Penn Study Points to New Evidence to Explain How
COX-2 Inhibitors Can Eventually Lead to
Heart Disease and Stroke
(Philadelphia, PA) - University of Pennsylvania School of Medicine
researchers have found additional evidence that may help explain how selective
inhibitors of COX-2 might predispose individuals to heart disease and
stroke. In Circulation Research, they report that a COX-2-derived
fatty substance — a prostaglandin called prostacyclin — controls
the blood-vessel response to stresses such as high-blood pressure, thereby
further linking COX-2 inhibitors to an increased risk of heart attack
or stroke. This knowledge, along with a growing literature on physiological
responses to COX-2 inhibitors, should help in the development of a rational
approach to clinical risk management for this class of drugs.
Two randomized trials of COX-2 inhibitors — the gold standard of
clinical evidence — conducted in 2004 at other institutions suggested
that risk of cardiovascular disease might increase gradually during continued
treatment with drugs such as Celebrex and Vioxx, even in individuals initially
at low risk of the disease.
“The risk of heart attack and stroke became progressively evident
during treatment with either Celebrex or Vioxx during the APPROVe and
APC trials last year,” says Garret FitzGerald, MD,
lead author of the study published online this week. FitzGerald is the
Director of the Institute for Translational Medicine and Therapeutics
These studies were designed to determine whether COX-2 inhibitors limited
the development of benign growths in the large bowel of patients who-to
the best of study authors’ knowledge-were at low risk of heart disease.
“While the results of these trials are not conclusive, they are
compatible with a gradual transformation of increased cardiovascular risk
during continued dosing with either Celebrex or Vioxx,” says FitzGerald.
“We need to determine how this might occur, and whether we can manage
this risk by developing tests that reflect the process.”
Earlier animal studies by Penn researchers and others showed that suppression
of the protective fat prostacyclin, which is made by COX-2, could predispose
individuals to a rise in blood pressure which, in turn, can accelerate
hardening of the arteries, or atherosclerosis. COX-2 inhibitors such as
older NSAIDs have been shown to raise blood pressure in people. In addition,
the Penn group has shown in previous studies that shutting down prostacyclin
hastens initiation and early development of atherosclerosis.
The current research expands on this notion. R. Daniel Rudic,
PhD, and Derek Brinster, MD, and others in FitzGerald's
laboratory, report that COX-2-derived prostacyclin also controls the changes
that occur in the muscular lining of blood vessels in response to pressure-related
changes in blood flow.
They used two animal models to test their ideas. In one, they looked at
changes in a blood vessel that had been transplanted into mice of a different
genetic make-up; in fact, the model mimicks the events of human organ
transplant rejection. Here, they found that they had, in effect, removed
a brake on the response of the blood vessel to the challenge of transplantation
by deactivating prostacyclin by genetically deleting its receptor. The
result was that muscle cells proliferated dramatically, which normally
reduces the openness of the blood vessel. However, the openness of the
blood vessel was not changed, through a process of structural reorganization
of the blood vessel called vascular remodeling.
In the second model, they reduced blood flow in arteries in the neck and
looked at the downstream effects in the blood vessel. This time, instead
of suppressing prostacyclin receptor signaling by genetic deletion, they
did so by giving a COX-2 inhibitor. Indeed, they saw the same effect.
Cells in the muscular lining of the vessel wall multiplied (just like
in the transplant model). Additionally, despite the vessel growth caused
by the COX-2 inhibitor, openness of the blood vessel was again preserved.
This occurred despite lower blood flow caused by the COX-2 inhibitor.
Thus, prostacylin may act to remodel blood vessels to preserve adequate
“What is really convincing here is how similarly the two models
responded and how the genetics of the pharmacological approach to disrupting
the effects of COX-2 had the same effect,” says Rudic. In further
studies-also described in the paper and performed in collaboration with
Thomas Coffman, of Duke University-FitzGerald's group showed that the
consequences of shutting down COX-2-derived prostacyclin could be limited,
in part, by removing a receptor activated by thromboxane A2, the fatty
product of COX-1 in platelets. This mirrors a similar balancing effect
between COX-1 and COX-2, which has been noted in the case of blood clotting,
blood pressure, and atherosclerosis. This suggests that suppression of
thromboxane with low-dose aspirin could reduce the risk of heart disease
if taking COX-2 inhibitors.
These findings suggest that during prolonged dosing with COX-2 inhibitors,
several consequences of drug action-a rise in blood pressure, initiation,
and early development of atherosclerosis, and now the architectural and
functional response of blood vessels to such stress-could all interact
in a reinforcing fashion to transform the risk of heart attack and stroke,
even in previously healthy individuals. “We need to determine whether
these mechanisms are operative in people, and if so, we should be able
to develop tests which reflect this process,” says FitzGerald. “This
may allow us to detect the small number of individuals at risk of rapidly
developing heart disease and stop the drugs before they run into trouble.
We could also determine how quickly risk might dissipate on stopping the
drugs. Certainly, the development of a rational approach to risk management
will be key to giving Celebrex or other COX-2 inhibitors safely, even
to healthy patients, for extended periods.”
The study was funded in part by the National Institutes of Health. Study
co-authors Yan Cheng, Susanne Fries, Wen Liang Song, and Sandra Austin
are from Penn, as well as Thomas M. Coffman from Duke University.
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