Objectives New and Emerging Anticoagulants Adraine Lyles, PharmD, BCPS Clinical Pharmacy Specialist VCU Medical Center Describe the pharmacology of the novel oral anticoagulants Discuss the clinical evidence that led to the approval of dabigatran, rivaroxaban and apixaban Review the prescribing information for the initiation and discontinuation of the new anticoagulants Objectives (continued) Discuss safety concerns associated with the new anticoagulants Review the patient education necessary for safe administration of dabigatran, rivaroxaban and apixaban Development of New Anticoagulants Wish list for healthcare providers Improvements in anticoagulant safety More predictability in response Simplified dosing Wish list for patients Improvements in anticoagulant safety Less frequent monitoring Ease of administration 1
New Anticoagulant Classes Oral Direct Thrombin (Factor IIa) Inhibitors Dabigatran (Pradaxa ) Factor Xa Inhibitors Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Arterioscler Thromb Vasc Biol. ; 32: 569 574 Development Timeline 2003: clinical trials conducted on ximelagatran (Exanta) 2006: Exanta NDA withdrawn by FDA 2010: FDA approval of dabigatran 2011: FDA approval of rivaroxaban : FDA approval of apixaban Arterioscler Thromb Vasc Biol. ; 32: 569 574 Dabigatran Rivaroxaban Apixaban Brand Name Pradaxa Xarelto Eliquis Rx Class DTI Factor Xa Inhibitor Factor Xa Inhibitor Indication(s) CVA prevention in AF VTE prevention in ortho surgery; VTE treatment Half life (hrs) 12 14 5 9 12 Bioavailability (%) 3 7% 80 100% ~66% Renal Cl (%) 80 66 25 DDIs P gp inducers/ P gp and CYP3A4 inducers/ Frequency BID QD BID P gp and CYP3A4 inducers/ Dabigatran Evidence From RE LY 18113 pts with Afib Outcomes: CVA or systemic embolism Comparator: Adjusted dose warfarin Avg CHADS2=2; TTR=64 in warfarin gp Results 150mg dose superior to warfarin in reduction of hemorrhagic and ischemic CVA; 110mg dose noninferior to warfarin; no increase in bleeding but increase in MI Connolly S el al. NEJM 2009; 361: 1139 1151 Adapted from Clinical Pharmacology and Therapeutics.Oct 2011;90 (4):503 2
Dabigatran Dosing 150 mg PO twice daily Special Populations Renal Insufficiency 80% renal excretion 75mg PO twice daily in pts with CrCl 15 30 No dosing recommendations for pts with CrCl<15 Dabigatran Conversions Warfarin to dabigatran Start dabigatran when INR < 2.0 Dabigatran to warfarin CCl CrCl >50: start warfarin 3 days bf before d/c CrCl 31 50: start warfarin 2 days before d/c CrCl 15 30: start warfarin 1 day before d/c CrCl < 15: no recommendations Dabigatran Conversions Dabigatran to Parenteral Wait 12 24 hrs (depending on RF) after last dose of dabigatran to start parenteral Parenteral to Dabigatran Start dabigatran 0 2hrs before next scheduled dose of parenteral, OR Start dabigatran at the d/c of a continuous infusion Dabigatran Advantages As safe and effective as warfarin, without the monitoring and extensive list of interactions Disadvantages Major safety concerns due to increase risk of major bleeding, esp. in the elderly Controversy over approved 75mg dose ADR of dyspepsia No immediate future for additional indications Practice Guideline Support ACCF/AHA Dabigatran is useful as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with atrial fibrillation and risk factors for stroke or systemic embolization (Level of evidence: B) ACCP For patients with AF, including those with paroxysmal AF, for recommendations in favor of oral anticoagulation, we suggest dabigatran 150mg BID rather than adjusted dose vitamin K antagonist (Grade 2B) Includes patients with AF and a CHADS 2 score of >/= 1 Rivaroxaban was not approved at the time of the writing of the guidelines. Circulation. 2011; 123:1144 1150., CHEST ; 141(2)(Suppl):e531S e575s Dabigatran Rivaroxaban Apixaban Brand Name Pradaxa Xarelto Eliquis Rx Class DTI Factor XaInhibitor Factor XaInhibitor Indication(s) CVA prevention in AF VTE prevention in ortho surgery; VTE treatment Half life (hrs) 12 14 5 9 12 Bioavailability (%) 3 7% 80 100% ~66% Renal Cl (%) 80 66 25 DDIs P gp inducers/ P gp and CYP3A4 inducers/ Frequency BID QD BID P gp and CYP3A4 inducers/ Adapted from Clinical Pharmacology and Therapeutics.Oct 2011;90 (4):503 3
Rivaroxaban Evidence From ROCKET AF 14,000 pts w/ Afib Outcomes: CVA or systemic embolism Comparator: Adjusted dose warfarin Avg CHADS2=3.5; TTR=58 in warfarin gp Results non inferior to warfarin; no increase in incidence of ICH, but increase seen in GI bleeding Rivaroxaban Evidence From RECORDS 1 and 3 4541 pts s/p hip replacement (1) and 2531 pts s/p total knee replacement (3) Outcomes: DVT, nonfatal PE, or death from any cause Comparator: Enoxaparin 40mg daily Results rivaroxaban superior to enoxaparin 40mg daily (unpreferred/unapproved dose for both procedures) Patel MR et al.. NEJM 2011; 3845(10): 883 891 Rivaroxaban Evidence for the EINSTEIN Trials EINSTEIN DVT 3449 pts with acute DVT (w/o PE) Rivaroxaban vs. enoxaparin warfarin x 3 12mos Non inferior in efficacy and safety EINSTEIN PE 4883 pts with acute PE +/ DVT Rivaroxaban vs. enoxaparin warfarin x 12mos Non inferior in efficacy and safety, plus 50% reduction in major bleeding EINSTEIN EXT 1197 pts with acute DVT or PE who had completed 6 12 months of anticoagulant tx with rivaroxaban or VKA Study pts given rivaroxaban or placebo for another 6 12 months 82% relative risk reduction in VTE recurrence Significant increase in overall bleeding N Engl J Med 2010;363:2499 510 N Engl J Med ;366:1287 97 N Engl J Med 2010;363:2499 510 Rivaroxaban Administration VTE Prevention s/p ortho surgery 10mg daily Start 6 10 hrs s/p surgery and hemostasis Treat for 35 days (hip) or 12 days (knee) CVA Prevention (Afib) 15 20mg daily with evening meal VTE Treatment 15 mg with food twice daily for the first 21 days, then 20mg with food daily for remainder of treatment Rivaroxaban/Apixaban Drug Drug Interactions Strong P glycoprotein & CYP3A4 Conivaptan Clarithromycin Indinavir Lopinavir Ritonavir Itraconazole Ketoconazole Strong P glycoprotein & CYP3A4 inducers Carbamazepine Phenytoin Rifampin St. John s wort Tipranavir/ritonavir Listed medications are contraindicated in combination with rivaroxaban and apixaban Xarelto prescribing information. Raritan, NJ. Janssen Pharmaceuticals, Inc; 4
Rivaroxaban Conversions Warfarin to rivaroxaban D/c warfarin and start rivaroxaban when INR <3.0 No data on how to switch hfrom rivaroxaban to warfarin Other anticoagulants to rivaroxaban Switch to Rivaroxaban 0 2 hrs before scheduled evening dose of the other med Dabigatran Rivaroxaban Apixaban Brand Name Pradaxa Xarelto Eliquis Rx Class DTI Factor Xa Inhibitor Factor Xa Inhibitor Indication(s) CVA prevention in AF VTE prevention in ortho surgery; VTE treatment Half life (hrs) 12 14 5 9 12 Bioavailability (%) 3 7% 80 100% ~66% Renal Cl (%) 80 66 25 DDIs P gp inducers/ P gp and CYP3A4 inducers/ Frequency BID QD BID P gp and CYP3A4 inducers/ Xarelto prescribing information. Raritan, NJ. Janssen Pharmaceuticals, Inc; Adapted from Clinical Pharmacology and Therapeutics.Oct 2011;90 (4):503 Apixaban Evidence from ARISTOTLE 18,201 pts with atrial fibrillation Outcomes: ischemic or hemorrhagic stroke, or systemic embolism Comparator: adjusted dose warfarin Avg CHADS2=2.1, TTR=66% Results 5mg dose superior to warfarin reduction of hemorrhagic stroke, but not ischemic Superior in reduction of major bleeding and all cause mortality (secondary objectives) NEJM 2011; 365:981 92 Apixaban Dosing 5mg twice daily 2.5mg daily in certain pts with at least 2 of the following: Age 80 years Weight 60kg Scr 1.5mg/dl Conversion guidelines similar to that of rivaroxaban Eliquis prescribing information. Princeton, NJ Bristol Meyers Squibb Co. December Data Comparison in Afib Data Comparison in Afib J Am Coll Cardiol ; 59:1413 25 J Am Coll Cardiol ; 59:1413 25 5
Data Comparison in Afib Data Comparison in Afib J Am Coll Cardiol ; 59:1413 25 J Am Coll Cardiol ; 59:1413 25 Data Comparison in Afib Primary Endpoint of CVA or Systemic Embolism Data Comparison in Afib Primary Safety Endpoint of Major Bleeding J Am Coll Cardiol ; 59:1413 25 J Am Coll Cardiol ; 59:1413 25 Dabigatran Administration Dabigatran Administration 6
Dabigatran Administration Tablets cannot be broken/crushed/chewed Available in unit dose blister packs or bulk bottles of 60 tablets Must be dispensed in original container to avoid tablet degradation Tablets in opened bottles lose stability after 120 days 120 Dabigatran Administration Take doses at the same time each day Missed doses should be skipped if they cannot be taken at least 6 hours before the next dose Assist patients by lbli labeling bottles and including auxillary labels with expiration dates Rivaroxaban Administration 15 and 20mg doses should be taken with the evening meal Missed dose should be taken as soon as possible on the same day Patel MR et al.. NEJM 2011; 3845(10): 883 891 Bleeding Complications Bleeding with Dabigatran No antidote/reversal agent If bleeding occurs, drug should be discontinued Activated charcoal can be used in overdose (if ingestion is recent) Drug can be dialyzed over 2 3 hours(about 60% removal) Limited data with PCC 7
Bleeding with Rivaroxaban and Apixaban No antidote/reversal agent Drugs should be discontinued in the event of bleeding Dialysis i is not an option d/t high h protein binding Surgical hemostasis, FFP or PRBC tranfusion should be considered PCC, factors may be useful Risk and Evaluation Mitigation Strategy (REMS) Patel MR et al.. NEJM 2011; 3845(10): 883 891 Patient and Provider Safety Information 15 and 20mg rivaroxban doses must be taken with the evening meal Increased risk of VTE with rivaroxaban and apixaban if doses are skipped without introduction of an adequate alternative anticoagulant 68 year old with nonvalvular A fib On warfarin x 12 years with stable INRs CHADS2=2 CrCl>60 ml/min www.xareltorems.com www.eliquisrems.com 57 year old with A fib and CAD Active lifestyle; avid traveler to Europe CHADS2=1 36 year old with idiopathic, recurrent DVT/PE Full time worker, part time student Has difficulty coming to clinic for INR monitoring 8
48 year old with recurrent DVTs and HIV Non adherence issues due to polypharmacy 62 year old with a fib, HTN and h/o PUD TTR on warfarin = 15% Poor health literacy Thoughts for the future Safety issues Antidotes/reversal mechanisms Special populations (elderly, pregnant pts) Use in hepatic/renal dysfunction Use in hepatic/renal dysfunction Long term safety and efficacy Clinical significance of trial data Implications for warfarin /heparin therapy Conversion dosing 9