Gastrointestinal and cardiovascular adverse events associated with NSAIDs

ABSTRACT

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed pharmacological groups, especially in elderly patients.

Areas Covered

The main GI and CV adverse events associated with NSAID use are reviewed. Risk factors and prophylactic strategies are also covered.

Expert Opinion

COX-2 selective agents are safer to the GI tract but have a worst CV profile. On the contrary, naproxen seems safer for CV system, but it is one of the NSAIDs with higher GI toxicity. Co-therapy with aspirin reduces the GI benefits of COX-2 selective agents, whereas ibuprofen and naproxen may neglect the antiplatelet effect of aspirin. NSAIDs increase the risk of both upper and lower GI complications. Co-therapy with PPI reduces the risk of upper but not lower GI complications, and seems to induce dysbiosis in the small bowel, which may be implicated in the damage induced by NSAIDs. Celecoxib, a COX-2 selective agent, seems safer for both the upper and the lower GI tract. Prescription of type and dose of NSAIDs must be individualized based on the stratification of the CV and GI risk of patients.

KEYWORDS:

• Cardiovascular event
• coxibs
• enteropathy
• gastrointestinal bleeding
• NSAIDs
• peptic ulcer

Article highlights

• NSAIDs are one of the most prescribed pharmacological groups worldwide. Compared to other analgesics, they have advantages in terms of efficacy and lack of dependence. A risk minimization strategy and a correct assessment at the cardiovascular digestive and renal levels is essential before prescribing this type of drug to reduce the occurrence of adverse events. Naproxen has been reported in several studies to be the NSAID with the lowest cardiovascular risk, although with higher GI risk compared to other NSAIDs.

• Suffering from structural heart disease or chronic renal failure are the main risk factors for the development of cardiac arrhythmias in patients treated with NSAIDs.

• The use of either non-selective NSAIDs or COX2 selective inhibitors are risk factors for the development of heart failure and hospitalization for this reason.

• NSAIDs can damage both the upper and the lower gastrointestinal tract. Upper GI lesions can be found in 30–50% patients taking NSAIDs, whereas small-bowel injury is detected in up to 70% of chronic NSAID users, with erosions and ulcers in 30–40% of the patients. The clinical significance of most of these lesions is weak, although the risk of peptic ulcer complication is increased 4 times when compared to non-users.

• Strategies to prevent NSAID-associated upper gastrointestinal damage (PPIs, coxibs) should be implemented in high-risk patients, which include a history of peptic ulcer, age >60 years, high doses, presence of comorbidities, and concomitant use of ≥2 NSAIDs, aspirin/antiplatelets, anticoagulants, corticosteroids, or selective serotonin reuptake inhibitors.

• Strategies to prevent lower gastrointestinal damage are less established, as evidence is scarce. If relevant lower gastrointestinal damage is detected, NSAIDs should be discontinued if possible. PPIs are not useful in this area and may induce intestinal dysbiosis. Misoprostol could be the first choice for treating NSAID-induced enteropathy, but it is usually not well tolerated. Low-dose celecoxib is an alternative in this setting, if NSAID treatment is needed. Future studies will determine the potential use of microbiota modulation as an effective therapeutic target.

• This box summarizes key points contained in the article.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

List of abbreviations

CI: confidence interval; COX: cyclooxygenase; CV: cardiovascular; GI: gastrointestinal; LDA: low-dose aspirin; NOACs: new oral anticoagulants; NSAIDs: non-steroidal anti-inflammatory drug; MI: myocardial infarction; PPIs: proton pump inhibitors; RR: relative risk.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.