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.

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."