Nonsteroidal anti-inflammatory drugs and cardiovascular safety – translating pharmacological data into clinical readouts

ABSTRACT

Introduction: The pharmacological management of pain includes the use of nonsteroidal anti-inflammatory drugs(NSAIDs). They comprise traditional(t) NSAIDs and selective cyclooxygenase(COX)-2 inhibitors (named coxibs). The analgesic and anti-inflammatory effects of NSAIDs are dependent on the extent and duration of COX-2 inhibition in the spinal cord and inflammatory sites. However, the simultaneous inhibition of COX-2 in the vasculature translates into a prothrombotic phenotype and promotes hypertension and heart failure.

Areas covered: The results of the clinical pharmacology of coxibs and the most used tNSAIDs provide a mechanistic interpretation of the cardiovascular(CV) outcomes found in randomized clinical trials(RCTs), meta-analyses of RCTs and epidemiological studies. A critical analysis of the design and results of the PRECISION trial, which compared the CV risk of celecoxib, ibuprofen, and naproxen in high‐risk CV patients, was performed.

Expert opinion: tNSAIDs and coxibs may increase the chance of a heart attack or stroke. The reduction of the dose of NSAIDs may mitigate, but not avoid, the risk of CV adverse effects. The development of novel biomarkers which identify susceptibility phenotypes associated with increased risk of CV complications by COX-2 inhibition is an unmet clinical need that once filled will lead to personalized treatments with NSAIDs.

KEYWORDS:

• Aspirin
• Cardiovascular toxicity
• Coxibs
• Cyclooxygenase
• Gastrointestinal toxicity
• Nonsteroidal anti-inflammatory drugs
• Prostacyclin
• Prostaglandin E₂
• Thromboxane
• Whole blood assays

Article highlights

• The analgesic and anti-inflammatory effects of NSAIDs are dependent on the extent and duration of COX-2 inhibition in the spinal cord and inflammatory sites.

• The inhibition of COX-2 in the vasculature translates into a prothrombotic phenotype and promotes hypertension and heart failure; these side effects are common to tNSAIDs and coxibs.

• The CV hazard of NSAIDs occurs especially in patients with underlying heart or circulatory conditions or with certain CV risk factors.

• High-dose naproxen is associated with less CV risk than coxibs, diclofenac, and ibuprofen, but the drug is more gastrotoxic.

• The results of the PRECISION trial do not alter practice on the use of celecoxib and tNSAIDs in pain management.

• The use of the lowest dose of tNSAIDs or coxibs which are effective for the shortest duration possible is recommended.

This box summarizes key points contained in the article.

Acknowledgements

We wish to thank Dr. Melania Dovizio and Annalisa Contursi for critical discussion and suggestions

Declaration of interest

PP has received grants from Associazione Italiana per la Ricerca sul Cancro, Ministero dell’Istruzione, dell’Università e della Ricerca; has received speaker fees from Bayer and Iroko Pharmaceuticals; and has provided consulting services to and received honoraria from Iroko Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper has not been funded.