NSAIDs and CV Risk: The Bottom Line

The Best Option: Acetaminophen

While it's true that acetaminophen may not always provide sufficient pain relief, it's equally important to emphasize the risks associated with nonsteroidal anti-inflammatory drugs (NSAIDs). These risks should limit the use of ibuprofen, diclofenac, or celecoxib in this patient with a history of an MI.

The rationale for avoidance of opioids like oxycodone for chronic osteoarthritic pain requires no further discussion.

NSAIDs and Risk for MI

What is the evidence that NSAIDs are associated with cardiovascular risk? Investigators in Denmark examined the pharmacy and medical records of almost 100,000 patients over the age of 30 years (mean age, 69) admitted with a first MI over a 12-year period.^[1] The hazard ratio (HR) for death and second MI associated with subsequent NSAID use was calculated. At 1 year, the HR for death was 1.59 (95% confidence interval [CI], 1.49-1.69) whereas the HR for nonfatal MI was 1.3 (95% CI, 1.22-1.39). At 5 years, the HR for death was 1.63 (95% CI, 1.52-1.74) and the HR for nonfatal MI was 1.41 (95% CI, 1.28-1.55). While these results do not indicate a huge relative risk on an individual basis, because of the widespread use of these drugs, the population risk is substantial.

Short-term use. What about short-term use of NSAIDs? Does a 3- to 5-day course of treatment for gout or a musculoskeletal injury convey risk in the post-MI patient? Yes. Even short-term treatment with most NSAIDs has been found to be associated with increased risk for death and recurrent MI in patients with prior MI.^[2]

No MI history. What about patients without a history of MI? A study published in 2017 concluded that use of oral NSAIDs during an acute respiratory infection increased the risk for MI three fold (adjusted odds ratio [aOR], 3.41; 95% CI, 2.80-4.16) whereas parenteral NSAIDs increased the risk seven fold (aOR, 7.22; 95% CI, 4.07-12.81) when compared with baseline risk (no NSAID use or respiratory infection).^[3]

Selective NSAIDs. Selective NSAIDs—the coxibs—also pose cardiovascular (CV) risk. A large meta-analysis of trials^[4] published in 2013 examined risk with both nonselective NSAIDs and the selective coxibs. The analysis included 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another (229,296 participants, 165,456 person-years). The outcomes of interest in this analysis were death, major vascular or coronary events, stroke, hospitalization for heart failure (HF), death, and upper gastrointestinal (GI) complication (perforation, obstruction, or hemorrhage). Coxibs and diclofenac were associated with increased risk for major vascular events (rate ratio [RR] for coxibs, 1.37; 95% CI, 1.14-1.66; P = .0009; RR for diclofenac 1.41; 95% CI, 1.2-1.78; P = .0036), primarily owing to an increase in major coronary events.

Ibuprofen increased the risk for MI (RR, 2.22; 95% CI, 1.10-4.48; P = .0253). All NSAIDs, including coxibs, roughly doubled the risk for heart failure. All NSAIDs also increased GI bleeding risk, although coxibs were least likely to be associated with a GI bleed (RR, 1.8; 95% CI, 1.17-2.81, P = .0070) and naproxen most likely (RR, 4.22, 95% CI, 2.71-6.56, P < .0001).

This risk was confirmed more recently in a prospective randomized controlled trial. PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen) was a large noninferiority, multicenter, randomized, double-blind trial that examined use of celecoxib, ibuprofen, and naproxen.^[5] Patients were enrolled who required NSAIDs for management of pain in osteoarthritis or rheumatoid arthritis and were at increased CV risk. They were randomly assigned to receive celecoxib, ibuprofen, or naproxen. A primary composite outcome of CV death (including hemorrhagic death), nonfatal MI, or nonfatal stroke was measured with a goal of determining whether celecoxib was associated with lower CV risk. In the intention-to-treat analyses, CV events occurred in 2.3% of patients in the celecoxib group, 2.5% of patients in the naproxen group, and 2.7% of those in the ibuprofen group; these differences were not statistically significant. The risk for GI bleeding was lower with celecoxib, and renal events were more common with ibuprofen.

Use in the elderly. What about use of NSAIDs in older patients? A study^[6] published back in 2000 looked at 365 cases of elderly adults (mean age, 76.6 years) admitted to the hospital with congestive heart failure (CHF) and compared them with 658 control patients (mean age, 75.1 years) admitted without CHF. The investigators found that NSAID users had an odds ratio (OR) of 2.1 for admission for CHF, and that the OR increased to 10.5 for a first-time admission for CHF if the patient using NSAIDs also had heart disease. The risk for a CHF admission correlated with the NSAID dose and the duration of use.

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