By Sean D Pokorney
Patients with atrial fibrillation have a five- to seven-fold greater risk of stroke than the general population, and approximately 20% of ischaemic strokes are due to this arrhythmia. Vitamin K antagonists such as warfarin have been the long-standing anticoagulants for stroke prevention in atrial fibrillation. There are now direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban), which are novel oral anticoagulants, that have been studied in randomised controlled trials and approved in the United States and Europe for the prevention of cardioembolic events in non-valvular atrial fibrillation.
Anticoagulant options will probably increase, as data from ENGAGE AF-TIMI 48, comparing edoxaban (factor Xa inhibitor) and warfarin, are being presented at the American Heart Association Scientific Sessions this autumn. With the advent of these new oral anticoagulants many clinicians are already questioning themselves: “How should I approach the selection of an optimal agent for my patient?”
Novel oral anticoagulants are efficacious and safe, relative to warfarin. Apixaban in ARISTOTLE and dabigatran in RE-LY were superior and rivaroxaban in ROCKET-AF was non-inferior to warfarin in the prevention of stroke and systemic embolism1-3. Apixaban was the only novel oral anticoagulant superior to warfarin with respect to all-cause mortality and major bleeding, although all novel oral anticoagulants had lower rates of haemorrhagic stroke and intracranial bleeding compared with warfarin.
Cost and insurance coverage are important influences on the availability of novel oral anticoagulants and decision-making. Patient values and preferences, especially those based on prior personal experience with warfarin, may also impact decision-making. Beyond these central issues, the pharmacokinetics and pharmacodynamics of each anticoagulant vary by patient population. Special patient populations were represented to differing degrees in the clinical trials of novel oral anticoagulants. Patients with moderate renal impairment had the greatest reduction in risk of bleeding among patients taking apixaban compared with warfarin. In patients with mild or moderate renal insufficiency, one should consider apixaban or rivaroxaban, given that these agents have renal clearance of 27%4 and 36%5, respectively, as compared with 80%6 renal clearance with dabigatran. Warfarin remains the agent of choice for severe renal dysfunction (creatinine clearance
When selecting a novel oral anticoagulant for an elderly patient, it is important to be mindful of the high risk of acute kidney injury. It is reasonable to apply the results of novel oral anticoagulant trials to patients >75 years old, as these patients were well represented. The median ages of patients in ARISTOTLE, RE-LY, and ROCKET-AF were 70, 71.5, and 73 years old, respectively, and patients >75 year old represented more than 25% of patients in both ARISTOTLE and ROCKET-AF. Dosing frequency is a consideration in the elderly, as adherence is most favourable with daily medications. The daily dosing of rivaroxaban may be more attractive than twice-daily apixaban and dabigatran; however, any novel oral anticoagulant is reasonable to consider for elderly patients.
For patients with history of myocardial infarction, there remains a question of a signal of increased myocardial infarction with dabigatran, so apixaban and rivaroxaban may be better agents. ROCKET-AF found rivaroxaban to be non-inferior to warfarin in the highest stroke risk patients of the novel oral anticoagulant trials, so rivaroxaban has the best data for use in previous stroke or transient ischaemic attack (TIA), but it is also reasonable to consider apixaban and dabigatran for these patients.
Warfarin should be used with valvular disease/mechanical valves, given the premature termination of the RE-ALIGN trial (dabigatran versus warfarin with mechanical valves), due to increased thromboembolic and bleeding events in dabigatran patients. There are limited data on novel oral anticoagulants in patients with hepatic impairment (active liver disease or liver function tests greater than twice the upper limit of normal), extreme low (<60kg) or extreme high (>120kg) weights, and triple therapy (anticoagulation while taking aspirin and a P2Y12 inhibitor). Therefore, it may be preferable to use warfarin for these patients until additional data are available.
For certain groups, the optimal selection of an oral anticoagulant will be refined, as additional data become available. Ultimately, patient values, preferences, and cost are key factors that need to be incorporated into the decision-making process.
1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51
2. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91
3. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92
4. Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug metabolism and disposition: the biological fate of chemicals 2009;37:74-81
5.Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D. Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug metabolism and disposition: the biological fate of chemicals 2009;37:1056-64.
6. Stangier J, Rathgen K, Stahle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. British journal of clinical pharmacology 2007;64:292-303.
Sean D Pokorney is from the Division of Cardiology, Duke University Medical Center, and Duke Clinical Research Institute, Durham, USA