Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: A Brief Comparison of Four Agents Abbreviations AF: Atrial fibrillation ARISTOTLE: Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation FDA: Food and Drug Administration INR: International normalized ratio PT: Prothrombin time RE LY: Randomized Evaluation of Long Term Anticoagulation Therapy ROCKET AF: Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial n Atrial Fibrillation
Although appropriate use of warfarin can markedly reduce the risk of stroke in patients with atrial fibrillation (AF), warfarin therapy has been challenging for several reasons. There is no specific dose to start, frequent testing for adequacy of anticoagulation is necessary and inconvenient, and multiple drug food and drug drug interactions hinder the adherence to optimal anticoagulation. 1 These limitations of warfarin therapy have been the impetus for development of new oral anticoagulants. Ximelgatran, a direct thrombin inhibitor, was one of the first novel anticoagulants that was widely tested. Although it showed some early promising results for prevention of stroke in AF patients, ximelgatran was withdrawn from the market because of reports of fatal hepatotoxicity. 2 The past decade, however, has been a period of intense research and advancement in the development of new oral anticoagulants. Dabigatran, a direct thrombin inhibitor, and rivaroxaban and apixaban, two factor Xa inhibitors, have been tested in landmark clinical trials versus warfarin. In their respective large scale clinical trials, RE LY (dabigatran) 3, ROCKET AF (rivaroxaban) 4 and ARISTOTLE (apixaban) 5, these novel oral anticoagulants were shown to be non inferior to warfarin in reducing the rate of stroke or systemic embolism. 4 6 Compared with warfarin, all three agents showed a trend toward reduced rate of stroke or systemic embolism, which reached statistical significance for dabigatran (150mg bid), as well as for apixaban (5mg bid). Novel anticoagulants also showed a trend toward improved all cause mortality, which reached statistical significance only for apixaban. Interestingly, all these agents were associated with lower rates of intracranial bleeding compared with warfarin. Currently, dabigatran and rivaroxaban are available in the United States and the rest of the world for several indications. While still awaiting the FDA approval, apixaban is marketed in many other countries (Table 1). In light of these facts, several recent studies have provided indirect comparisons between dabigatran, rivaroxaban, and apixaban for stroke prevention in atrial fibrillation. 7 11 Although there were some differences in the methodology, the main results of the indirect comparison meta analyses were similar. Indirect comparison meta analyses by separate investigators showed that dabigatran (150mg bid) was significantly more effective than rivaroxaban (20mg daily) for prevention of stroke or systemic embolism. These indirect comparisons did not find a significant difference between apixaban (5mg bid) versus dabigatran (150mg bid) or versus rivaroxaban (20mg daily) for that endpoint. Apixaban, however, was associated with lower rate of major or clinically significant bleeding compared with both dabigatran (150mg bid) and rivaroxaban. Since patients in the ROCKET AF trial were more medically complex with higher CHADS 2 scores (a fact also represented by the higher control arm event rates as compared with patients in RE LY and ARISTOTLE), one of these indirect comparison meta analyses 7 also reported the subgroup results for the three novel anticoagulants only among the high risk patients. Although that analysis showed numerically superior efficacy for apixaban and dabigatran compared with rivaroxaban, the differences did not reach statistical significance. 7 Several reports, as well as a recent meta analysis of dabigatran trials have raised concerns about an increased risk of myocardial infarction in patients taking dabigatran. 3,12 Therefore, this issue was also addressed in some of the indirect comparison meta analyses of novel oral anticoagualnts. One 10, but not
all 9, of the existing indirect comparison meta analyses suggested an increased risk of myocardial infarction with dabigatran, compared with either rivaroxaban, or apixaban. This difference is presumably caused by release of high amounts of thrombin at the site of plaque rupture which could not be neutralized by dabigatran, compared with the Xa inhibitors; i.e. rivaroxaban and apixaban (Table 2). 12 There are several limitations to an indirect comparison meta analysis using these three major trials. Besides the differences in the level of medical complexity and co morbidity burden, the design of RE LY, ROCKET AF and ARISTOTLE was not completely identical. For example, RE LY was an open label trial while ROCKET AF and ARISTOTLE were both double blind studies. Yet, it is unlikely that mega trials for comparison of the efficacy of new anticoagulants will be conducted in the near future. Therefore, indirect comparisons and individual patient meta analysis of data remain as helpful alternatives. Particularly helpful might be an individual patient meta analysis focusing on net clinical benefit of these agents, taking into consideration the efficacy in reducing stroke and systemic embolism, all cause mortality, as well as clinically significant bleeding events. In addition to such analyses, long term followup of patients in the three trials, as well as observational reports from those who receive novel oral anticoagulants in the real world setting could improve our understanding of benefits and limitations of these novel oral anticoagulants. The decision to choose among these novel anticoagulants or even to choose one of these versus warfarin is not easy. For example, although apixaban seems to have an overall more impressive profile related to safety plus efficacy, as well as all cause mortality, the median follow up period in the trial that suggested such a profile (ARISTOTLE) was shorter compared with trials of dabigatran (RE LY) or rivaroxaban (ROCKET AF). Moreover, unlike dabigatran and rivaroxaban, apixaban is yet to be approved by the FDA. Therefore, real world data about its use and safety is limited to other countries where the drug has been in use. 13 Novel oral anticoagulants have added to our arsenal of therapies for stroke prevention in atrial fibrillation. Yet, the transition to novel agents would take place gradually as the patients out of pocket costs for these drugs are reduced, and as more data are accumulated about their safety, efficacy and particular usefulness in various patient subgroups. For example, we still await to see how these novel agents work in subgroups such as patients with prosthetic heart valves wherein vitamin K antagonists are frequently being used. Lack of agents that can effectively reverse the anticoagulant effects of novel oral agents in cases of unforeseen emergency is also a limitation. Although a recent study in healthy volunteers showed that prothrombin complex concentrate reversed the anticoagulant effects of rivaroxaban, that was not the case for dabigatran 14 and dialysis or the passage of time (short half life) remains to remove these agents from the circulation. Finally, given their partial or complete dependence on renal excretion, unlike vitamin K antagonists, novel agents may need dose adjustments in patients with renal impairment. In conclusion, while warfarin would probably remain as a major option for many patients, novel oral anticoagulants have brought exciting alternatives for physicians and patients. Table 1. Comparison of Advantages and Disadvantages of Novel Oral Anticoagulants and Warfarin
Need for frequent testing Commonplace assays to measure effective anticoagulant activity Need for frequent dose adjustments Need for dose adjustment in case of kidney impairment Vitamin K Novel Oral Anticoagulants Antagonists Warfarin Dabigatran (150mg bid) Rivaroxaban (20mg daily) Apixaban (5mg bid) Yes (PT and INR) No No No Yes (PT and INR) No No No Yes No No No No Yes Yes Yes Drug drug interactions Many Few Few Few Drug food interactions Many Few Few Few Dosing Daily Twice daily Daily Twice daily Out of pocket costs for patients Antidotes for reversal Clinical data about safety and efficacy Clinicians and patients experience Reduction in stroke or systemic embolism All cause death Inexpensive Expensive Expensive Expensive Vitamin K, Fresh frozen plasma, prothrombin complex concentrate 50 + years of experience all around the world Not available A few years of experience prothrombin complex concentrate? 14 Recent experience Extensive Growing Recently started Not available Not approved in the USA, recently in use in Europe and some other countries Minimal All novel anticoagulants proved non inferiority compared with warfarin. Superiority was achieved in cases of dabigatran (150mg bid) and apixaban (5mg bid) A trend toward improved all cause mortality with dabigatran (150mg bid), rivaroxaban (20mg daily), and apixaban (5mg bid) compared with warfarin. The trend reached statistical significance for apixaban. Major Bleeding Comparable among warfarin, dabigatran (150mg bid) and rivaroxaban (20mg daily); lower rate of major bleeding with apixaban (5mg bid). PTT: partial thromboplastin time, INR: international normalized ratio
Table 2. Efficacy and Safety of Novel Oral Anticoagulants Based on Indirect Comparisons from RE LY, ROCKET AF and ARISTOTLE T Trials Prevention of Stroke or systemic embolism Dabigatran (150mg bid) better than rivaroxaban (20mg daily) No significant difference between apixaban (5mg bid) versus either Dabigatran (150mg bid) or rivaroxaban (20mg daily) Major bleeding Significantly lower rate of major bleeding with apixaban (5mg bid) compared with either dabigatran (150mg bid) or rivaroxaban (20mg daily) No significant difference between dabigatran (150mg bid) or rivaroxaban (20mg daily) All cause mortality No significant difference between dabigatran (150mg bid), rivaroxaban (20mg daily), and apixaban* (5mg bid) Myocardial infarction No difference between apixaban (5mg bid) and rivaroxaban (20mg daily) Possibly more myocardial infarctions with dabigatran 10,12 Follow up duration of the landmark studies Longer median follow up for dabigatran, then for rivaroxaban, and then for apixaban Indirect comparisons may be prone to bias. ARISTOTLE: Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation, RE LY: Randomized Evaluation of Long Term Anticoagulation Therapy, ROCKET AF: Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial n Atrial Fibrillation, Disclosures: None
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