Electronic Database Studies May Not Accurately
Estimate Risk of Heart Attack
Among Users of Naproxen, Ibuprofen
Epidemiological Survey Study Links Heart Protection With Non-aspirin,
(Philadelphia, PA) - It is well known that aspirin, a non-selective,
non-steroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase
(COX), reduces the risk of heart attack and stroke. Non-aspirin non-steroidal
anti-inflammatory drugs (NANSAIDs) such as ibuprofen and naproxen may
reduce this same risk, but studies have shown conflicting results. Some
have shown no association between NANSAIDs and heart attacks; some have
shown an increased risk; and others have suggested a lower risk of heart
attack, particularly with naproxen.
A new epidemiological study from the University of Pennsylvania
School of Medicine, based on detailed patient surveys rather
than administrative databases of patient prescriptions and billing records,
suggests that these administrative-database studies may not accurately
estimate the risk of heart attack among users of naproxen and ibuprofen.
Indeed, results from the Penn study showed a protective relationship between
NANSAIDs and heart attack. The study findings are published in the August
issue of Pharmacoepidemiology and Drug Safety, and will be presented
at the 21st International Conference on Pharmacoepidemiology and Therapeutic
Risk Management (www.pharmacoepi.org)
on August 23 in Nashville, TN.
Previous studies on NANSAIDs used prescription records from billing data
or electronic medical records (referred to as “electronic databases”),
but not direct interviews with patients about their lifestyle or their
over-the-counter use of NANSAIDs or aspirin. However, a February 2005
study by lead author Stephen E. Kimmel, MD, Associate
Professor of Medicine in the Cardiovascular Division and Associate Professor
of Epidemiology in the Department of Biostatistics and Epidemiology at
Penn, suggested a benefit of non-selective NANSAIDs, when data were collected
from study participants instead of relying on the limited information
from electronic databases.
Although all epidemiological studies have potential limitations, electronic
databases have several limitations inherent in the source of data: First,
electronic databases record only prescription records, not over-the-counter
use, so most use of NANSAIDs like over-the-counter ibuprofen is unaccounted
for. “By using prescription databases you don’t completely
capture the non-steroidal use,” says Kimmel. “You are calling
people non-users of the drug when they really are. In our survey, 35 percent
of participants had taken a non-steroidal, mostly over-the-counter, in
the week prior to taking our survey.”
This misclassification of users as non-users of NANSAIDs skews interpretation
toward finding that NANSAIDs have no effect on the risk of heart attacks.
The researchers found that of all the non-steroidal use, 80% was over
the counter, and mostly ibuprofen (e.g., Advil).
Second, electronic databases do not capture complete information on nonprescription
aspirin use. “Many people use over-the-counter aspirin for everything
from headaches to protecting the heart,” says Kimmel. “This
means you can’t separate the aspirin users from the non-users.”
This lack of complete information makes it difficult to examine the effects
of NANSAIDs in the absence of the anti-platelet effects of aspirin.
Finally, electronic databases do not take into account risk factors for
heart attacks, such as lower physical activity and higher body mass index,
that may be more common in NANSAID users, who tend to have osteoarthritis.
The researchers hypothesized that the lack of these three types of data
or distinctions in studies based on electronic databases would bias results
toward showing no association between NANSAID use and lower risk of heart
attack. In the new study, participants-1,669 first-time heart-attack survivors
and 6,604 controls without a heart attack-were asked about their use of
both prescription and over-the-counter non-steroidal and aspirin use and
about several risk factors for heart attacks that are typically unavailable
or incomplete in administrative databases such as weight and level of
activity. When each potential category of bias was removed, NANSAIDs showed
a stronger protective association with heart attack. Because of this,
the researchers concluded that the limitations of electronic databases
might be responsible for the lack of association of NANSAIDs with lower
risk of heart attack seen in other studies. “As you add into the
model more and more useful and relevant information, the association between
non-steroidals and heart attacks changes and it changes in the direction
of showing more benefit, or less harm,” says Kimmel. The researchers
caution that their results are not definitive and suggest that randomized
trials are needed to more accurately address the possible risk and benefits
of NANSAID use.
“Some recent studies have shown an increased risk of heart attack
from traditional non-steroidals and most have not shown a lower risk,
except for our study,” says Kimmel. “The bottom line on this
paper is that we are not saying we know the whole answer, but our data
suggest there might be beneficial effects of non-steroidals and there
are clearly limitations to interpreting the epidemiological studies that
are now out there.” Kimmel states that “balancing the risks
and benefits of both traditional NANSAIDs and COX-2 inhibitors is so critical
to proper patient care that we need to put our resources into randomized
clinical trials that are designed to address this issue.
Study co-authors are Leonard Ilkhanoff, James D. Lewis, Sean Hennessy,
and Jesse A. Berlin, all from Penn. This research was funded by the National
Institutes of Health, and some data collection was supported by grants
from Searle Pharmaceuticals, Inc. (now Pfizer, Inc.) and Merck & Co.
Editor’s Note: Dr. Kimmel has served as a
consultant to Pfizer and Bayer, unrelated to NANSAIDs, and has received
grants from Pfizer, Merck and Bayer. Dr. Lewis has received research support
from GlaxoSmithKline, Pfizer, Wyeth, and Johnson and Johnson, all unrelated
to NANSAIDs, and from Bayer and Whitehall Robbins Healthcare, both related
to NANSAIDs. He has served as a paid consultant for Bayer, GlaxoSmithKline,
Pfizer, Merck, and Wyeth. Formerly with Penn, Dr. Berlin is now an employee
of Johnson and Johnson, who make ibuprofen. He also has performed consulting
for Wyeth, unrelated to NANSAIDs. Dr. Hennessy has received research funding
from Pfizer, unrelated to NANSAIDs.
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