High-Dose NSAIDs Hike Risk of Heart Attack and Stroke

Be careful out there.
http://www.medpagetoday.com/PainManagement/PainManagement/39457?
High doses of some commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) increased the risk of major vascular events by about a third, according to a new meta-analysis of clinical trials.
The increase -- mainly driven by a higher risk of myocardial infarction -- is similar to that seen with selective COX-2 inhibitors, or coxibs, according to Colin Baigent, MD, of the University of Oxford, and colleagues.
But the analysis suggests the size of the risk can be predicted, which could assist doctors and patients in making clinical decisions, the researchers reported online in The Lancet.
High-dose NSAIDs, widely used to manage pain in inflammatory disorders, have been linked previously with an increased risk of gastrointestinal complications.
The coxibs -- a newer generation of NSAIDs -- were developed to reduce gastrointestinal side effects, but were found to increase the risk of heart attacks and death.
But the vascular effects of the traditional NSAIDs -- diclofenac, ibuprofen, and naproxen at respective doses of 150, 2,400, and 1,000 mg daily -- has not been clear.
To help fill the gap, Baigent and colleagues in the Coxib and traditional NSAID Trialists' Collaboration undertook a meta-analysis of 639 trials of coxibs and traditional NSAIDs compared with each other or with placebo. The coxibs under study were mainly mainly celecoxib (Celebrex), rofecoxib (Vioxx), etoricoxib (Arcoxia), and lumiracoxib (Prexige).
The main outcomes were major vascular events, including non-fatal MI, non-fatal stroke, or vascular death, as well as major coronary events, stroke, mortality, heart failure, and upper gastrointestinal complications.
All told, the trials included more than 353,000 participants with patient-level data available for many of the studies.
The analysis showed:

• Major vascular events were increased by about a third by a coxib, where the rate ratio was 1.37 (95% CI 1.14-1.66, P=0.0009).
• The same was true for diclofenac: the rate ratio was 1.41 (95% CI 1.12-1.78, P=0.003).
• The increases were chiefly due to more major coronary events. The rate ratio for such events for coxibs was 1.76 (P=0.0001), while the ratio for diclofenac was 1.70 (P=0.003).
• Ibuprofen significantly increased major coronary events -- the rate ratio was 2.22 (95% CI 1.10 to 4.48, P=0.0253) -- but not major vascular events.
• Naproxen did not significantly increase major vascular events or vascular deaths.

Heart failure risk was roughly doubled by all NSAIDs and all NSAID regimens increased upper GI complications, with rate ratios of 1.81 for coxibs, 1.89 for diclofenac, 3.97 for ibuprofen, and 4.22 for naproxen.
Compared with placebo, Baigent and colleagues reported, the effect of coxibs or diclofenac was to slightly increase the risk of vascular events. For every 1,000 patients treated with either, rather than a placebo, there were three extra major vascular events, one of which was fatal.
On the positive side, high-dose naproxen seemed to be associated with less hazard, although it's "unclear" if that's true of the lower doses most commonly used in clinical practice, they reported.
"Whilst NSAIDs increase vascular and gastrointestinal risks to a varying extent," Baigent said in a statement, "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."
Indeed, the analysis "offers considerable certainty" about the risks of high doses of commonly used NSAIDS, commented Marie Griffin, MD, of Vanderbilt University Medical Center in Nashville.
But in an accompanying commentary, Griffin argued that the study has some major gaps -- the risks associated with lower doses, longer durations of use, and residual effects after stopping treatment.
Clinical trials are not the whole story, she noted, and information to help fill those gaps might be found in observational studies.
But the bottom line, Griffin wrote, is that "identification of safe and effective strategies for chronic pain is sorely needed."
Until those are worked out, she concluded, "long-term use of high-dose NSAIDs should be reserved for those who receive considerable symptomatic benefit from the treatment and understand the risks."