Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) include traditional (tNSAIDs), such as ibuprofen, naproxen, and diclofenac, as well as selective cyclooxygenase-2 inhibitors (COXIBs), principally celecoxib. COXIBs were developed to decrease gastrointestinal side effects. Recently, the US Food and Drug Administration strengthened its warning about the risks of non-aspirin NSAIDs on myocardial infarction and stroke. The Cyclooxygenase 2 and Non-Steroidal Anti-Inflammatory Drug Trialist collaboration conducted a comprehensive worldwide meta-analysis using individual patient data exploring the risks of various COXIBs and NSAIDs on cardiovascular disease (CVD). Recently, the results of the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial were published that tested risks of COXIBs and NSAIDs on CVD. Generally, data from meta-analyses of trials not designed a priori to test hypotheses are less reliable than large-scale randomized trials to test small to moderate benefits or harm. When the sample size is large, randomization provides control of confounding not possible to achieve in any observational study. Further, observational studies, and especially claims data, have inherent confounding by indication larger than the effects being sought. Nonetheless, trials must be of sufficient size and duration and achieve high compliance and follow-up to avoid bias and confounding. In this regard, PRECISION has high rates of nonadherence and losses to follow-up that may have introduced bias and confounding. At present, therefore, it may be most prudent for clinicians to remain uncertain about benefits and risks of these drugs and make individual clinical judgments for each of their patients.
Similar content being viewed by others
References
Zhou Y, Boudreau DM, Freedman AN. Trends in the use of aspirin and nonsteroidal anti-inflammatory drugs in the general U.S. population. Pharmacoepidemiol Drug Saf. 2014;23(1):43–50.
Frech EJ, Go MF. Treatment and chemoprevention of NSAID-associated gastrointestinal complications. Ther Clin Risk Manag. 2009;5(1):65–73.
Cyclooxygenase 2 and Traditional Non-Steroidal Anti-Inflammatory Drug Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs. Meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769–779.
Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016;37526:2519–2529.
Antman EM, Bennett JS, Daughtery A, Furberg C, Roberts H, Taubert KA. Use of nonsteroidal anti-inflammatory drugs. An update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007;115(12):1634–1642.
Hennekens C, Buring J. Epidemiology in Medicine. 1st ed. Philadelphia, PA: Lippincott Williams and Wilkins; 1987.
Hennekens C, DeMets D. Statistical association and causation: contributions of different types of evidence. JAMA. 2011;305(11):1134–1136.
Hennekens CH, DeMets D. The need for large-scale randomized evidence without undue emphasis on small trials, meta-analyses, or subgroup analyses. JAMA. 2009;302(21):2361–2362.
Doyle Arthur Conan. The Speckled Band: An Adventure of Sherlock Holmes. New York, NY: Samuel French Publishers; 1912.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rane, M.A., Foster, J.G., Wood, S.K. et al. Benefits and Risks of Nonsteroidal Anti-inflammatory Drugs: Methodologic Limitations Lead to Clinical Uncertainties. Ther Innov Regul Sci 53, 502–505 (2019). https://doi.org/10.1177/2168479018794159
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1177/2168479018794159