A new meta-analysis looking at the vascular and gastrointestinal effects of nonsteroidal anti-inflammatory drugs (NSAIDs) — including selective cyclooxygenase-2 [COX-2] inhibitors, also known as coxibs, as well as traditional NSAIDs such as diclofenac and ibuprofen — shows that the vascular risks associated with high-dose diclofenac and possibly ibuprofen are similar to the established risks associated with coxibs.

High-dose naproxen, however, was associated with less vascular risk than the other NSAIDs. Further analysis suggested that these risks can be predicted for individuals.

“Whilst NSAIDs increase vascular and gastrointestinal risk to a varying extent, our analyses indicate that the effects of different regimens in particular patients can be predicted, which may help physicians choosing between alternative NSAID regimens to weigh up which type of NSAID is safest in different patients,” lead author Professor Colin Baigent, FFPH, from the Clinical Trial Service Unit and Epidemiological Studies Unit at the University of Oxford, United Kingdom, said in a statement.

The meta-analysis is published online May 30 inThe Lancet.

Unequivocal Risk

COX-2 selective inhibitors were developed in the 1990s, and early trials showed that at doses similar for analgesic efficacy, coxibs had less gastrointestinal toxicity than traditional NSAIDs, the authors write. “Unfortunately, however, subsequent placebo-controlled trials also showed unequivocally that coxibs were associated with an increased risk of atherothrombotic vascular events,” they note.

Soon afterward, a meta-analysis of trials comparing coxibs to traditional NSAIDs showed that some of these other NSAIDs may also have adverse effects on cardiovascular events, but the hazards appeared to depend on the degree and duration of suppression of platelet COX-1. High-dose naproxen that can induce near-complete suppression of platelet thromboxane throughout the dosing interval appeared not to increase cardiovascular disease (CVD) risk, while other high-dose NSAID regimens with only transient effects on platelet COX-1 “were associated with a small but definite vascular hazard,” the authors write.

The US Food and Drug Administration already requires that all NSAIDs carry a boxed warning about the CVD risks, while the European Medicines Agency’s Committee for Medicinal Products for Human Use decided that coxibs, but not NSAIDs, should be contraindicated in patients with coronary heart disease or stroke and used with caution in patients with risk factors for coronary heart disease.

In this report, the authors, members of the Coxib and traditional NSAID Trialists’ (CNT) Collaboration, set out to quantify the cardiovascular and gastrointestinal risks associated with particular NSAID regimens in different types of patients, in particular those with increased risk for vascular disease.

Included were 280 trials of NSAIDs vs placebo, with 124,513 participants and 68,342 person-years of follow-up, and 474 trials comparing NSAIDs to one another, including 229,296 participants and 165,456 person-years of follow-up.

The primary outcomes of interest were major vascular events, including nonfatal myocardial infarction (MI), nonfatal stroke, or vascular death; major coronary events, including nonfatal MI and coronary death; stroke; mortality; heart failure; and upper gastrointestinal complications, including perforation, obstruction, and bleeding.

The authors found that major vascular evens were increased by about one third by a coxib or diclofenac, “chiefly due to an increase in major coronary events,” they note. Compared with placebo, they note, “of 1000 patients allocated to a coxib or diclofenac for a year, 3 more had major vascular events, 1 of which was fatal.”

Ibuprofen was associated with significantly increased risk for major coronary events but not major vascular events. There was no excess risk for major vascular events or major coronary events with high-dose naproxen.

Table. Meta-Analysis: Risk for Major Vascular and Major Coronary Events by NSAID

CI = confidence interval; NS = not significant.

There was no signal that any of these NSAIDs increased stroke risk, they note, but few strokes were recorded, and “the absence of any stroke risk for drug regimens known to increase blood pressure is implausible.”

Vascular death was increased significantly by coxibs and diclofenac, nonsignificantly increased by ibuprofen, but again not increased by naproxen. All NSAIDs, though, were associated with a roughly doubling of the risk for heart failure, “consistent with this being a COX-2 dependent hazard unrelated to variable platelet inhibition.”

As expected, they add, NSAIDs increased the risk for upper gastrointestinal complications by 2 to 4 times, although coxibs yielded the lowest risk for these complications.

They found that the proportional effects of coxibs and traditional NSAIDs seemed similar irrespective of baseline characteristics, including vascular risk. Using this assumption, they did hypothetical calculations of the annual excess risks for each of the main NSAIDs vs placebo for patients at high, medium, and low risk for major vascular events and for upper gastrointestinal complications.

“Although NSAIDs increase vascular and gastrointestinal risks to a varying extent, our analyses indicate that the effects of different regimens in particular patients can be predicted, which could help in guiding decisions about the clinical management of inflammatory disorders,” they conclude.

Risks “Not Fully Appreciated”

In a Commentary accompanying the publication, Marie R. Griffin, MD, from the Department of Preventive Medicine at Vanderbilt University Medical Center, Nashville, Tennessee, points out that while no therapeutic intervention is free of risk, the risks for MI and death associated with the use of high-dose NSAIDs “are probably not fully appreciated by many patients using these drugs.”

The findings of this new meta-analysis, she writes, “should facilitate informed individual decision making about the use of NSAIDs for chronic painful conditions.”

Unfortunately, she writes, older adults at high risk for adverse effects from NSAIDs “comprise a substantial portion of people with chronic pain. For those at high risk of heart failure or chronic kidney disease, these drugs are generally avoided. Opioids may be an option but have serious risks and little data on their efficacy in chronic pain.

Patients should be offered evidence-based nonpharmacologic treatments, including application of heat or cold, exercise, weight loss, or self-management programs; NSAID or non-NSAID topical treatments; or NSAID regimens that minimize risk, using the lowest-risk agents at the lowest dose for short periods.

“Identification of safe and effective strategies for chronic pain is sorely needed,” Dr. Griffin concludes. “In the meantime, long-term use of high dose NSAIDs should be reserved for those who receive considerable symptomatic benefit from the treatment and understand the risks.”

The study was funded by the UK Medical Research Council and British Heart Foundation. The Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU) where the CNT Secretariat is located has a policy of staff not accepting fees, honoraria, or paid consultancies. CTSU staff are, however, involved in clinical trials of lipid-modifying therapy funded by research grants from Merck to the University of Oxford, with the University the trial sponsor in all cases. In particular, Dr. Baigent was chief investigator of the Study of Heart and Renal Protection of ezetimibe/simvastatin prior to 2011. Disclosures for coauthors appear in the paper. Dr. Griffin has disclosed no relevant financial relationships.

Lancet. Published online May 30, 2013. Abstract

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