 0 Intermediate CHADS2 = 1 Aspirin (1A) Aspirin (75-325mg) > OAC (2B) or aspirin + clopidogrel (2B) OAC > no therapy (1B) Warfarin (1A) OAC > aspirin (2B) or aspirin + clopidogrel (2B) Aspirin, if patient preference (1A) OAC unsuitable or pt refuses: aspirin + clopidogrel over aspirin monotherapy (2B) OAC > no therapy (1A) Warfarin (1A) Dabigatran (1B) Rivaroxaban (2A) Apixaban (1B) OAC > aspirin (1B) or aspirin + clopidogrel (1B) High Risk CHADS2 > 2 OAC unsuitable or pt refuses: aspirin + clopidogrel over aspirin monotherapy (1B) Dabigatran 150mg BID > warfarin (2B) OAC = oral anticoagulation Chest 2012; 141:e531Se575S Stroke 2012;43: 3442-3453 New OAC: Pros: Easy administration Immediate effect Much less food and drug interactions One dose fits all The names sound so much cooler than WARFARIN. Cons: Expensive Inability to monitor compliance Short duration: loss of effect with a single missed dose No safe/reliable antidotes ? Bleeding. Observational bias vs real difference. Renal dosing Take home message: Coumadin still remains the drug of choice for many patients due to cost, past experience and known side effects. Many new OAC are in the pipeline, expect a barrage of pharma bombardments, must remain objective as many of the studies have different inclusion/exclusion criteria, definition of end points and side effects. Each patient may benefit from a different type of OAC based on comorbidities and drug side effect profile. Watch out for recall bias with the new OAC among your own colleagues. Patient compliance is a major factor: remember with the new OAC one missed dose means a lot! The End!