Naproxen Best NSAID for Heart-Disease Patients

June 04, 2009

June 4, 2009 (Nashville, Tennessee) — One of the first large studies to look at the safety of different nonsteroidal anti-inflammatory drugs (NSAIDs) specifically in patients with heart disease has found that naproxen appears to have better cardiovascular safety than diclofenac, ibuprofen, and higher doses of rofecoxib (Vioxx, Merck) and celecoxib (Celebrex, Pfizer) [1].

The study, published in the May 2009 issue of Circulation: Cardiovascular Quality and Outcomes, was conducted by a group led by Dr Wayne Ray (Vanderbilt University School of Medicine, Nashville, TN).

They explain that the cardiovascular safety of NSAIDs is highly controversial, with several studies suggesting increased cardiovascular risk associated with the new COX-2 inhibitors and also some older traditional NSAIDs, and that this issue is particularly important for patients with existing serious coronary heart disease, whose baseline risk of adverse cardiovascular events is increased. In addition, many of these patients take low-dose aspirin, which may interact with the NSAID.

But they note that data on the cardiovascular safety of these drugs in heart-disease patients is limited. They therefore conducted the current retrospective cohort study in which they examined the cardiovascular safety of individual NSAIDs in 48 566 patients with a hospitalization for MI, revascularization, or unstable angina that had been recorded in one of three large databases-- Tennessee's expanded Medicaid program, Saskatchewan Health databases in Canada, and the United Kingdom's General Practice Research Database--between 1999 and 2004. Medications given outside the hospital were identified from pharmacy and physician records. The primary study end point was serious coronary heart disease, defined as MI or out-of-hospital death from CHD. A secondary end point was the composite of serious cardiovascular disease (MI or stroke) and death from any cause. Preplanned analyses were conducted for the most frequently prescribed NSAIDs, which were naproxen, ibuprofen diclofenac, celecoxib, and rofecoxib.

Results showed that cardiovascular safety was best for naproxen, which had a lower incidence rate ratio (IRR) for serious cardiovascular disease than non-NSAID users. In contrast, there was evidence that cardiovascular risk was increased for users of the other study NSAIDs.

Incidence Rate Ratios (IRRs) for Serious CV Disease or Serious CV Disease and Death for Users of Various Nsaids vs Non-NSAID Users

Drug IRR (serious CV disease) IRR (serious CV disease/death)
Naproxen 0.88 0.91
Ibuprofen 1.18 1.14
Diclofenac 1.27 1.38
Celecoxib 1.03 0.99
Rofecoxib 1.19 1.07

Other results showed that individuals who took diclofenac had a 50% increased risk of MI, stroke, or death from any cause compared with naproxen users. The authors point out that diclofenac is widely used outside the US and has been the reference drug in several COX-2-inhibitor outcome trials, and this excess risk was present for low and moderate doses (<150 mg/day) as well as higher doses. Ibuprofen users had a 25% increased risk for the MI, stroke, or death end point compared with naproxen users. In a comparison with high-dose naproxen use, users of higher doses of celecoxib (>200 mg/day) and rofecoxib (>25 mg/day) had increased risk of serious coronary heart disease.

Relative to NSAID nonusers, serious coronary heart disease risk increased with short-term (less than 90 days) use for ibuprofen, diclofenac, celecoxib, and rofecoxib, but not for naproxen. The authors note that this is in contrast to a widely publicized post hoc analysis of the APPROVE trial data, interpreted by some as suggesting no risk for use of less than 18 months. But they point out that observational studies of rofecoxib have reported increased risk within the first month of therapy, and in the VICTOR trial, rofecoxib patients had increased risk after a mean duration of 7.4 months. "Thus, our findings add to the evidence that at least one of the mechanisms for increased cardiovascular risk is acute," they say.

They comment that their current findings are generally consistent with previous studies, most of which were not restricted to patients with serious coronary heart disease. They caution that the follow-up in this study began 45 days after the qualifying hospitalization admission for coronary heart disease, so these results do not apply to the early postdischarge period, during which NSAID use may be particularly hazardous.

Breaking New Ground

In an accompanying editorial [2], Dr Daniel Solomon (Brigham and Women's Hospital, Boston, MA) says that this study breaks new ground in focusing on patients with known cardiovascular disease. As arthritis and cardiovascular disease commonly coexist, studying the cardiovascular safety of NSAIDs in this subgroup is of great public-health value, he comments.

Noting that the relative risks for rofecoxib were consistently lower when death from any cause was also included in the end point, Solomon suggests that this raises the possibility that death from gastrointestinal bleeds may have been reduced in persons using rofecoxib. He says this leads to questions about how to measure the overall safety of a drug. "Cardiovascular safety in patients with known cardiovascular disease is tremendously important, but clinicians and patients should focus on 'net' safety," he writes. But he adds that this is difficult concept to understand and even harder to measure.

Solomon continues that the use of NSAIDs in patients with cardiovascular disease is concerning because of the cardiovascular and gastrointestinal toxicities associated with these agents, but until newer analgesics are developed, these agents will continue to be used in this patient group.

While more information will come from the PRECISION trial, a large randomized comparison of celecoxib, naproxen, and ibuprofen in patients at moderate cardiovascular risk, these results will not be available until 2011 or later, and thus, until then, doctors will continue to rely on well-done pharmacoepidemiology to help answer questions about the relative safety of various analgesic strategies in important subgroups of patients, Solomon says.

He concludes that the current study "gives us new and useful information from an observational study focusing on an important subgroup with known cardiovascular disease" and that "diclofenac use should be limited in this group and naproxen appears relatively safe, but non-NSAID analgesic strategies might also be considered."

This study was funded by an unrestricted grant from Pfizer. Ray has consulted with plaintiff's attorneys and insurance companies regarding rofecoxib. Two other authors were employees of Pfizer when this research began, and other authors have received research support from Merck, AstraZeneca, Novartis, and Pfizer. Solomon receives salary support for research from Amgen and Abbott. He serves as an unpaid member of the executive committee of the Pfizer-sponsored PRECISION trial, and he serves as an unpaid member of the data safety monitoring board of a Pfizer-sponsored trial investigating a non-NSAID analgesic for osteoarthritis.

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