Oral Anticoagulants Update Elizabeth Renner, PharmD, BCPS, BCACP, CACP Outpatient Cardiology and Anticoagulation
Objectives List the direct oral anticoagulant (DOAC) drugs currently available Describe advantages and disadvantages to DOAC use Compare efficacy and safety of DOACs with warfarin Describe adverse effect profile of DOACs Determine which patients are good candidates for DOAC therapy vs warfarin
Warfarin
Kinetics Absorption: complete Distribution: 99% protein binding Only FREE warfarin is available for use at VKORC1 Metabolism: broken down by cytochrome P450 enzymes in the liver R-warfarin primary via 3A4 S-warfarin (SERIOUS WARFARIN) primary via 2C9 2C9 inhibitors will RAISE INR significantly. 3A4 inhibitors will RAISE INR to a lesser extent. Elimination: 92% renal LOTS of reasons why genetics can have effects on warfarin
Factors that affect warfarin dosing Body size Age Renal function Liver function Drug-drug interactions Dietary vitamin K intake Acute & chronic illness Smoking Alcohol Physical activity Genetics Warfarin manufacturer
Warfarin PROS Effective Inexpensive INR monitoring Reversible CONS Variable Dosing INR Monitoring Drug-drug interactions Lifestyle interactions Requirement for anticoagulation care provider
Other Oral Options?
TSOACs / DOACs / NOACs Current favorite acronym: DOAC (Direct Oral AntiCoagulant) Mechanisms of action DIRECT binding to active sites of factor II (thrombin) or Xa DabigaTran (Pradaxa) T for THROMBIN rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa) factor Xa Cost per 30 days = $300-400 Reversible?
The Clotting Cascade
What can we use DOACs for? The Big Three: (non-valvular) Atrial Fibrillation Treatment of Venous Thromboembolism (VTE) Prevention of Recurrent VTE Post-joint-replacement VTE Prophylaxis Still Being Investigated: VTE Associated with Cancer VTE Associated with Hypercoagulable State Patients with Bioprosthetic Heart Valves With Dual Antiplatelet Therapy (DAPT) Not For Use In: Mechanical Heart Valves Left Ventricular Assist Devices
Dabigatran (Pradaxa) Absorption: 3-7% bioavailable Dosage form relies on low gastric ph No opening/crushing capsules
Dabigatran (Pradaxa) Absorption: 3-7% bioavailable Dosage form relies on low gastric ph No opening/crushing capsules Distribution: 35% protein bound Metabolism: metabolized readily after absorption from dabigatran etexilate to the active moiety, dabigatran Gut: p-glycoprotein Elimination: 80% renal t 1/2 = 12-17 hours in healthy people
Dabigatran (Pradaxa ) Dosage Forms Capsules: 150 mg, 110 mg, 75 mg Do not break, chew, or open capsules before administration. Keep in original bottle. Monitoring Serum creatinine Adverse Effects Risk of bleeding Dyspepsia (11.3%)
Dabigatran in Atrial Fibrilation: RE-LY P < 0.001 superiority
Dabigatran in Atrial Fibrilation: RE-LY P = 0.31 Note: Dabigatran 150 mg increased the rate of GI bleeding (p<0.001), decreased ICH (p<0.001) when compared to warfarin.
Dabigatran in VTE: RE-COVER Rate of Recurrent VTE 5 P < 0.001 for noninferiority 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 2.1 warfarin (INR 2-3) 2.4 dabigatran 150mg BID
Dabigatran in VTE: RE-COVER Rate of Major Bleeding 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 1.9 warfarin (INR 2-3) 1.6 dabigatran 150mg BID
Other Clinical Trials for Pradaxa RE-ALIGN: Mechanical Heart Valves RE-SONATE: prevention of recurrent VTE vs placebo RE-MEDY: prevention of recurrent VTE vs warfarin RE-NOVATE: prevention of VTE after hip replacement surgery (vs enoxaparin)
Dabigatran Dosing VTE prevention after hip-replacement surgery Crcl 30ml/min or above Crcl less than 30ml/min Crcl 50ml/min or above with P-gp inhibitor Crcl less than 50ml/min with P-gp inhibitor 220mg daily Avoid 220mg daily Avoid
Xa Inhibitors
Rivaroxaban (Xarelto) Absorption: 66-100% bioavailable Better absorption with smaller doses & with food Distribution: 92-95% protein binding Metabolism: Gut: p-glycoprotein Liver: CYP450 3A4 Elimination: 66% renal T 1/2 : 5-12 hours
Rivaroxaban (Xarelto ) Dosage Forms Tablets: 20 mg, 15 mg, 10 mg Breakable/Crushable Monitoring Renal function Adverse Effects Bleeding risk
Rivaroxaban in Atrial Fib: ROCKET-AF Rate of stroke or systemic embolism (%) 2.5 2.2 P<0.001 for non-inferiority 1.7 2 1.5 1 0.5 0 Warfarin Rivaroxaban
Rivaroxaban in Atrial Fib: ROCKET-AF Rate of major bleeding (%) 5 4.5 3.4 3.6 4 3.5 3 2.5 2 1.5 1 0.5 0 Warfarin Rivaroxaban
Rivaroxaban in VTE: EINSTEIN Rate of Recurrent VTE 3.5 3 2.5 P<0.001 for noninferiority 3 P=0.003 for noninferiority 2.1 2.1 2 1.5 1.8 Rivaroxaban Warfarin 1 0.5 0 Einstein DVT Einstein PE
Rivaroxaban in VTE: EINSTEIN 2.5 Rate of Major Bleeding (%) 2.2 2 1.5 P=0.21 P=0.03 1 0.8 1.2 1.1 Rivaroxaban Warfarin 0.5 0 Einstein DVT Einstein PE
Other Rivaroxaban Clinical Trials Einstein Choice: Rivaroxaban 10mg daily for extended prophylaxis of VTE RECORD 1-4: post-joint-replacement VTE prophylaxis PIONEER: low-dose riva + P2Y12 vs. ultra-low-dose riva + DAPT vs. VKA + DAPT for post-pci afib patients
Rivaroxaban Dosing
Apixaban (Eliquis) Absorption: 50% bioavailable No effect of food Distribution: 92-95% protein binding Metabolism: Gut: p-glycoprotein Liver: CYP450 3A4 Elimination: 27% renal T 1/2 : 7-15 hours
Apixaban (Eliquis ) Dosage Forms Tablets: 5 mg, 2.5 mg Breakable, crushable May be administered without regard to food Monitoring Serum creatinine Adverse Effects Risk of bleeding
Apixaban in Atrial Fibrillation: ARISTOTLE Rate of Stroke or Systemic Embolism (%) 3 2.5 2 1.6 P=0.01 for superiority 1.27 1.5 1 0.5 0 Warfarin Apixaban
Apixaban in Atrial Fibrillation: ARISTOTLE Rate of Major Bleed (%) 3 P<0.001 2.5 1.69 2 0.96 1.5 1 0.5 0 Warfarin Apixaban
Apixaban in VTE: AMPLIFY & AMPLIFY-EXT Rate of Recurrent VTE (%) in AMPLIFY 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 2.7 Warfarin P<0.001 for non-inferiority 2.3 Apixaban Rate of Recurrent VTE (%) in AMPLIFY-EXT 9 8 7 6 5 4 3 2 1 0 Apixaban 2.5mg BID P<0.001 for superiority of both doses vs placebo 1.7 1.7 Apixaban 5mg BID 8.8 Placebo
Apixaban in VTE: AMPLIFY & AMPLIFY-EXT Rate of Major Bleeding (%) in AMPLIFY 3 2.5 1.8 P<0.001 2 1.5 0.6 1 0.5 0 Warfarin Apixaban Rate of Major Bleeding (%) in AMPLIFY-EXT 3 2.5 2 1.5 1 0.5 0.2 0.1 0.5 0 Apixaban 2.5mg BID Apixaban 5mg BID Placebo
Apixaban: Other Clinical Trials AVERROES: atrial fib trial vs. ASA ADVANCE 1-3: post-joint-replacement VTE prophylaxis
Apixaban Dosing Extended VTE treatment Without concomitant P- gp/cyp3a4 inhibitor With concomitant P- gp/cyp3a4 inhibitor 2.5mg BID Avoid
Edoxaban (Savaysa) Absorption: 62% bioavailable No effect of food Distribution: 55% protein binding Metabolism: Gut: p-glycoprotein Elimination: 50% renal T 1/2 : 10-14 hours
Edoxaban (Savaysa ) Dosage Forms Tablets: 15mg, 30mg, 60mg May be administered without regard to food Monitoring Renal function Adverse Effects Risk of bleeding
Edoxaban Clinical Trials ENGAGE AF TIMI 48 (atrial fibrillation) Efficacy: non-inferior to warfarin Safety: less bleeding than warfarin HOKUSAI (VTE treatment) Efficacy: non-inferior to warfarin Safety: less bleeding than warfarin
Edoxaban Dosing Indication Dose Crcl 15-50ml/min Atrial fibrillation DVT/PE Crcl >95 ml/min Body weight < 60kg 60mg daily 30mg daily Do not use No adjustment 60mg daily (after 5-10 days of parenteral) 30mg daily No adjustment 30mg daily P-gp inhibitor No adjustment 30mg daily Post-joint replacement 30mg daily
DOAC Trial Data Summary Atrial Fibrillation DVT/PE treatment stroke prevention (compared to warfarin) rates of bleeding (compared to warfarin) rate of recurrent VTE (compared to LMWH bridged warfarin) rates of bleeding (compared to warfarin) Pradaxa (dabigatran) superior same same same Xarelto (rivaroxaban) same same same same Eliquis (apixaban) superior superior same superior Savaysa (edoxaban) same superior same superior
DOAC Drug-Drug Interactions Dabigatran (substrate of p-glycoprotein) Inducers (rifampin): avoid co-administration Inhibitors (dronedarone, ketoconazole): dose reduce or avoid (see prescribing info) Verapamil: separate by 2 hours Xa Inhibitors (substrates of CYP 3A4 & p-gp) Dual inducers (carbamazepine, phenytoin, phenobarb, rifampin, St. John s wort): avoid coadministration Dual inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin): reduce dose or avoid (see prescribing info)
Reversal Agents Supportive therapies (all anticoagulants) Fresh frozen plasma, fluids, blood products Prothrombin complex concentrates (all anticoagulants) 3-Factor: factors II, IX, X 4-Factor: factors II, VII, IX, X Warfarin: Vitamin K Dabigatran: idarucizumab (Praxbind) Xa Inhibitors: andexanet alfa (not available yet)
Peri-Procedural Management PLEASE DON T BRIDGE DOACs!!
The Ideal DOAC Patient Diagnosed with one of the Big Three Good kidney function Compliant with medications Average body size Not on strong p-gp or 3A4 inhibitors or inducers History of unstable INRs not related to medication noncompliance Commercially insured
Patient-Centered Care Indication & clinical data Patient preferences Don t make assumptions Utilize manufacturer assistance when appropriate Beware the donut hole
Clinical References at Your Fingertips Anticoagulationtoolkit.org European Heart Rhythm Associate Practical Guide on the Use of Non-Vitamin K Antagonist Anticoagulants in Patients with Non- Valvular Atrial Fibrillation
References Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2012. Connolly SJ et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. NEJM. 2009; 361:1139-1151 Schulman S et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. NEJM 2009; 361:2342-2352. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; November 2011. Patel MR. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. NEJM 2011; 365:883-891. The Einstein Investigators. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. NEJM 2010; 363:2499-2510. Eliquis [Package insert]. Princeton, NJ: Bristol-Myers Squibb Company. July, 2016. Granger CB et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. NEJM 2011; 365:981-992. Agnelli G et al. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. NEJM 2013; 369:799-808. Agnelli G et al. Apixaban for Extended Treatment of Venous Thromboembolism. NEJM 2013: 368;699-708. Savaysa [package insert]. Parsippany, NJ. Daiichi Sankyo, Inc. 2015. Giugliano RP et al. Edoxaban versus Warfarin in Patients with Atrial Fibrillation. NEJM 2013; 369:2093-2104. The Hokusai-VTE Investigators. Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism. NEJM 2013; 369:1406-1415. 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation: A Report of the American College of Cardiology Clinical Expert Consensus Document Task Force. JACC 2017 epub ahead of print. Heidbuchel H et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013; 15(5):625-51.