Direct oral anticoagulants for Japanese atrial fibrillation in the elderly
2017; Elsevier BV; Volume: 71; Issue: 3 Linguagem: Inglês
10.1016/j.jjcc.2017.10.010
ISSN1876-4738
AutoresYusuke Kondo, Keitaro Senoo, Yoshio Kobayashi,
Tópico(s)Venous Thromboembolism Diagnosis and Management
ResumoAtrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice, and its prevalence is strongly correlated with age, predisposing the elderly to an increased risk of embolic stroke [[1]Lloyd-Jones D.M. Wang T.J. Leip E.P. Larson M.G. Levy D. Vasan R.S. et al.Lifetime risk for development of atrial fibrillation: the Framingham Heart Study.Circulation. 2004; 110: 1042-1046Crossref PubMed Scopus (1601) Google Scholar]. Prevalence estimates of AF are as follow: age <55 years, 80 years, >8% [[2]Go A.S. Hylek E.M. Phillips K.A. Chang Y. Henault L.E. Selby J.V. et al.Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.JAMA. 2001; 285: 2370-2375Crossref PubMed Scopus (5191) Google Scholar]. Patients with AF have a 5-fold greater risk of stroke [1Lloyd-Jones D.M. Wang T.J. Leip E.P. Larson M.G. Levy D. Vasan R.S. et al.Lifetime risk for development of atrial fibrillation: the Framingham Heart Study.Circulation. 2004; 110: 1042-1046Crossref PubMed Scopus (1601) Google Scholar, 3Vidaillet H. Granada J.F. Chyou Po Maassen K. Ortiz M. Pulido J.N. et al.A population-based study of mortality among patients with atrial fibrillation or flutter.Am J Med. 2002; 113: 365-370Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar]. Therefore, anticoagulant therapy is essential for managing the thrombotic risks, particularly among the elderly. Vitamin K antagonists (VKAs) such as warfarin have, until recently, been the only available oral anticoagulant treatment option. Although effective, VKAs have unpredictable pharmacologic effects, thus requiring regular coagulation monitoring and dose adjustment to maintain effects within the therapeutic range. These limitations increase the complexity of VKA use in the clinical setting, creating a burden for patients, physicians, and pharmacists. Therefore, the current focus of clinical development is on new oral anticoagulants that directly target thrombin or activated factor X. Four direct oral anticoagulants (DOACs)—dabigatran, rivaroxaban, apixaban, and edoxaban—have undergone trials investigating their safety and efficacy in the management of thromboembolic risk in AF. DOACs are more efficacious than VKAs for the prevention of stroke and systemic embolism in patients with AF. With the risk of intracranial bleeding lower than that when using VKAs, they appear to have a favorable safety profile, making them promising alternatives to VKAs worldwide [[4]Miller C.S. Grandi S.M. Shimony A. Filion K.B. Eisenberg M.J. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation.Am J Cardiol. 2012; 110: 453-460Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar]. A meta-analysis showed that DOACs are effective in the prevention of stroke and systemic embolism in Japanese patients with AF, and they have been adopted in clinical practice because they confer certain practical advantages over VKAs [[5]Senoo K. Lau Y.C. Dzeshka M. Lane D. Okumura K. Lip G.Y. Efficacy and safety of non-vitamin K antagonist oral anticoagulants vs. warfarin in Japanese patients with atrial fibrillation – meta-analysis.Circ J. 2015; 79: 339-345Crossref PubMed Scopus (32) Google Scholar]. However, DOACs are reported to have fewer drug-drug and drug-food interactions and have been licensed for use without the need for routine monitoring of anticoagulation effect-related effectiveness. It must be kept in mind that limited long-term efficacy and safety data are available and that patient adherence to DOACs may be a major issue in the real-world clinical setting. Although several reviews have evaluated the safety and efficacy of DOACs in the general population, the specific evidence base for their use by the Japanese elderly population remains unclear [6Castellucci L.A. Cameron C. Le Gal G. Rodger M.A. Coyle D. Wells P.S. et al.Efficacy and safety outcomes of oral anticoagulants and antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic review and network meta-analysis.BMJ. 2013; 347: f5133Crossref PubMed Scopus (145) Google Scholar, 7Ruff C.T. Giugliano R.P. Braunwald E. Hoffman E.B. Deenadayalu N. Ezekowitz M.D. et al.Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.Lancet. 2014; 383: 955-962Abstract Full Text Full Text PDF PubMed Scopus (3316) Google Scholar]. In the ARISTOTLE and ENGAGE AF-TIMI 48 trials, the absolute major bleeding rates were consistently lower with edoxaban and apixaban use than with VKA use across all age groups [8Halvorsen S. Atar D. Yang H. De Caterina R. Erol C. Garcia D. et al.Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial.Eur Heart J. 2014; 35: 1864-1872Crossref PubMed Scopus (265) Google Scholar, 9Kato E.T. Giugliano R.P. Ruff C.T. Koretsune Y. Yamashita T. Kiss R.G. et al.Efficacy and safety of edoxaban in elderly patients with atrial fibrillation in the ENGAGE AF-TIMI 48 Trial.J Am Heart Assoc. 2016 May 20; 5 (pii:e003432)https://doi.org/10.1161/JAHA.116.003432Crossref Scopus (183) Google Scholar]. This is in contrast with the results from the RE-LY and Rocket AF trials, in which there were statistically significant treatment interactions with age with respect to bleeding outcomes, and bleeding rates in older adults treated with dabigatran and with rivaroxaban were higher than in those treated with VKAs [10Eikelboom J.W. Wallentin L. Connolly S.J. Ezekowitz M. Healey J.S. Oldgren J. et al.Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial.Circulation. 2011; 123: 2363-2372Crossref PubMed Scopus (982) Google Scholar, 11Halperin J.L. Hankey G.J. Wojdyla D.M. Piccini J.P. Lokhnygina Y. Patel M.R. et al.Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF).Circulation. 2014; 130: 138-146Crossref PubMed Scopus (302) Google Scholar]. In comparison with VKAs, the risk of harm with DOACs, particularly with respect to bleeding risks, warrants clarity given the presence of more comorbidities, polypharmacy, and altered pharmacokinetics in older adults. Special care is therefore needed when managing, elderly patients because of high risk of stroke. DOACs exhibited efficacy at least equal to that of VKAs for acute venous thromboembolism and AF in older adults. However, the bleeding patterns seen with DOACs were different from those seen with VKAs. A meta-analysis reported that dabigatran, in particular, showed a significantly higher risk of gastrointestinal bleeding and a non-significantly higher major bleeding risk than VKA [[12]Sharma M. Cornelius V.R. Patel J.P. Davies J.G. Molokhia M. Efficacy and harms of direct oral anticoagulants in the elderly for stroke prevention in atrial fibrillation and secondary prevention of venous thromboembolism: systematic review and meta-analysis.Circulation. 2015; 132: 194-204Crossref PubMed Scopus (185) Google Scholar]. This suggests that caution is warranted in prescribing where there may be concomitant risk factors for gastrointestinal bleeding in older adults. A benefit of reduced intracranial bleeding was seen with dabigatran, apixaban, and rivaroxaban. Insufficient published data for apixaban, edoxaban, and rivaroxaban efficiencies limited the extent to which bleeding risks, particularly gastrointestinal risks, could be fully explored in the older adult population. Greater availability of unpublished trial data and more research is needed to further elucidate the risks. In Japan, a large community-based prospective cohort study demonstrated that elderly patients of age ≥85 years with AF have a higher incidence of stroke but the risk of major bleeding is similar compared to that observed in the younger population with AF [[13]Yamashita Y. Hamatani Y. Esato M. Chun Y.H. Tsuji H. Wada H. et al.Clinical characteristics and outcomes in extreme elderly (age ≥ 85 years) Japanese patients with atrial fibrillation: The Fushimi AF Registry.Chest. 2016; 149: 401-412Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar]. However, in this study, data were collected when VKAs were the most common treatment: in addition, no data were collected on the quality of VKA control and adherence to OAC therapies. Another Japanese prospective cohort study conducted at a time when DOACs were used, also suggested that the DOAC users were at a lower risk of stroke than VKA users [[14]Okumura Y. Yokoyama K. Matsumoto N. Tachibana E. Kuronuma K. Oiwa K. et al.Current use of direct oral anticoagulants for atrial fibrillation in Japan: findings from the SAKURA AF Registry.J Arrhythm. 2017; 33: 289-296Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. However, the dose was inappropriately reduced for about 20% of the elderly patients (age >70 years) treated with DOACs for AF in this cohort study. In this issue, Bando et al. focused on the efficacy and safety of rivaroxaban in older adults with AF [[15]Bando S. Nishikado A. Hiura N. Ikeda S. Kakutani A. Yamamoto K. et al.Efficacy and safety of rivaroxaban in extreme elderly patients with atrial fibrillation: analysis of the Shikoku Rivaroxaban Registry Trial (SRRT).J Cardiol. 2018; 71: 197-201Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. This is the first report to show the clinical characteristics and outcomes in Japanese patients using DOAC and to compare the older adult group of patients with other age groups of patients. The authors conducted a retrospective observational survey of the use of rivaroxaban for stroke prevention in 453 patients aged ≥80 years in Japan. Of those, only 333 patients (73.5%) met the recommended dosing criteria. The doses were determined by the patients’ physicians. The incidence of adverse events was not significantly different from that of the control group (thromboembolic events 0.94%/person-year; intracranial hemorrhage 0.89%/person-year). These results are presumed to be valid in this specific population. Despite the benefits of DOACs, previous Japanese studies have demonstrated that OAC therapies are underused in AF, especially for elderly patients, and that OAC use decreases gradually as patients age [[14]Okumura Y. Yokoyama K. Matsumoto N. Tachibana E. Kuronuma K. Oiwa K. et al.Current use of direct oral anticoagulants for atrial fibrillation in Japan: findings from the SAKURA AF Registry.J Arrhythm. 2017; 33: 289-296Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. The treatment of AF in older patients presents a clinical challenge because of the high risk of complications such as intracranial hemorrhage. Many physicians often inappropriately prescribe lower doses of anticoagulants in elderly patients with AF. There are several reasons for physicians to withhold OAC therapy for elderly patients including comorbidities, polypharmacy, general frailty, age-related cognitive decline, inability to attend monitoring appointments, and the increased risk of falling in this patient population, which further increases the risk of intracranial hemorrhage. And these patients’ shorter life expectancy can also influence decision-making. The decision to treat AF patients aged ≥85 years with OAC should be based on a thorough consideration of the absolute individual benefits, treatment risks, and patient preferences. Large prospective randomized studies are required to understand the efficacy and safety of the use of direct anticoagulants for sufficient reduction of embolic stroke, and consideration of the optimal DOAC dose for Japanese AF patients aged ≥85 years. Moreover, it is necessary to evaluate the neurocognitive function as a preliminary stage to dementia and adherence to OAC therapy of enrolled patients using a specific tool, such as a medication diary, during follow-up. None. Efficacy and safety of rivaroxaban in extreme elderly patients with atrial fibrillation: Analysis of the Shikoku Rivaroxaban Registry Trial (SRRT)Journal of CardiologyVol. 71Issue 2PreviewAtrial fibrillation (AF) is a global healthcare problem, currently affecting 2.5% of the population worldwide, its prevalence steeply increases with age [1], ranging from 9% in patients aged 76–85 years to >10% in those aged over 85 years. Currently, four types of direct oral anticoagulants (DOACs) are available in Japan. Rivaroxaban 20 mg once daily (o.d.) is used for the prevention of stroke and systemic embolism in patients with non-valvular AF in the global ROCKET AF trial. In Japan, however, old Japanese patients (age >70 years) receiving anticoagulant therapy may require lower therapeutic ranges than Westerners [international normalized ratio (INR) target level of 1.6–2.6]. Full-Text PDF Open Archive
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