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Eur Heart J Cardiovasc Pharmacother. 2019 Aug 10. pii: pvz038. doi: 10.1093/ehjcvp/pvz038. [Epub ahead of print]

Differential effects on out-of-hospital cardiac arrest of dihydropyridines: real-world data from population-based cohorts across two European countries.

Author information

1
Department of Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
2
Department of Cardiology, Copenhagen University Hospital Gentofte, Kildegårdsvej 28, 2900 Hellerup, Denmark.
3
Department of Medical Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
4
Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80082, Utrecht 3508 TB, The Netherlands.
5
Unit of Epidemiology and Biostatistics, Aalborg University Hospital, Sdr. Skovvej 15, 9000 Aalborg, Denmark.
6
Department of Cardiology, Aalborg University Hospital, Sdr. Skovvej 15, 9000 Aalborg, Denmark.
7
Department of Health Science and Technology, Aalborg University Hospital, Sdr. Skovvej 15, 9000 Aalborg, Denmark.
8
Department of Anatomy and Embryology, Leiden University Medical Center, Einthovenweg 20, 2300 RC Leiden, The Netherlands.
9
National Institute of Public Health, University of Southern Denmark, Studiestræde 6, 1455 Copenhagen, Denmark.
10
The Danish Heart Foundation, Vognmagergade 7, 1120 Copenhagen, Denmark.

Abstract

AIMS:

Various drugs increase the risk of out-of-hospital cardiac arrest (OHCA) in the general population by impacting cardiac ion channels, thereby causing ventricular tachycardia/fibrillation (VT/VF). Dihydropyridines block L-type calcium channels, but their association with OHCA risk is unknown. We aimed to study whether nifedipine and/or amlodipine, often-used dihydropyridines, are associated with increased OHCA risk, and how these drugs impact on cardiac electrophysiology.

METHODS AND RESULTS:

We conducted a case-control study with VT/VF-documented OHCA cases with presumed cardiac cause from ongoing population-based OHCA registries in the Netherlands and Denmark, and age/sex/index date-matched non-OHCA controls (Netherlands: PHARMO Database Network, Denmark: Danish Civil Registration System). We included 2503 OHCA cases, 10 543 non-OHCA controls in Netherlands, and 8101 OHCA cases, 40 505 non-OHCA controls in Denmark. To examine drug effects on cardiac electrophysiology, we performed single-cell patch-clamp studies in human-induced pluripotent stem cell-derived cardiomyocytes. Use of high-dose nifedipine (≥60 mg/day), but not low-dose nifedipine (<60 mg/day) or amlodipine (any-dose), was associated with higher OHCA risk than non-use of dihydropyridines [Netherlands: adjusted odds ratios (ORadj) 1.45 (95% confidence interval 1.02-2.07), Denmark: 1.96 (1.18-3.25)] or use of amlodipine [Netherlands: 2.31 (1.54-3.47), Denmark: 2.20 (1.32-3.67)]. Out-of-hospital cardiac arrest risk of (high-dose) nifedipine use was not further increased in patients using nitrates, or with a history of ischaemic heart disease. Nifedipine and amlodipine blocked L-type calcium channels at similar concentrations, but, at clinically used concentrations, nifedipine caused more L-type calcium current block, resulting in more action potential shortening.

CONCLUSION:

High-dose nifedipine, but not low-dose nifedipine or any-dose amlodipine, is associated with increased OHCA risk in the general population. Careful titration of nifedipine dose should be considered.

KEYWORDS:

Amlodipine; Epidemiology; Nifedipine; Sudden cardiac arrest

PMID:
31504369
DOI:
10.1093/ehjcvp/pvz038

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