Cardiovascular risk of non-steroidal anti-inflammatory drugs
The cardiovascular safety of the selective cyclooxygenase (COX)-2 inhibitor celecoxib as compared with non‑selective non‑steroidal anti‑inflammatory drugs (NSAIDs) was assessed as part of the recently published large Prospective, Randomised Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial . Results of this study found that celecoxib was not inferior to ibuprofen or naproxen with regard to cardiovascular safety. Furthermore, the risk of gastrointestinal events was significantly lower with celecoxib compared with naproxen or ibuprofen and the risk of renal events was significantly lower with celecoxib compared with ibuprofen. These results are reassuring however study limitations include the large number of patients who stopped taking the study drug during the period of follow-up and also the failure to include a placebo or an active comparator grouping.
Non‑steroidal anti‑inflammatory drugs and cardiovascular risk
The development of selective COX-2 inhibitors represented an exciting development for patients requiring NSAIDs for control of joint pain and inflammation . As the gastrointestinal toxic effects of non‑selective NSAIDs are linked to COX-1 inhibition, the development of selective COX-2 inhibitors offers the potential to retain COX-2 inhibition benefits whilst not exposing the gastrointestinal tract to COX-1-related adverse effects.
The subsequent finding of adverse cardiovascular outcomes in patients receiving the selective COX-2 inhibitor rofecoxib in a placebo‑controlled trial resulted in the withdrawal of the drug in 2004. The US Food and Drug Administration (FDA) allowed continued marketing of celecoxib however they mandated that a cardiovascular safety trial be conducted. This PRECISION trial was designed to assess cardiovascular outcomes in patients treated with celecoxib as compared with the two non‑selective NSAIDs ibuprofen and naproxen.
This study enrolled patients who, as determined by patient and physician, required daily treatment with NSAIDs for arthritis pain. A further key inclusion criterion was that patients should have either an established cardiovascular disease or an increased risk of the development of cardiovascular disease. Patients could have either rheumatoid arthritis or osteoarthritis and the use of aspirin was permitted, although enrolment was stratified accordingly to aspirin use. Among the treatment groups, patients were randomly assigned to receive low doses of the NSAIDs including celecoxib at 200 mg daily, ibuprofen at 1800 mg daily, or naproxen at 750 mg daily. Doses could be adjusted to a max of 400 mg of celecoxib daily, 2400 mg of ibuprofen daily, or 1000 mg of naproxen daily with the exception that dose escalation for celecoxib in patients with osteoarthritis was not permitted because of regulatory dosing restrictions. Notably esomeprazole was provided to all patients for gastric protection. It is a limitation in my view that a placebo or an active comparator arm was not included as this study therefore does not address whether the use of either selective or non‑selective NSAIDs is associated with an increase of cardiovascular risk or other outcomes compared with placebo or active comparator. The authors quote a 2015 paper, which would argue that acetaminophen may be ineffective for the treatment of patients with NSAID-dependent arthritis . At the time of designing this study prior to 2006 however, the use of a acetaminophen would have been a reasonable alternative for comparison purposes.
A total of 24,081 patients were randomly assigned to each of the NSAIDs. Mean treatment duration was 20 months and mean follow-up period was 34 months. Notably 68.8% of patients stopped taking the study drug for reasons that are unclear although low levels of adherence and retention have been found in other similar studies. In both the intention‑to‑treat analysis and the on-treatment analysis, there was no difference in the number of patients meeting the primary composite outcome (Anti‑platelet Trialists Collaboration [APTC] criteria such as death from cardiovascular causes including haemorrhagic death, non‑fatal myocardial infarction, or non‑fatal stroke) and celecoxib met all four pre‑specified non‑inferiority requirements. The number of patients dying from any cause was lower in patients receiving celecoxib as compared with naproxen but this did not reach statistical significance. The event rate for the composite outcome of serious gastrointestinal events was lower in the celecoxib group than in both the naproxen and ibuprofen group. In addition, serious renal events occurred at a significantly lower rate in the celecoxib group compared with ibuprofen.
This PRECISION study provides statistically strong evidence that the cardiovascular risk associated with moderate doses of celecoxib is not greater than that associated with non‑selective NSAIDs. The trial results do not support the belief that naproxen treatment as compared with other NSAIDs results in better cardiovascular outcomes. In addition, this study showed significantly fewer gastrointestinal events in patients treated with celecoxib and this despite the fact that all patients were given a prescription of esomeprazole. Celecoxib also appeared to be better in terms of renal outcomes as compared with ibuprofen.
These results are certainly encouraging but as there was no placebo or acetaminophen group, one cannot conclude that these agents are not associated with adverse cardiovascular outcomes. In addition, the dose of celecoxib used in this study was low and higher doses may be associated with higher risk of cardiovascular and other events. The high numbers of patients who drop out or are lost to follow-up also make interpretation difficult. Interestingly, neither aspirin use nor background diagnosis appeared to affect the outcome of this study, though how compliant patients are with aspirin is unclear.
Thus this study would suggest that the use of moderate doses of celecoxib is at least as safe as naproxen or ibuprofen in patients requiring NSAID use for control of their musculoskeletal symptoms. Lower rates of gastrointestinal and renal adverse events were also seen. The limitations of the study however are such that one could not conclude that the use of NSAIDs including celecoxib is safe in patients with established or at increased risk of cardiovascular disease.
About the author
- Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celocoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016;375:2519-2529.
- Whittle BJ. COX-1 and COX-2 products in the gut: therapeutic impact of COX-2 inhibitors. Gut. 2000;47:320-325.
Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 2015;350:h1225.