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

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.

Authors+Show Affiliations

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

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31504369

Citation

Eroglu, Talip E., et al. "Differential Effects On Out-of-hospital Cardiac Arrest of Dihydropyridines: Real-world Data From Population-based Cohorts Across Two European Countries." European Heart Journal. Cardiovascular Pharmacotherapy, 2019.
Eroglu TE, Mohr GH, Blom MT, et al. Differential effects on out-of-hospital cardiac arrest of dihydropyridines: real-world data from population-based cohorts across two European countries. Eur Heart J Cardiovasc Pharmacother. 2019.
Eroglu, T. E., Mohr, G. H., Blom, M. T., Verkerk, A. O., Souverein, P. C., Torp-Pedersen, C., ... Tan, H. L. (2019). Differential effects on out-of-hospital cardiac arrest of dihydropyridines: real-world data from population-based cohorts across two European countries. European Heart Journal. Cardiovascular Pharmacotherapy, doi:10.1093/ehjcvp/pvz038.
Eroglu TE, et al. Differential Effects On Out-of-hospital Cardiac Arrest of Dihydropyridines: Real-world Data From Population-based Cohorts Across Two European Countries. Eur Heart J Cardiovasc Pharmacother. 2019 Aug 10; PubMed PMID: 31504369.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential effects on out-of-hospital cardiac arrest of dihydropyridines: real-world data from population-based cohorts across two European countries. AU - Eroglu,Talip E, AU - Mohr,Grimur H, AU - Blom,Marieke T, AU - Verkerk,Arie O, AU - Souverein,Patrick C, AU - Torp-Pedersen,Christian, AU - Folke,Fredrik, AU - Wissenberg,Mads, AU - van den Brink,Lettine, AU - Davis,Richard P, AU - de Boer,Anthonius, AU - Gislason,Gunnar H, AU - Tan,Hanno L, Y1 - 2019/08/10/ PY - 2019/06/27/received PY - 2019/07/20/revised PY - 2019/08/08/accepted PY - 2019/9/11/entrez PY - 2019/9/11/pubmed PY - 2019/9/11/medline KW - Amlodipine KW - Epidemiology KW - Nifedipine KW - Sudden cardiac arrest JF - European heart journal. Cardiovascular pharmacotherapy JO - Eur Heart J Cardiovasc Pharmacother N2 - 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. SN - 2055-6845 UR - https://www.unboundmedicine.com/medline/citation/31504369/Differential_effects_on_out-of-hospital_cardiac_arrest_of_dihydropyridines:_real-world_data_from_population-based_cohorts_across_two_European_countries L2 - https://academic.oup.com/ehjcvp/article-lookup/doi/10.1093/ehjcvp/pvz038 DB - PRIME DP - Unbound Medicine ER -