Adverse Events with NSAIDs Linger


A new systematic review and meta-analysis shows that while NSAIDs peaks at two weeks, while gastrointestinal and cardiovascular adverse events linger.

Acetaminophen (©AdobeStock_SherryYoung)

A systematic review and meta-analysis recently published in the journal Arthritis Care & Research, shows that efficacy for nonsteroidal anti-inflammatory drugs, or NSAIDs, peaks at two weeks, coupled with a consistent, early rise of minor gastrointestinal and cardiovascular adverse events.

The findings, by Raveendhara R. Bannuru, M.D., of Tufts Medical Center, also found that these adverse events may occur in the short term.

While NSAIDs produced significant pain and function improvements that peaked at two weeks, but decreased over time, minor gastrointestinal and cardiovascular adverse events consistently rose, reaching significance as early as four weeks.

“Clinicians should weigh the durability of efficacy with the early onset of minor adverse events along with patient tolerability and preferences when formulating an NSAID regimen,” Dr. Bannuru and colleagues wrote.

The analysis included 26,424 patients from 72 randomized controlled trials for Celecoxib (35 trials), Naproxen (18 trials), Diclofenac (11 trials), Nabumetone (seven trials), Ibuprofen (six trials), Meloxicam (three trials), Etodolac (two trials), Indomethacin (one trial), and Piroxicam (one trial). Most studies were of moderate quality.

The studies, which were published between 1976 to 2017, showed that NSAIDs provide rapid pain relief and function restoration, but at least three NSAID classes tapered and lost clinical significance by eight weeks. Simultaneously, gastrointestinal and cardiovascular adverse events incidence rose as soon as two weeks and remained elevated. Traditional NSAIDs had the least favorable safety profile.

Traditional NSAIDs consistently performed better than other classes. At two weeks, pain reductions were 24 percent and 64 percent greater than Celecoxib and Intermediate COX inhibitors, respectively. They also showed better functional improvement, ranging from 14 percent-to-42 percent better than Celecoxib. The impact, however, waned, losing clinical significance over time.

Celecoxib patients had a statistically significantly higher gastrointestinal adverse events risk, but cardiovascular risk effect wasn’t significant. Intermediate COX inhibitor patients also had a significantly higher gastrointestinal, but not cardiovascular adverse events.

These results, the authors wrote, support current recommendations for the lowest-effective, shortest-duration NSAID dose. Guidelines suggest using traditional NSAIDs with proton-pump inhibitors or Celecoxib use with or without proton-pump inhibitors to minimize gastrointestinal toxicity risk in moderate-or-high comorbidity risk patients. Naproxen or Celecoxib is recommended to minimize cardiovascular adverse events risk in patients with cardiovascular comorbidities.

Ultimately, they said, clinicians should consider NSAID risk-versus-benefit as results suggest long-term treatment can lack efficacy and increase adverse events.


Bannuru R, Omani M, Vaysbrot E, Zhou M, McAlindon T, Duration of Sumptom Relief and Early Trajectory of Adverse Events for Oral NSAIDs in Knee Osteoarthritis: A Systematic Review and Meta-analysis. Arthritis Care & Research (2019), doi: 10.1002/acr.23884

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