Using oral nitrates and phosphodiesterase type 5 inhibitors together can lead to abnormally low blood pressure, which in turn could cause harms such as syncope, stroke, and acute myocardial infarction. The study described in this article examined whether these possible harms occur in everyday use of the drugs.
Background:
Concomitant use of oral organic nitrates (nitrates) and phosphodiesterase type 5 (PDE5) inhibitors is contraindicated.
Objective:
To measure temporal trends in the coprescription of nitrates and PDE5 inhibitors and to measure the association between cardiovascular outcomes and the coprescription of nitrates with PDE5 inhibitors.
Design:
Case-crossover design.
Setting:
Nationwide study of Danish patients from 2000 to 2018.
Patients:
Male patients with International Classification of Diseases, 10th Revision (ICD-10) codes for ischemic heart disease (IHD), including those who had a continuing prescription for nitrates and a new, filled prescription for PDE5 inhibitors.
Measurements:
Two composite outcomes were measured: 1) cardiac arrest, shock, myocardial infarction, ischemic stroke, or acute coronary arteriography and 2) syncope, angina pectoris, or drug-related adverse event.
Results:
From 2000 to 2018, 249 541 male patients with IHD were identified. Of these, 42 073 patients had continuing prescriptions for nitrates. During this period, the prescription rate for PDE5 inhibitors in patients with IHD who were taking nitrates increased from an average of 0.9 prescriptions (95% CI, 0.5 to 1.2 prescriptions) per 100 persons per year in 2000 to 19.5 prescriptions (CI, 18.0 to 21.1 prescriptions) in 2018. No statistically significant association was found between the coprescription of nitrates with PDE5 inhibitors and the risk for either composite outcome (odds ratio [OR], 0.58 [CI, 0.28 to 1.13] for the first outcome and OR, 0.73 [CI, 0.40 to 1.32] for the second outcome).
Limitation:
An assumption was made that concurrently filled prescriptions for nitrates and PDE5 inhibitors equaled concomitant use.
Conclusion:
From 2000 to 2018, the use of PDE5 inhibitors increased 20-fold among Danish patients with IHD who were taking nitrates. A statistically significant association between concomitant use of these medications and cardiovascular adverse events could not be identified.
Primary Funding Source:
Ib Mogens Kristiansens Almene Fond and Helsefonden.
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Author, Article, and Disclosure Information
Department of Cardiology, Copenhagen University Hospital–Herlev and Gentofte, Copenhagen, Denmark (A.H., N.N., D.R., M.H.J., M.E., M.S., M.L.)
Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark (P.B., A.K.G.J.)
Department of Cardiology, Zealand University Hospital, Roskilde, and The Danish Heart Foundation, Copenhagen, Denmark (A.S.)
Department of Cardiology, Copenhagen University Hospital–Herlev and Gentofte, Copenhagen, and The Danish Heart Foundation, Copenhagen, Denmark (G.G.)
Department of Clinical Research, North Zealand Hospital, Hillerød, and Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark (C.T.)
William Harvey Research Institute, Queen Mary University of London, London, United Kingdom (P.M.).
Note: Patient and public involvement has not been possible for this study. The work was performed in the Research Division, Department of Cardiology, Herlev and Gentofte Hospital, Hellerup, Denmark.
Grant Support: The lead investigator, Dr. Holt, and this study have been funded by external, independent grants from Ib Mogens Kristiansens Almene Fond (J. nr. 30206-383), Helsefonden (20-B-0035), Snedkermester Sophus Jacobsen og hustru Astrid Jacobsen Fond (J 167/1), Marie og M.B. Richters Fond (J. nr. 2020-0379), and Dagmar Marshalls Fond.
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M21-3445.
Reproducible Research Statement: Study protocol: Available from Dr. Holt (e-mail, anders.
Corresponding Author: Anders Holt, MD, Research Division, Department of Cardiology, Herlev and Gentofte Hospital, Gentofte Hospitalsvej 6, Postbox 635, 2900 Hellerup, Denmark; e-mail, anders.
Author Contributions: Conception and design: A. Holt, P. Blanche, A.K.G. Jensen, A. Schjerning, M. Lamberts.
Analysis and interpretation of the data: A. Holt, P. Blanche, A.K.G. Jensen, A. Schjerning, M. Schou, G. Gislason, P. McGettigan, M. Lamberts.
Drafting of the article: A. Holt, N. Nouhravesh, M. El-Sheikh, A. Schjerning, M. Schou, C. Torp-Pedersen, P. McGettigan, M. Lamberts.
Critical revision of the article for important intellectual content: A. Holt, P. Blanche, D. Rajan, M.H. Jensen, A. Schjerning, M. Schou, G. Gislason, C. Torp-Pedersen, P. McGettigan, M. Lamberts.
Final approval of the article: A. Holt, P. Blanche, A.K.G. Jensen, N. Nouhravesh, D. Rajan, M.H. Jensen, M. El-Sheikh, A. Schjerning, M. Schou, G. Gislason, C. Torp-Pedersen, P. McGettigan, M. Lamberts.
Provision of study materials or patients: A. Holt, G. Gislason, M. Lamberts.
Statistical expertise: A. Holt, P. Blanche, A.K.G. Jensen, C. Torp-Pedersen, M. Lamberts.
Obtaining of funding: A. Holt, M. Lamberts.
Administrative, technical, or logistic support: A. Holt, G. Gislason, C. Torp-Pedersen, M. Lamberts.
Collection and assembly of data: A. Holt, G. Gislason, M. Lamberts.
This article was published at Annals.org on 19 April 2022.
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