TY - JOUR
T1 - Differential effects on out-of-hospital cardiac arrest of dihydropyridines
T2 - 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.
N1 - Funding Information: This work was supported by the European Union's Horizon 2020 research and innovation programme under the acronym ESCAPE-NET, registered under grant agreement No 733381 (T.E.E., M.T.B., and H.L.T.) and the Netherlands CardioVascular Research Initiative (Dutch Heart Foundation, Dutch Federation of University Medical Centers, Netherlands Organization for Health Research and Development, and Royal Netherlands Academy of Sciences) grant CVON-2018-30 Predict 2 (M.T.B. and H.L.T.). The Danish Cardiac Arrest Registry is supported by Trygfonden. Work by L.v.d.B. and R.P.D. was supported by a European Research Council Starting Grant (STEMCARDIORISK; grant agreement #638030), and a VIDI fellowship from the Netherlands Organisation for Scientific Research (ILLUMINATE; grant agreement #91715303). Publisher Copyright: © 2019 The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2020/11/1
Y1 - 2020/11/1
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.
AB - 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.
KW - Amlodipine
KW - Epidemiology
KW - Nifedipine
KW - Sudden cardiac arrest
UR - http://www.scopus.com/inward/record.url?scp=85087490012&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/ehjcvp/pvz038
DO - https://doi.org/10.1093/ehjcvp/pvz038
M3 - Article
C2 - 31504369
SN - 2055-6837
VL - 6
SP - 347
EP - 355
JO - European Heart Journal - Cardiovascular Pharmacotherapy
JF - European Heart Journal - Cardiovascular Pharmacotherapy
IS - 6
ER -