Efficacy and Safety of Edoxaban 15 mg According to Renal Function in Very Elderly Patients With Atrial Fibrillation: A Subanalysis of the ELDERCARE-AF Trial
2022; Lippincott Williams & Wilkins; Volume: 145; Issue: 9 Linguagem: Inglês
10.1161/circulationaha.121.057190
ISSN1524-4539
AutoresTetsuro Yoshida, Akihiro Nakamura, Junichi Funada, Mari Amino, Wataru Shimizu, M. Fukuzawa, Saori Watanabe, Takuya Hayashi, Takeshi Yamashita, Ken Okumura, Masaharu Akao,
Tópico(s)Cardiac Arrhythmias and Treatments
ResumoHomeCirculationVol. 145, No. 9Efficacy and Safety of Edoxaban 15 mg According to Renal Function in Very Elderly Patients With Atrial Fibrillation: A Subanalysis of the ELDERCARE-AF Trial Open AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toOpen AccessLetterPDF/EPUBEfficacy and Safety of Edoxaban 15 mg According to Renal Function in Very Elderly Patients With Atrial Fibrillation: A Subanalysis of the ELDERCARE-AF Trial Tetsuro Yoshida, MD, PhD, Akihiro Nakamura, MD, PhD, Junichi Funada, MD, PhD, Mari Amino, MD, PhD, Wataru Shimizu, MD, PhD, Masayuki Fukuzawa, MS, Saori Watanabe, BS, Takuya Hayashi, MS, Takeshi Yamashita, MD, PhD, Ken Okumura, MD, PhD and Masaharu Akao, MD, PhD Tetsuro YoshidaTetsuro Yoshida Correspondence to Tetsuro Yoshida, MD, PhD, Department of Cardiovascular Medicine, Onga Nakama Medical Association Onga Hospital, 1725-2 Ooaza-Ozaki, Onga-cho, Onga-gun, Fukuoka 811-4342, Japan. Email E-mail Address: [email protected] https://orcid.org/0000-0002-6259-1403 Department of Cardiovascular Medicine, Onga Nakama Medical Association Onga Hospital, Japan (T. Yoshida). , Akihiro NakamuraAkihiro Nakamura Department of Cardiology, Iwate Prefectural Central Hospital, Morioka, Japan (A.N.). , Junichi FunadaJunichi Funada https://orcid.org/0000-0001-8810-0425 Department of Cardiology, National Hospital Organization Ehime Medical Center, Toon, Japan (J.F.). , Mari AminoMari Amino Department of Cardiology, Tokai University, Isehara, Japan (M.A.). , Wataru ShimizuWataru Shimizu https://orcid.org/0000-0001-9941-8973 Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan (W.S.). , Masayuki FukuzawaMasayuki Fukuzawa Cardiovascular Group, Primary Medical Science Department, Japan Business Unit (M.F.), Daiichi Sankyo Co., Ltd., Tokyo, Japan. , Saori WatanabeSaori Watanabe Clinical Development Department III, Development Function, Research and Development Division (S.W.), Daiichi Sankyo Co., Ltd., Tokyo, Japan. , Takuya HayashiTakuya Hayashi The Data Intelligence Group, Data Intelligence Department, Digital Transformation Management Division (T.H.), Daiichi Sankyo Co., Ltd., Tokyo, Japan. , Takeshi YamashitaTakeshi Yamashita https://orcid.org/0000-0002-2544-8464 Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan (T. Yamashita). , Ken OkumuraKen Okumura Division of Cardiology, Saiseikai Kumamoto Hospital, Kumamoto, Japan (K.O.). and Masaharu AkaoMasaharu Akao https://orcid.org/0000-0002-2348-7646 Department of Cardiology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan (M.A.). Originally published28 Feb 2022https://doi.org/10.1161/CIRCULATIONAHA.121.057190Circulation. 2022;145:718–720The ELDERCARE-AF trial (The Edoxaban Low-Dose for Elder Care in AF Patients) demonstrated that a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding than placebo in very elderly Japanese patients with nonvalvular atrial fibrillation (NVAF) who were not appropriate candidates for standard doses of oral anticoagulants.1 In this prespecified subanalysis of the ELDERCARE-AF trial, we evaluated the association of renal function with the efficacy and safety of edoxaban 15 mg in these patients.Eligible patients were ≥80 years of age and had a history of NVAF and a CHADS2 score of ≥2. Patients had to be considered ineligible for oral anticoagulants (warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban) at the recommended therapeutic strength or approved dose for ≥1 of the following reasons: low creatinine clearance (CrCl; 15–30 mL/min), history of bleeding from a critical area or organ, low body weight (≤45 kg), continuous use of nonsteroidal anti-inflammatory drugs, and current use of an antiplatelet drug. The primary efficacy end point was the incidence of stroke or systemic embolism, and the primary safety end point was the International Society on Thrombosis and Haemostasis major bleeding. Other end points were all-cause mortality and net clinical outcome (the composite of stroke, systemic embolism, major bleeding, or all-cause mortality). Anonymized trial data will be made available at https://search.vivli.org/ to researchers on reasonable request to the corresponding author with approval by Daiichi Sankyo Co., Ltd.In this trial, 984 patients were randomly assigned to treatment (edoxaban group, n=492; placebo group, n=492) and 681 completed the trial. For this analysis, patients in the ELDERCARE-AF trial were classified into 3 subgroups on the basis of their baseline renal function: severe renal dysfunction (CrCl 15 to 50 mL/min, n=161). The median duration of follow-up was 466.0 days (interquartile range, 293.5–708.0). Event rates for primary end points were calculated for each renal function subgroup. The cumulative incidences of stroke or systemic embolism and major bleeding were estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to compare outcomes between the treatment groups, with the results expressed as a hazard ratio with a 95% confidence interval. Proportionality of hazards for the primary end point was confirmed by inspection of log-log survival plots. Interaction effects between treatment arms and CrCl subgroups were tested on the basis of a joint test using Wald statistics. The protocol was approved by the institute ethics committee. Written informed consent was obtained from all participants (or legal representatives for patients with cognitive impairment) before enrollment.Kaplan-Meier curves and forest plots showing the risk of stroke/systemic embolism (primary efficacy end point) and major bleeding (primary safety end point) in the edoxaban and placebo groups according to baseline CrCl subgroups are shown in the Figure. The effect of edoxaban versus placebo on stroke/systemic embolism was consistent among all CrCl subgroups (P value for interaction=0.91). The increase in major bleeding with edoxaban was nonsignificant, and there was no heterogeneity between the CrCl groups (P value for interaction=0.63). Regarding all-cause mortality, the hazard ratios of the edoxaban groups were 0.97 for the CrCl 15 to 50 mL/min subgroup (P value for interaction=0.90), and those for net clinical outcome were 0.91, 0.87, and 0.77 for each CrCl subgroup, respectively (P value for interaction=0.96). No heterogeneity was observed between the groups.Download figureDownload PowerPointFigure. Relationship between stroke/systemic embolism or major bleeding and renal function in patients with nonvalvular atrial fibrillation. Kaplan-Meier curves and forest plots for stroke/systemic embolism and major bleeding in the edoxaban and placebo groups according to baseline creatinine clearance. CI indicates confidence interval; CrCl, creatinine clearance; and HR, hazard ratio.In a subanalysis of the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48), the advantage of edoxaban over warfarin was consistent across the range of renal function in patients with NVAF (the minimum renal function was CrCl 30 mL/min).2 Another study showed that edoxaban 15 mg in patients with NVAF and severe renal dysfunction (CrCl 15 to <30 mL/min) exhibited safety and plasma concentration similar to the 30-mg dose in patients with normal renal function or mild dysfunction (CrCl ≥50 mL/min).3 In the present study, edoxaban 15 mg reduced the incidence of stroke/systemic embolism regardless of the level of renal dysfunction. There was no increase in intracranial hemorrhage or fatal bleeding events in the edoxaban group.1 Thus, the use of edoxaban 15 mg may be a feasible and clinically acceptable therapy even in very elderly patients with severe renal dysfunction, under appropriate measures for preventing bleeding.In addition to the study limitations described in our previous report,1 the sample size of this subanalysis was small, our findings are limited to very elderly patients, and the event rates were low, which may result in indeterminate conclusions. Further studies are warranted.In conclusion, the efficacy and safety of edoxaban 15 mg compared with placebo was broadly consistent across renal function subgroups in very elderly Japanese patients with NVAF who were not appropriate candidates for standard doses of oral anticoagulants.Article InformationRegistration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02801669.AcknowledgmentsWe thank Michelle Belanger, MD, of Edanz (www.edanz.com) for providing medical writing support, which was funded by Daiichi Sankyo Co., Ltd. All authors meet the ICMJE's authorship criteria.Sources of FundingThis study was supported by Daiichi Sankyo Co., Ltd.Nonstandard Abbreviations and AcronymsCrClcreatinine clearanceNVAFnonvalvular atrial fibrillationDisclosures Dr Yoshida has received funding for research expenses (Onga Hospital) from Daiichi Sankyo Co., Ltd. Dr Shimizu has received grants from Daiichi Sankyo Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd.; and honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Daiichi Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Bristol-Meyers Squibb, K.K., Bayer Yakuhin, Ltd., Pfizer Japan, Inc., Ono Pharmaceutical Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. M. Fukuzawa, S. Watanabe, and T. Hayashi are employees at Daiichi Sankyo Co., Ltd. Dr Yamashita has received personal fees (as a medical expert) from Daiichi Sankyo Co., Ltd. for this study; and grants and lecture fees from Daiichi Sankyo Co., Ltd., Bristol-Myers Squibb K.K., and Bayer Yakuhin Ltd.; lectures fees from Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., and Ono Pharmaceutical Co., Ltd.; medical advisory fees from Toa Eiyo Ltd.; and lecture and medical advisory fees from Novartis Pharma K.K. outside the submitted work. Dr Okumura has received grants and a commission fee for the study design from Daiichi Sankyo Co., Ltd. for the submitted work; and lecture fees from Daiichi Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Bristol-Myers Squibb K.K., Medtronic Japan Co., Ltd., Johnson & Johnson K.K., and Bayer Yakuhin Ltd. outside the submitted work. Dr Akao has received funding support for the present manuscript from Daiichi Sankyo Co., Ltd. and grants from Bayer Yakuhin, Ltd., Pfizer Japan, Inc., Bristol-Meyers Squibb, K.K., Nippon Boehringer Ingelheim Co., Bayer Yakuhin, Ltd., and Daiichi Sankyo Co., Ltd. The other authors report no conflicts.FootnotesCirculation is available at www.ahajournals.org/journal/circFor Sources of Funding and Disclosures, see page 720.Correspondence to Tetsuro Yoshida, MD, PhD, Department of Cardiovascular Medicine, Onga Nakama Medical Association Onga Hospital, 1725-2 Ooaza-Ozaki, Onga-cho, Onga-gun, Fukuoka 811-4342, Japan. Email [email protected]comReferences1. Okumura K, Akao M, Yoshida T, Kawata M, Okazaki O, Akashi S, Eshima K, Tanizawa K, Fukuzawa M, Hayashi T, et al.; ELDERCARE-AF Committees and Investigators. Low-dose edoxaban in very elderly patients with atrial fibrillation.N Engl J Med. 2020; 383:1735–1745. doi: 10.1056/NEJMoa2012883CrossrefMedlineGoogle Scholar2. Bohula EA, Giugliano RP, Ruff CT, Kuder JF, Murphy SA, Antman EM, Braunwald E. Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 Trial.Circulation. 2016; 134:24–36. doi: 10.1161/CIRCULATIONAHA.116.022361LinkGoogle Scholar3. Koretsune Y, Yamashita T, Kimura T, Fukuzawa M, Abe K, Yasaka M. Short-term safety and plasma concentrations of edoxaban in Japanese patients with non-valvular atrial fibrillation and severe renal impairment.Circ J. 2015; 79:1486–1495. doi: 10.1253/circj.CJ-14-0942CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails March 1, 2022Vol 145, Issue 9Article InformationMetrics © 2022 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.https://doi.org/10.1161/CIRCULATIONAHA.121.057190PMID: 35226559 Originally publishedFebruary 28, 2022 Keywordsanticoagulantsagedthromboembolismedoxabankidneyhemorrhageatrial fibrillationPDF download Advertisement SubjectsAtrial FibrillationHeart Failure
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