Antiplatelet and Antiinflammatory Drug Treatment in Atherosclerosis May Promote Plaque Instability Ralph G. DePalma MD, Washington, DC
meta-analysis of randomized trials published in
atheromas in Figure 2. Similar deeply stained cores and
A the Journal of the American Medical Association more severe lesions as compared with controls appeared
in 2001 raised cautionary flags about the effects of
in plaques sampled from the femoral, inferior mesen-
cyclooxygenase-2 (COX-2) inhibitors Vioxx and
teric, and spermatic arteries and the infrarenal aorta.
Celecoxib, which increased the relative risk of cardio-
Clearly, dipyridamole differs in its action from the
vascular events and sudden or unexplained death and
current COX-2 inhibitors and other NSAIDs by its
significantly increased the annual rates of myocardial
action as a coronary vasodilator. It acts on platelets as
infarction for patients receiving these agents.1 In the
a phosphodiesterase inhibitor and antiaggregant. Was
interval following this report, over 120 publications
it this action that related to the development of accel-
appeared concerning these unexpected problems,2 par-
erated atherosclerosis in our model? Would different
ticularly as nonsteroidal antiinflammatory drugs
doses of either aspirin or dipyridamole have made a
(NSAIDs) had been prescribed in patient cohorts where
atherosclerosis was likely to be prevalent.3 The results
This single study, though labor intensive, did not
of randomized trials and observational studies led to
answer these questions. I was surprised at the time,
the withdrawal of Vioxx from the market in September
however, that these observations did not attract more
attention and interest, but let the matter drop. I now
This communication revisits effects of high-dose
believe that the issue needs to be revisited for these
aspirin _(13.5 mg/kg) and dipyridamole (15 mg/kg) in
classes of drug combinations. In cynomolgus monkeys,
two animal models4,5 using equivalent doses of these
Hollander, long past, noted that the addition of aspirin-
agents prescribed for man for stroke prevention and
dipyridamole to a regression diet did not improve the
treatment during the 1980s. Direct observations of arter-
course of disease in their model,7 but they did not impute
ies showed two unexpected effects: in arterial trauma,
inhibition of reendothelization after injury with thicker
At a time when some believe that all clinical scien-
intimal lesions after healing; and, in subhuman primates
tific truth can be derived solely from randomized clinical
with atherosclerosis, progression of more severe plaques
trials, and given the expense, risks, and equivocations
with unstable cores and thrombosis of arteries not before
of some current trials, I suggest that COX-2 inhibitors
for pain and other antiinflammatory/antiplatelet agents
In rabbits, after a standard arterial injury that caused
should be tested by preliminary observations on estab-
aortic endothelialization, described by Bomberger and
lished atherosclerotic disease using animal models.
colleagues,4 endothelial regrowth was inhibited by 66%
Subhuman primates exhibit similar atherogenic
at 4 days, 22% at 7 days, and 28% at 14 days in ani-
responses to human disease: results will become evi-
mals receiving this drug combination. Sample results
dent by 12 months. Studies in affected subhuman
primates could provide dose-related data and suggest
Later studies showed that the retarded healing caused
guidelines before antiplatelet and antiinflammatory
by the aspirin-dipyridamole combination caused thicker
drugs are widely and publicly marketed to human beings
intimal lesions.6 We recommended at that time that
antiplatelet drugs should be used cautiously in our ath-erosclerotic patients. References
In a study using 10 atherosclerotic rhesus monkeys
1. Mukherjee D, Nissen SE, Topol EJ. Risk of
in whom disease had developed after 58 months, we
cardiovascular events associated with selective
measured disease severity by angiography and arterial
COX-2 inhibitors. JAMA 2001;286:_954-9.
biopsies and then treated seven individuals with aspirin-
2. Drazen JM. COX-2 inhibitors-A lesson in unex-
dipyridamole for 12 months in equivalent daily doses
pected problems. N Engl J Med 2005;352:1131-2.
suggested for humans at that time (four regular aspirin
3. Hippisley-Cox J, Coupland C. Risk of myocardial
and eight dipyridamole tablets). The results proved dra-
infarction in patients taking cyclooxygenase-2
matic and unexpected. Despite comparable serum
inhibitors or conventional non-steroidal anti-inflam-
cholesterol levels during the treatment period, ranging
matory drugs: population based nested case-
309 to 668 mg/dL (average 501 experimental; 525 con-
control analysis. BMJ 2005;330:1366.
trol), atherosclerotic plaques progressed much more
4. Bomberger RA, DePalma RG, Ambrose TA,
rapidly in the ensuing 12 months in animals receiving
Manalo P. Aspirin and dipyridamole inhibit
the antiplatelet combination as measured by angio-
endothelial healing. Arch Surg 1982;117:1459-64.
graphic and morphometric grading. One animal on drug
5. DePalma RG, Bellon EM, Manalo PM, Bomberger
treatment developed thrombosis on a plaque of the left
RA. Failure of antiplatelet treatment in dietary ath-
subclavian artery, its origin. Most significantly, plaques
erosclerosis: a serial intervention study. In: Gallo
in the treated animals all exhibited deeply staining
LL, editor. Cardiovascular disease. Washington,
potentially unstable cores shown in representative carotid
DC: Plenum Publishing; 1987. p. 407-26.
6. Bomberger RA, Wilburn J, DePalma RG. Aspirin
and dipyridamole increase intimal thickening after
7. Hollander W, Kirkpatrick B, Paddock J, et al.
Studies on the progression and regression of coronary and peripheral atherosclerosis in thecynomolgus monkey. I. Effects of dipyridamoleand aspirin. Exp Mol Path 1979;30:55-73.