Oral Anticoagulation in Older Persons The Next Generation

Oral Anticoagulation in Older Persons The Next Generation Luis Viana B.Sc. Phm., Pharm D (candidate), M.Ed., ACPR, CGP Clinical Consultant Pharmacist, Medical Pharmacies Group Limited Adjunct Clinical Assistant Professor, School of Pharmacy, University of Waterloo Speaker Disclosure Form Luis Viana I have not in the past 2 years, had a financial interest, arrangement or affiliation with one or more organizations that could be perceived as a direct/indirect conflict of interest in the content of the subject of this or any other program. A Pragmatic Approach Pragmatist: one who defines a proposition as true if it works satisfactorily one who believes in practical solutions and empirical evidence discards beliefs that have no rational basis http://answers.ask.com/society/philosophy/what_is_pragmatism Ali A, Bailey C, Abdelhafiz AH. Aging and Disease 2012:3:339-51. 1

A Pragmatic Approach A "pragmatic" approach focuses on the question, "What is the better treatment in the particular clinical circumstances of the patients?" Schwartz D, Lellouch J. J Clin Epidemiol 2009;62:499-505. A Pragmatic Approach 1. Should the patient receive oral anticoagulation? 2. Which anticoagulant should be prescribed in the particular clinical circumstances of the patient?" Ali A, Bailey C, Abdelhafiz AH. Aging and Disease 2012;3:339-51. prevention and treatment of venous thrombosis/pulmonary embolus prevention and treatment of thromboembolism due to atrial fibrillation or prosthetic heart valve prevention of reinfarction and thromboembolism post-mi PL Detail-Document, Comparison of Oral Antithrombotics. Pharmacist s Letter/Prescriber s Letter. February 2013. 2

STROKE (ischemic) http://www.hearthealthywomen.org/am-i-at-risk/featured/atrial-fibrillation-page-2.html Clinical conditions associated with stroke: atrial fibrillation left ventricular dysfunction prosthetic heart valves Sinnaeve PR, Brueckmann M, Clemens A, et al. J Intern Med 2012;271:15-24 Rate of thromboembolic events by age (annual rate per 100) Sinnaeve PR, Brueckmann M, Clemens A, et al. J Intern Med 2012;271:15-24 3

Atrial fibrillation (AF): highly prevalent in older adults 1.5% of adults aged 60 to 70 years 10% of adults aged >80 years risk of stroke or TIA is 4-5 times greater in patients with AF Sinnaeve PR, Brueckmann M, Clemens A, et al. J Intern Med 2012;271:15-24 Prevalence of atrial fibrillation by age Sinnaeve PR, Brueckmann M, Clemens A, et al. J Intern Med 2012;271:15-24 Atrial fibrillation (AF): in older persons, strokes in AF are more severe and disabling, and associated with high mortality ~50% at 1 year any risk score will place the average older adult with AF in a high risk category, favouring the use of anticoagulation Sinnaeve PR, Brueckmann M, Clemens A, et al. J Intern Med 2012;271:15-24 4

Risk scores: CHADS 2 CHA 2 DS 2 VAS C Sinnaeve PR, Brueckmann M, Clemens A, et al. J Intern Med 2012;271:15-24 Risk scores: CHADS 2 Grewal J, Farouque O. J Pharm Pract Res 2012;42:228-34. Risk scores: CHA 2 DS 2 VASc Grewal J, Farouque O. J Pharm Pract Res 2012;42:228-34. 5

Warfarin the gold standard for 60 years Fatal bleeding in cattle in the 1920s after eating mouldy silage made from sweet clover 1940 anticoagulant in sweet clover isolated 1948 warfarin synthesized 1952 warfarin approved as rat poison 1954 warfarin approved for human use Pirmohamed M. Br J Clin Pharmacol 2006;62:509-511. + arin (from coumarin) Why Anticoagulate with Warfarin? Warfarin in non-valvular atrial fibrillation (NVAF): efficacy of oral anticoagulation is maintained across all age groups, even the very old (> 85 years) efficacy of oral anticoagulation is maintained across all CHADS 2 scores even in those with low risk (CHADS 2 score 1-2) Ali A, Bailey C, Abdelhafiz AH. Aging and Disease 2012;3:339-51. Why Anticoagulate with Warfarin? Warfarin in non-valvular atrial fibrillation (NVAF): the greatest net clinical benefit of oral anticoagulation is observed in those > 85 years old due to their high base line stroke risk good quality of INR control is achievable regardless of age Ali A, Bailey C, Abdelhafiz AH. Aging and Disease 2012;3:339-51. 6

Why Anticoagulate with Warfarin? Warfarin in non-valvular atrial fibrillation (NVAF): aspirin has very little benefit in stroke risk reduction in patients with NVAF and this benefit tends to be attenuated further in old age oral anticoagulation therapy remains superior to the combination of antiplatelet agents Ali A, Bailey C, Abdelhafiz AH. Aging and Disease 2012;3:339-51. Underuse of Warfarin in Older Persons Statistics: > 85 years: 1 in 3 eligible patients were receiving warfarin on admission for stroke may have valid reason to avoid warfarin patient refusal, non-compliance with INR monitoring, bleeding diathesis, history of major bleeding or significant, alcohol consumption < 75 years old: 3 out of 4 eligible patients were receiving warfarin on admission for stroke Partington SL, Abid S, Teo K, et al. Thromb Res 2007;120:663-9. Underuse of Warfarin in Older Persons Reasons: underestimation of thromboembolic risk overestimating bleeding risk intracranial hemorrhage frailty history of non-adherence falls risk advanced illness need for monitoring malignancy cognitive impairment advanced age Sinnaeve PR, Brueckmann M, Clemens A, et al. J Intern Med 2012;271:15-24 7

Underuse of Warfarin in Older Persons Reasons: bleeding risk Alternatives to Warfarin The development of novel oral anticoagulants, such as direct thrombin inhibitors (DTI s) and factor Xa inhibitors, may provide a safer and more effective alternative for stroke prevention. Sinnaeve PR, Brueckmann M, Clemens A, et al. J Intern Med 2012;271:15-24 Oral Anticoagulants Vitamin K Antagonists New Oral Anticoagulants Warfarin Direct Thrombin Inhibitors dabigatran Factor Xa Inhibitors rivaroxaban apixaban edoxaban 8

Oral Anticoagulants Mechanism of Action warfarin rivaroxaban, apixaban Factor Xa inhibitors dabigatran Direct Thrombin Inhibitor Major results of phase 3 trials of NGOA compared to warfarin in atrial fibrillation Drug/Trial Stroke or thromboembolism Hemorrhagic stroke dabigatran (RE-LY) 34% reduction 74% reduction rivaroxaban (ROCKET-AF) non-inferior to warfarin 40% reduction apixaban (ARISTOTLE) 20% reduction 50% reduction Connolly SJ, Ezekowitz MD, Yusuf S, et al. N Engl J Med 2009;361:1139-51. (RE-LY) Patel MR, Mahaffey KW, Garg J, et al. N Engl J Med 2011;365:883-91. (ROCKET-AF) Granger CB, Alexander JH, McMurray JJ, et al. N Engl J Med 2011;365:981-92. (ARISTOTLE) Major bleeding similar similar 30% reduction Class effects compared with warfarin efficacy non inferior or possibly better than warfarin in terms of prevention of ischemic/hemorrhagic stroke or systemic embolism less intracranial bleeding than warfarin Connolly SJ, Ezekowitz MD, Yusuf S, et al. N Engl J Med 2009;361:1139-51. (RE-LY) Patel MR, Mahaffey KW, Garg J, et al. N Engl J Med 2011;365:883-91. (ROCKET-AF) Granger CB, Alexander JH, McMurray JJ, et al. N Engl J Med 2011;365:981-92. (ARISTOTLE) Weitz JI, Gross PL. Hematology Am Soc Hematol Educ Program. 2012;2012:536-40. 9

Class effects compared with warfarin trend for reduced mortality compared with warfarin no hepatic toxicity Connolly SJ, Ezekowitz MD, Yusuf S, et al. N Engl J Med 2009;361:1139-51. (RE-LY) Patel MR, Mahaffey KW, Garg J, et al. N Engl J Med 2011;365:883-91. (ROCKET-AF) Granger CB, Alexander JH, McMurray JJ, et al. N Engl J Med 2011;365:981-92. (ARISTOTLE) Weitz JI, Gross PL. Hematology Am Soc Hematol Educ Program. 2012;2012:536-40. Differentiating effects compared with warfarin dabigatran small increase in risk of myocardial infarction compared to warfarin dabigatran and rivaroxaban more gastrointestinal bleeding than with warfarin Connolly SJ, Ezekowitz MD, Yusuf S, et al. N Engl J Med 2009;361:1139-51. (RE-LY) Patel MR, Mahaffey KW, Garg J, et al. N Engl J Med 2011;365:883-91. (ROCKET-AF) Weitz JI, Gross PL. Hematology Am Soc Hematol Educ Program. 2012;2012:536-40. Differentiating effects compared with warfarin dabigatran (150 mg po bid) lower risk of ischemic stroke than warfarin apixaban lower risk of stroke and major bleeding compared with warfarin Connolly SJ, Ezekowitz MD, Yusuf S, et al. N Engl J Med 2009;361:1139-51. (RE-LY) Granger CB, Alexander JH, McMurray JJ, et al. N Engl J Med 2011;365:981-92. (ARISTOTLE) Weitz JI, Gross PL. Hematology Am Soc Hematol Educ Program. 2012;2012:536-40. 10

Summary of characteristics compared to warfarin Feature Warfarin Onset Slow Rapid Dosing Variable Fixed Food effect Yes No (vitamin K rich foods) Drug interactions Many Some Monitoring Yes No Offset Long Shorter Antidote Yes No Weitz JI, Gross PL. Hematology Am Soc Hematol Educ Program. 2012;2012:536-40. Pharmacokinetics Feature Warfarin Dabigatran Rivaroxaban Apixaban Bioavailability 100% 6% 60-80% 60% Dosing once daily twice daily once or twice twice daily daily Time to peak effect 4-5 days 1-3 hrs 2-4 hrs 1-2 hrs Half-life 40 hrs 8-15 hrs 7-11 hrs 12 hrs Renal clearance none 80% 33% 25% Drug interactions multiple P-gp 3A4/P-gp 3A4/P-gp Weitz JI, Gross PL. Hematology Am Soc Hematol Educ Program. 2012;2012:536-40. Indications (Canada) Indication Warfarin Dabigatran Rivaroxaban Apixaban (stroke) in NVAF (stroke) with prosthetic heart valve (stroke) in patients who have undergone elective THR or TKR YES YES YES YES YES NO NO NO YES YES YES YES Treatment of venous YES NO YES NO thromboembolic events (DVT & PE) and prevention of recurrent Pradaxa DVT and PE (product monograph). Boehringer Ingelheim Canada Ltd. January 27, 2012. Xarelto (product monograph). Bayer Inc. April 12, 2013. Eliquis (product monograph). Pfizer Canada Inc. November 27, 2012. 11

Indication and Dosage (Canada) Indication (stroke) in NVAF (stroke) with prosthetic heart valve (stroke) in patients who have undergone elective THR or TKR Treatment of venous thromboembolic events (DVT & PE) and prevention of recurrent DVT and PE Dabigatran (Pradax ) 150 mg po twice daily (CrCl > 30 ml/min) 110 mg po twice daily (> 80 years old) NOT INDICATED 220 mg (2 x 110 mg) po once daily 150 mg (2 x 75 mg) po once daily (> 75 years old) 75 mg (initial dose 1-4 hrs post-op), then 150 mg po once daily (CrCl 30-50 ml/min) NOT INDICATED Severe renal impairment (CrCl < 30 ml/min) contraindicated Pradax (product monograph). Boehringer Ingelheim Canada Ltd. January 27, 2012. Indication and Dosage (Canada) Indication Rivaroxaban (Xarelto ) (stroke) in NVAF (stroke) with prosthetic heart valve (stroke) in patients who have undergone elective THR or TKR Treatment of venous thromboembolic events (DVT & PE) and prevention of recurrent DVT and PE 20 mg po once daily with food (CrCl > 50 ml/min) 15 mg po once daily (CrCl = 30-49 ml/min) NOT INDICATED 10 mg po once daily (initial dose given with 6-10 hrs post-op) THR give for 35 days TKR give for 14 days 15 mg po bid for first 3 weeks, then 20 mg po once daily Severe renal impairment (CrCl < 30 ml/min) contraindicated Xarelto (product monograph). Bayer Inc. April 12, 2013. Indication and Dosage (Canada) Indication (stroke) in NVAF (stroke) with prosthetic heart valve (stroke) in patients who have undergone elective THR or TKR Treatment of venous thromboembolic events (DVT & PE) and prevention of recurrent DVT and PE Apixaban (Eliquis ) 5 mg po bid (> 25 ml/min) 2.5 mg po bid (if patient has at least 2 of the following: age > 80 years, body weight < 60 kg, serum creatinine > 133 mmol/l NO 2.5 mg po bid (initial dose to be taken 12-24 hrs post-op) THR give for 32-38 days TKR give for 10-14 days NO Severe renal impairment (CrCl < 15 ml/min) contraindicated Eliquis (product monograph). Pfizer Canada Inc. November 27, 2012. 12

Drug Interactions Mechanism Dabigatran Rivaroxaban Apixaban CYP 3A4 NO YES YES/NO P-glycoprotein (P-gp) YES YES YES CYP 3A4 involved with metabolism of many drugs P-gp intestinal efflux transporter of many drugs CYP 3A4 + P-gp interactions are a concern Walenga JM, Adiguzel C. Int J Clin Pract 2010;64:835-8. Drug Interactions antiplatelet agents (increased bleeding risk) aspirin, clopidogrel NSAID s (increased bleeding risk) naproxen, diclofenac Walenga JM, Adiguzel C. Int J Clin Pract 2010;64:835-8. Drug Interactions dabigatran P-gp inhibitors ( levels, anticoagulant effect) verapamil, dronaderone, quinidine, amiodarone, ketoconazole CYP 3A4 + P-gp inhibitors ( levels, anticoagulant effect) clarithromycin CYP 3A4 + P-gp inducers ( levels, anticoagulant effect) rifampin, St. John s Wort, pantoprazole Pradaxa (product monograph). Boehringer Ingelheim Canada Ltd. January 27, 2012 Walenga JM, Adiguzel C. Int J Clin Pract 2010;64:835-8. 13

Drug Interactions dabigatran antacids ( levels, anticoagulant effect) administer dabigatran 2 hrs before taking antacid pantoprazole ( levels, anticoagulant effect) dabigatran absorption is ph dependent peak concentrations reduced by 11-54% when given with pantoprazole 40 mg po bid clinical significance is unclear Pradaxa (product monograph). Boehringer Ingelheim Canada Ltd. January 27, 2012 Walenga JM, Adiguzel C. Int J Clin Pract 2010;64:835-8. Drug Interactions rivaroxaban CYP 3A4 + P-gp inhibitors ( levels, anticoagulant effect) clarithromycin ketoconazole, itraconzole, voriconazole ritonavir CYP 3A4 + P-gp inducers ( levels, anticoagulant effect) rifampin, St. John s Wort phenytoin, carbamazepine, phenobarbital Xarelto (product monograph). Bayer Inc. April 12, 2013. Walenga JM, Adiguzel C. Int J Clin Pract 2010;64:835-8. Drug Interactions apixaban limited information available CYP 3A4 + P-gp inhibitors ( levels, anticoagulant effect) ketoconazole, itraconazole diltiazem, amiodarone, dronaderone CYP 3A4 + P-gp inducers ( levels, anticoagulant effect) rifampin, St. John s Wort phenytoin, carbamazepine, phenobarbital Xarelto (product monograph). Bayer Inc. April 12, 2013. Walenga JM, Adiguzel C. Int J Clin Pract 2010;64:835-8. 14

Choice of anticoagulant based on patient characteristics Characteristic Drug Choice Rationale Mechanical valve or valvular atrial fibrillation Liver dysfunction with increased INR warfarin warfarin next generation oral anticagulants not studied new agents require hepatic metabolism Poor compliance warfarin or nothing missed doses of greater consequence with shorter acting new agents Stable on warfarin warfarin consider switching at patient request CrCl < 30 ml/min warfarin safety for persons with significant renal dysfunction has not been established CrCl 30-50 ml/min rivaroxaban, apixaban oral factor Xa inhibitors are less affected by impaired renal function than dabigatran Weitz JI, Gross PL. Hematology Am Soc Hematol Educ Program. 2012;2012:536-40. Choice of anticoagulant based on patient characteristics Characteristic Drug Choice Rationale Cannot swallow medication whole warfarin, rivaroxaban or apixaban dabigatran must be swallowed whole capsule cannot be opened Recent GI bleed apixaban more GI bleeding with dabigatran (150 mg po bid) or rivaroxaban than with warfarin Recent ischemic stroke on warfarin dabigatran dabigatran (150 mg po bid) associated with lower risk of ischemic stroke than warfarin Recent acute coronary syndrome rivaroxaban or apixaban slight increased risk of MI with dabigatran Poor compliance with twice daily or request for a once daily regimen rivaroxaban only agent given once daily Weitz JI, Gross PL. Hematology Am Soc Hematol Educ Program. 2012;2012:536-40. 15

Final Considerations: conversion to or from warfarin: dependant on renal function see individual product monographs for detailed information stop before elective surgery dependant on renal function see individual product monographs for detailed information Final Considerations: consider the possibility of clinically significant drug interactions clinical effect of drug interaction may not be apparent with warfarin, dose adjust based on change in INR no antidote with warfarin, use vitamin K WARFARIN DABIGATRAN RIVAROXABAN APIXABAN 16

QUESTIONS 17