Tier 2 — strong

A New Perspective on the Nitrate-Phosphodiesterase Type 5 Inhibitor Interaction

Kloner RA, Goggin P, Goldstein I, Hackett G, Kirby MG, Osterloh I, Parker JD, Sadovsky R

Journal of Cardiovascular Pharmacology and Therapeutics 2018 23(5):375-386

Bibliography

PubMed: PMID 29739235
DOI: 10.1177/1074248418771896
Funding: This manuscript was sponsored by Pfizer Limited. Editorial assistance was provided by Patricia B. Leinen, PhD, of Complete Healthcare Communications, LLC (West Chester, Pennsylvania), a CHC Group company, and funded by Pfizer Limited.
Competing interests: R. Kloner is a consultant for Pfizer, Bayer, and Sanofi. P. Goggin is an employee of Pfizer Ltd, Sandwich, UK. I. Goldstein is a consultant for Dornier, has served as a speaker for Coloplast and Dornier, has served on advisory boards for Aytu, Bayer, Lipocine, and Pfizer, and has received research grants from Auxilium, Dornier, Ixchelsis, Lipocine, and Tissue Genesis. G. Hackett is an occasional speaker for Bayer and Besins and advisory board member for Pfizer. M.G. Kirby has received funding for research, conference attendance, lecturing and advice from Astellas, Pfizer, Takeda, Bayer, Merck Sharp & Dohme, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, AstraZeneca, and Menarini. I. Osterloh is a former employee of Pfizer, serves as a consultant for Pfizer, and owns shares of Pfizer stock. J.D. Parker has consulting relationships with Bayer, Servier, Novartis and Theracos. R. Sadovsky has served as a consultant for Pfizer.

Why this tier. Authoritative narrative clinical pharmacology review by cardiology and sexual-medicine specialists, synthesising an extensive human clinical trial and pharmacovigilance evidence base underlying a well-established, guideline-level drug contraindication. Full-text review confirms the manuscript was sponsored by Pfizer Limited (maker of sildenafil/Viagra), with editorial assistance also funded by Pfizer, and that most of the eight authors disclose consulting, employment, speaker, advisory-board, or shareholding relationships with Pfizer and/or other PDE5-inhibitor or cardiovascular drug manufacturers. This funding and the extensive author COI are material and are disclosed in full below. They do not undermine the specific contraindication itself, which is independently confirmed in drug labelling and cardiology guidelines worldwide and predates this review, but they should be weighed when reading this paper's framing and recommendations (e.g., its washout-interval guidance) rather than treating it as an independent source.

Study snapshot

Design	Narrative clinical pharmacology review
Model	N/A - review of human pharmacology and clinical trial/pharmacovigilance data
Sample	N/A - review
Intervention	N/A - review of organic nitrate and PDE5 inhibitor (sildenafil, vardenafil, tadalafil) co-administration
Duration	N/A - review
Endpoints	Magnitude and duration of blood-pressure-lowering synergy between organic nitrates and PDE5 inhibitors; Recommended washout intervals between PDE5 inhibitor and nitrate administration by drug half-life

What the study showed, in plain terms

Nitrate drugs used for angina and phosphodiesterase-5 (PDE5) inhibitor drugs used for erectile dysfunction (like sildenafil/Viagra and tadalafil/Cialis) both widen blood vessels through nitric oxide signalling. Taken together, their blood-pressure-lowering effects add up in a way that can cause dangerous, sometimes life-threatening drops in blood pressure. This review confirms that combining the two is an absolute contraindication, and sets out how long patients need to wait between one and the other depending on which specific drug and dose they've taken.

Key findings

Organic nitrates and PDE5 inhibitors are both vasodilators, and taken together can cause synergistic, clinically significant hypotension.
PDE5 inhibitors are an absolute contraindication in patients taking organic nitrates for angina or heart failure.
Nitrates can generally be taken 24 hours after the last dose of short-acting PDE5 inhibitors (sildenafil, vardenafil) and 48 hours after the last dose of long-acting PDE5 inhibitors (tadalafil), reflecting differences in drug half-life.
Patients on nitrate therapy who wish to use a PDE5 inhibitor should be counselled on the interaction and evaluated for whether nitrate therapy can be safely discontinued first.

What this study can and cannot tell us

This is a narrative expert review rather than a systematic review. It focuses specifically on organic nitrate drugs (e.g., nitroglycerin, isosorbide mononitrate) rather than dietary nitrate/nitrite from food or supplements, so it does not directly quantify risk from combining PDE5 inhibitors with beetroot juice or nitrate/citrulline supplements - a related but pharmacologically distinct exposure that this article flags as a caution by extension, not as directly studied here.

Full-text review confirms this manuscript was sponsored by Pfizer Limited, with Pfizer also funding the editorial assistance used to prepare it. Of the eight authors, one is a Pfizer employee, one is a former Pfizer employee and Pfizer shareholder, and the remainder disclose consulting, speaking, advisory-board, or research-funding relationships with Pfizer and/or other manufacturers of PDE5 inhibitor or cardiovascular drugs. This is a materially industry-funded and industry-affiliated review; the underlying nitrate-PDE5-inhibitor contraindication is independently corroborated elsewhere (drug labelling, cardiology consensus statements), but readers should treat this specific paper's framing, emphasis, and washout-interval recommendations with that funding and authorship in mind.

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