Cardiovascular Risk with Non-Steroidal Anti-Inflammatory Drugs: Systematic Review of Population-Based Controlled Observational Studies – Forum

Date: 2013-03-06

Reference number: OPUSeJ 201303052316CRN

Links: to published article http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001098

to cover page:http://www.opusej.org/library/cardiovascular-risk-with-non-steroidal-anti-inflammatory-drugs-systematic-review-of-population-based-controlled-observational-studies-cover/

Title: Cardiovascular Risk with Non-Steroidal Anti-Inflammatory Drugs: Systematic Review of Population-Based Controlled Observational Studies

Authors: Patricia McGettigan & David Henry

Moderator: N/A

Overview:

Background: The analgesic (pain relieving), anti-pyretic (fever reducing), and anti-inflammatory (inflammation reducing) properties of the class of drug called non-steroidal anti-inflammatory drugs (NSAIDs)—so called to distinguish this class of drug from steroids, which have similar but additional effects—make NSAIDs one of the most frequently used drugs for the symptomatic treatment of many common conditions. Some preparations of NSAIDs can be bought over the counter, and all are available on prescription, but this class of drug has well documented side effects and risks: people taking NSAIDs are on average four times more likely to develop gastrointestinal complications than people not taking these drugs (that is, the relative risk of gastrointestinal complications is 4), and the relative risk for associated cardiovascular complications—cardiovascular events during treatment with NSAIDs has been one of the most studied adverse drug reactions in history—ranges from 1.0 to 2.0. Why Was This Study Done? Several large systematic reviews, including one conducted by these researchers, have previously highlighted apparent differences in cardiovascular risk between individual drugs, but these reviews have provided limited information on dose effects and relevant patient characteristics and have not directly compared the cardiovascular risks of each drug. Furthermore, most of these analyses extensively investigated only a few drugs, with little information on some widely available compounds, such as etoricoxib, etodolac, meloxicam, indomethacin, and piroxicam. Therefore, the researchers conducted this study to update cardiovascular risk estimates for all currently available NSAIDs and to compare the risks between individual drugs. In order to investigate the likely effects of over-the-counter use of NSAIDS, the researchers also wanted to include in their review an analysis of the cardiovascular risk at low doses of relevant drugs, over short time periods, and in low risk populations.

What Did the Researchers Do and Find? The researchers included only controlled observational studies in their literature search and review (conducted by searching a wide range of databases for studies published from 1985 until November 2010) because randomized controlled trials have reported only small numbers of cardiovascular events that are insufficient for the purposes of this study. The researchers assessed the methodological quality of selected studies, analyzed adjustment variables (for example, age, sex, other medications), and summarized overall results for individual drugs across studies as pooled relative risk estimates. For the subsets of studies that provided relevant data, they pooled within-study relative risk estimates with high and low doses and in people at high and low risk of cardiovascular events, and performed a series of within-study (pair-wise) comparisons and for each pair of drugs, to estimate their comparative relative risks by using a validated online tool to give a ratio of relative risks.

Using this methodology, the researchers included 30 case-control studies and 21 cohort studies: the highest overall risks were with rofecoxib and diclofenac, and the lowest risks were with ibuprofen and naproxen, The researchers found that risk was elevated with low doses of rofecoxib, celecoxib, and diclofenac, and rose with higher doses. Ibuprofen risk was only evident with higher doses. Naproxen did not cause any additional risks at any dose. Of the less studied NSAIDs, etoricoxib, etodolac, and indomethacin had the highest risks. In the pair-wise comparisons, the researchers found that etoricoxib had a higher relative risk than ibuprofen and naproxen, etodolac was not significantly different from naproxen and ibuprofen, and naproxen had a significantly lower risk than ibuprofen. Finally, the researchers showed that relative risk estimates were constant with different background risks for cardiovascular disease and increased early the course of treatment.

What Do These Findings Mean? This updated systematic review gives some new information on some familiar NSAIDs, and provides potentially important information on some little studied ones, which will help to inform clinical and regulatory decisions. The specific findings suggest that among widely used NSAIDs, naproxen and low-dose ibuprofen are least likely to increase cardiovascular risk, whereas diclofenac in doses available without prescription elevates risk. Based on sparse data, etoricoxib has a high risk of cardiovascular events and is similar to drugs that have been withdrawn because of safety concerns. Indomethacin is an older, rather toxic drug, and the new evidence on cardiovascular risk casts doubt on its continued clinical use.

Addendum: none

Erratum:

1. References,…5. Solomon DH, Schneeweiss S, Glynn RJ, Kiyota Y, Levin R, et al. (2004) Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 109: 2068–2073.

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Citation: McGettigan, Patricia and David Henry, 2011, “Cardiovascular Risk with Non-Steroidal Anti-Inflammatory Drugs: Systematic Review of Population-Based Controlled Observational Studies”, PLoS Med 8(9): e1001098. doi:10.1371/journal.pmed.1001098 http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001098

Academic citations forward: Cited by 46 as of 2013-03-06:

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