The impact of kidney function in patients on antithrombotic therapy: a post hoc subgroup analysis focusing on recurrent bleeding events from the AFIRE trial

Kunihiko Matsui, Satoshi Yasuda, Koichi Kaikita, Masaharu Akao, Junya Ako, Tetsuya Matoba, Masato Nakamura, Katsumi Miyauchi, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Hisao Ogawa, Kunihiko Matsui, Satoshi Yasuda, Koichi Kaikita, Masaharu Akao, Junya Ako, Tetsuya Matoba, Masato Nakamura, Katsumi Miyauchi, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Hisao Ogawa

Abstract

Background: The success of antithrombotic therapies is assessed based on thrombotic and bleeding events. Simultaneously assessing both kinds of events might be challenging, and recurrent bleeding events are often ignored. We tried to confirm the effects of kidney function on outcome events in patients undergoing antithrombotic therapy.

Methods: As a post hoc subgroup analysis of the Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial, a randomized clinical trial with a median follow-up of 36 months, patients were divided into high and low estimated glomerular filtration rate (eGFR) groups with a cutoff value of 50 mL/min. The cumulative incidence of bleeding and crude incidence of recurrent bleeding per 100 patient-years were calculated. We used the Cox regression model with multiple failure time data for recurrent bleeding events.

Results: Among 2092 patients, 1386 (66.3%) showed high eGFR. The cumulative bleeding events per 100 patients at 1 year were 5.4 and 6.2 in the high and low eGFR groups, respectively. The difference continued to increase over time. The hazard ratio for time to the first bleeding event in the high eGFR group was 0.875 (95% confidence interval 0.701-1.090, p = .234) and that for the first composite event was 0.723 (95% confidence interval 0.603-0.867, p < .000). The recurrent bleeding events per 100 person-years were 11.3 and 15.3 in the high and low eGFR groups, respectively, with a rate ratio of 0.738 (95% confidence interval 0.615-0.886, p = .001). During the observation period, the risk of bleeding changed with time. It peaked soon after the study enrollment in both groups. It decreased continuously in the high eGFR group but remained high in the low eGFR group.

Conclusions: We reaffirmed that kidney function affects bleeding events in patients on antithrombotic therapy, considering recurrent events. Patients should have detailed discussions with physicians regarding the possible bleeding events when continuing antithrombotic therapy, especially in patients with decreased kidney function.

Trial registration: UMIN Clinical Trials Registry, UMIN000016612 . ClinicalTrials.gov, NCT02642419 . Registered on 21 October 2015.

Keywords: Antithrombotic therapy; Atrial fibrillation; Bleeding event; Creatinine clearance; Estimated glomerular filtration rate; Kidney function; Non-vitamin K antagonistic oral anticoagulants; Recurrent event; Thrombotic event.

Conflict of interest statement

KMa has no relationships relevant to the contents of this paper to disclose. SY reports grants from Takeda Pharmaceutical, Abbott, and Boston Scientific and personal fees from Daiichi-Sankyo and Bristol-Meyers. KKa reports grants from Grants-in-Aid for Scientific Research (20K08451) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and grants and personal fees from Bayer Yakuhin and Daiichi Sankyo. MA reports grants from the Japan Agency for Medical Research and Development (AMED), personal fees from Bristol-Myers Squibb and Nippon Boehringer Ingelheim, and grants and personal fees from Bayer Yakuhin and Daiichi Sankyo. JA reports personal fees from Bayer Yakuhin and Sanofi and grants and personal fees from Daiichi Sankyo. TM reports grants from Japan Cardiovascular Research Foundation and personal fees from Nippon Boehringer Ingelheim, Daiichi Sankyo, Astra Zeneca, and Bayer Yakuhin. MN reports grants and personal fees from Bayer Yakuhin, Daiichi Sankyo, and Sanofi and personal fees from Bristol-Myers Squibb and Nippon Boehringer Ingelheim. KMi reports personal fees from Amgen Astellas BioPharma, Astellas Pharma, MSD, Bayer Yakuhin, Sanofi, Takeda Pharmaceutical, Daiichi-Sankyo, Nippon Boehringer Ingelheim, and Bristol-Myers Squibb. NH reports grants and personal fees from Bayer Yakuhin, grants from Nippon Boehringer Ingelheim, and personal fees from Bristol-Myers Squibb. KKi reports grants from the Japan Cardiovascular Research Foundation; grants and personal fees from Bayer Yakuhin, Daiichi Sankyo, Sanofi, MSD, and AstraZeneca; and personal fees from Bristol-Myers Squibb and Nippon Boehringer Ingelheim. AH reports grants and personal fees from Boston Scientific Japan, Otsuka Pharmaceutical, Sanofi, Astellas Pharma, Bristol-Myers Squibb, Daiichi Sankyo, and Bayer Yakuhin; grants from Fukuda Denshi, Abbott Japan, Japan Lifeline, Takeda Pharmaceutical, and Sumitomo Dainippon Pharma; and personal fees from Toa Eiyo, Nippon Boehringer Ingelheim, Amgen Astellas BioPharma, and AstraZeneca. HO reports personal fees from Towa Pharmaceutical, Bristol-Meyers Squibb, Pfizer, Toa Eiyo, Bayer Yakuhin, and Novartis Pharma.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Estimated cumulative number of bleeding events per 100 patients. Time since enrollment (days)
Fig. 2
Fig. 2
Estimated risk of bleeding events, Cockcroft–Gault equation at 50 mL/min. Time since enrollment (days)

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