04:23am Tuesday 14 July 2020

Large International Study Finds Widely Used Painkillers Increase Risk of Heart Attack

PHILADELPHIA — A study led by an international consortium called the Coxib and traditional NSAID Trialists (CNT) Collaboration showed that, using a meta-analysis of 639 clinical trials including more than 350,000 patients, non-steroidal anti-inflammatory drugs (NSAIDs) painkillers can increase the risk of heart attacks and other cardiovascular problems. The research is published today in The Lancet and was funded by the Medical Research Council (United Kingdom) and the British Heart Foundation.

Garret FitzGerald, MD, director of the Institute for Translational Medicine and Therapeutics at the Perelman School of Medicine, University of Pennsylvania, is a member of the CNT group that crafted the report.  He first predicted almost 20 years ago, and then mechanistically explained the cardiovascular hazard from NSAIDs. FitzGerald, also chair of Penn’s Pharmacology Department has worked on NSAIDs and related drugs for more than 30 years.

For example, the new study found that, when used in high doses, diclofenac increases the risk of cardiovascular disease, on average causing about 3 extra heart attacks a year in every 1000 patients treated, one of which would be fatal.

The study authors emphasize the risks are mainly relevant to people with arthritis who need to take high doses over a long period. A short course of lower-dose NSAIDs purchased without a prescription, for example for a muscle sprain, is not likely to be hazardous.

The study also found that high doses of diclofenac increased the risk of a major vascular event (heart attack, stroke, or dying from cardiovascular disease) by around one third. Most of this additional risk was due to an increased risk of heart attacks. In contrast, high doses of naproxen did not appear to increase the risk of heart attacks. The researchers say this may be because naproxen also has protective effects that balance out any extra risk of heart attacks.

Concerns about the possible heart risks of NSAIDs, many of which have been on the market for several decades, arose after randomized trials showed that a newer class of NSAIDs known as COX-2 inhibitors or coxibs increased the risk of heart attacks. 

“The complicated NSAID story, which has unfolded over a decade, reveals the predictive power of integrating data drawn from detailed studies of drug action in small numbers of humans, genetically and pharmacologically manipulated animal models, observational studies and randomized trials and from human genetics,” said FitzGerald. “It is remarkable how so many of our predictions from human and animal studies  – the similar thrombotic risk from celecoxib and rofecoxib, the diverse cardiovascular risks of diclofenac and naproxen, the pattern of NSAID induced heart failure – are borne out by this analysis.

“A few uncertainties remain. We did not have much data with ibuprofen and it is unclear whether the small signal of risk relates to ibuprofen or its ability to undermine the benefit from concomitant low-dose aspirin. Also the failure to provide data on the trials of valdecoxib has limited our ability to relate drug-related risk to previous underlying risk of cardiovascular disease, which was especially high in the trials of this agent.

Despite these limitations, we now have perhaps the most diversified set of information on any aspect of any drug action, and it is a remarkable how faithfully it integrates mechanism with clinical consequence – a true example of translational therapeutics.”


Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 16 years, according to U.S. News & World Report‘s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $398 million awarded in the 2012 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania — recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2012, Penn Medicine provided $827 million to benefit our community.

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