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 1954 Pradaxa® dabigatran 2010 Xarelto® rivaroxaban 2011 Eliquis® apixaban 2012

Mechanism of Action Medication Mechanism of Action Coumadin (warfarin) Vitamin K Antagonist Pradaxa (dabigatran) Direct Thrombin Inhibitor Xarelto (rivaroxaban) Factor Xa Inhibitor Eliquis (apixaban)

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% 3-7% 60-100% 50% Protein bound 99% 30% 90-95% 80-85% Metabolism CYP Conjugation Half Life 40hrs 12-17hrs 5-9hrs 12hrs Onset of action 72hrs 1-2hrs 2-4hrs Elimination Liver Renal

Indications: US + + (RELY) + (ROCKET-AF) + (Aristotle) + (EINSTEIN) Coumadin Dabigatrn Rivaroxaban Apixaban Afib + + (RELY) + (ROCKET-AF) + (Aristotle) + (AVERROES) DVT/PE Not yet. (RECOVER) + (EINSTEIN) Post TKA/THA DVT prophylaxis + (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) 5 mg BID 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 Lack of and/or limited clinical evidence for reduced doses

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

Perioperative Recommendations Dabigatran Hold 1-2 days before procedure CrCl < 50  hold 3-5 days Rivaroxaban Low bleed risk  hold 1 day 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 ECT: ecarin clotting time, a thrombin clotting time assay.

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 Dabigatran Stop warfarin, initiate dabigatran when INR < 2 Initiate warfarin 3 days before D/C dabigatran Rivaroxaban Stop warfarin, initiate rivaroxaban when INR < 2-3 Initiate warfarin with bridging 24 hours after D/C rivaroxaban Apixaban Stop warfarin, initiate apixaban when INR < 2 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 PCC: prothrombin compex concentrates. 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 Comparator Dabigatran Rivaroxaban Apixaban Design Open-label, blind outcomes, noninferiority Double-blind, noninferiority Sample size n = 18,113 n = 14,264 n = 18,201 Randomization D 150mg BID D 110mg BID W (INR 2-3) R 20mg daily* A 5mg BID* 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 < 25 * 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 0-1 32% 0% 34% 2 36% 13% 3-6 87% 30% Prior TIA/stroke 20% 55% 19% TTR (INR @ goal) 64% 62% Median follow-up 2 yrs 1.9 yrs 1.8 yrs Primary endpoint Stroke (ischemic, hemorrhagic) + systemic embolism

Major Findings: RELY ROCKET-AF ARISTOTLE: 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 APIX 1o bleeding endpoint* 2.71 3.11 3.36 14.9 14.5 2.13 3.09 Major bleed 5.55 5.42 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: RE-LY  major hemorrhage ROCKET-AF  major + non-major clinically relevant bleeding 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 Evidence- Based Medicine: 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 Expert opinion

Anticoagulation Recommendations (AF) Risk/CHADS2 CHEST 2012 AHA/ASA Low Risk CHADS2 = 0 No therapy > antithrombotic therapy (2B) Aspirin (75-325mg) > OAC (2B) or aspirin + clopidogrel (2B) Aspirin (1A) Intermediate CHADS2 = 1 OAC > no therapy (1B) OAC > aspirin (2B) or aspirin + clopidogrel (2B) OAC unsuitable or pt refuses: aspirin + clopidogrel over aspirin monotherapy (2B) Warfarin (1A) Aspirin, if patient preference (1A) High Risk CHADS2 > 2 OAC > no therapy (1A) OAC > aspirin (1B) or aspirin + clopidogrel (1B) OAC unsuitable or pt refuses: aspirin + clopidogrel over aspirin monotherapy (1B) Dabigatran 150mg BID > warfarin (2B) Dabigatran (1B) Rivaroxaban (2A) Apixaban (1B) Chest 2012; 141:e531S-e575S Stroke 2012;43: 3442-3453 OAC = oral anticoagulation

New OAC: Pros: Cons: 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!