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Association between dihydropyridine calcium channel blockers and ischemic strokes in patients with nonvalvular atrial fibrillation

Hypertension Research volume 45, pages 1028–1036 (2022)Cite this article

Abstract

Outside of clinical trials, the prophylactic effect of dihydropyridine calcium channel blockers (CCBs) on ischemic events in patients with nonvalvular atrial fibrillation (NVAF) has not been confirmed. We compared the effect of dihydropyridine CCBs on ischemic events in anticoagulated NVAF patients. We conducted a multicenter historical cohort study at 71 centers in Japan. The inclusion criterion was taking vitamin K antagonists for NVAF. The exclusion criteria were mechanical heart valves and a history of pulmonary thrombosis or deep vein thrombosis. Consecutive patients (N = 7826) were registered in February 2013 and were followed until February 2017. The primary outcomes were ischemic events and ischemic strokes; the secondary outcomes were all-cause mortality, major bleeding, and hemorrhagic strokes. The mean patient age was 73 years old, and 67% of the patients were male. Seventy-eight percent of the patients had hypertension, and dihydropyridine CCBs were used by 2693 (34%) patients (CCB group). The cumulative incidences of ischemic events and ischemic strokes at 4 years in the CCB and No-CCB groups were 5.9% vs. 5.2% and 5.6% vs. 4.8%, respectively. The adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) of the CCB group for ischemic events and ischemic strokes were 1.22 (0.95–1.57) and 1.32 (1.02–1.71), respectively; the adjusted HRs (95% CIs) of the CCB group for all-cause mortality, major bleeding, and hemorrhagic strokes were 0.85 (0.69–1.04), 1.12 (0.92–1.35), and 1.08 (0.62–1.88), respectively. Dihydropyridine CCB use by anticoagulated NVAF patients significantly increased ischemic strokes in a real-world setting.

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Acknowledgements

We are indebted to the data managers of the Institute for Clinical Effectiveness (Ms. Makiko Ohtorii, Ms. Ai Sunagawa, Ms. Kaori Yamamoto, Ms. Sachiko Kitamura, Ms. Hirono Saito, and Ms. Saeko Nagano) for managing the data and performing the statistical analyses.

Funding

This study was supported in part by Bristol-Myers Squibb and JSPS KAKENHI (JP21H03176). The funders did not participate in any part of the study from the conception to article preparation.

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Authors and Affiliations

  1. Department of Clinical Epidemiology, Hyogo College of Medicine, Nishinomiya, Japan

    Fumihiro Sakakibara, Kazutaka Uchida, Norito Kinjo, Hideki Arai, Mari Nezu & Takeshi Morimoto

  2. Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Japan

    Fumihiro Sakakibara, Kazutaka Uchida & Norito Kinjo

  3. Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus, Okinawa, Japan

    Shinichiro Ueda

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  1. Fumihiro Sakakibara
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Contributions

FS, SU, and TM: study conception and design. SU and TM: data acquisition and management. FS, NK, and TM: statistical analyses. FS, SU, KU, NK, HA, MN, and TM: interpretation of the data. FS and TM: drafting of the paper. SU, KU, NK, HA, and MN: critical revision of the paper. All authors: final approval of the paper.

Corresponding author

Correspondence to Takeshi Morimoto.

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Conflict of interest

FS reports paper fees from Medicus Shuppan. SU reports receiving research grants from Bristol-Myers Squibb, Chugai, Kowa, MSD, Pfizer, and Takeda, lecturer fees from Boehringer Ingelheim, MSD, and Taiho, and paper fees from Kowa. He served on an advisory board for Otsuka. KU reports receiving lecturer fees from Daiichi Sankyo, Bristol-Myers Squibb, Stryker, and Medtronic. NK reports receiving lecturer fees from Medtronic and paper fees from Medicus Shuppan. HA and MN have no disclosures to report. TM reports receiving lecturer fees from Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray, receiving paper fees from Bristol-Myers Squibb and Kowa, and served on an advisory board for Sanofi.

Ethics approval and consent to participate

The institutional review boards of the University of the Ryukyus (No. 597) and all 71 participating centers approved the study protocol. The institutional review boards waived the need for written informed consent and approved the study following the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan.

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Sakakibara, F., Ueda, S., Uchida, K. et al. Association between dihydropyridine calcium channel blockers and ischemic strokes in patients with nonvalvular atrial fibrillation. Hypertens Res 45, 1028–1036 (2022). https://doi.org/10.1038/s41440-022-00855-x

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