which may also be pathogentically related to atheros- clerosis. Rials of Aspirin in Secondary Prevention of. Myocardial Ischemia. Aspirin in Myocardial Infarction.
Clin. Cardiol. 12, 179-184 (1989)
Review Aspirin in Myocardial Ischemia: Why, When, and How Much? J. L. MEHTA.M.D.. c. R . CONTI. M.D.
DivisiclIl of Cardiology, Department of Medicine, University of Florida, College of Medicine, and the Veterans Administration Medical Center, Gainesville, Florida, USA
Aspirin is one of the oldest drugs in use, first synthesized in 1859. Because of increasingly available information on its efficacy, as well as description of its novel mechanisms of action, its consumption in the United States and throughout the world has grown substantially in the last several years. This review discusses the multiple actions of aspirin and its usefulness in secondary and primary prevention of myocardial ischemia.
Mechanisms of Action of Aspirin Although initially developed and used as antipyretic and analgesic, it was in the late 1960s when aspirin was discovered to have antiplatelet effects. Since then several other mechanisms of its action have been described which may relate to its efficacy in myocardial ischemia, as well as in the treatment of the common cold and other viral infections. With expanding information on the formation of potent vasoactive metabolites of arachidonic acid, aspirin was identified to irreversibly inhibit the enzyme cyclooxygenase which allows conversion of arachidonic acid to cyclic endoperoxides, the precursors of thrombxane and prostacyclin in platelets and blood vessels, Rspectively. It is important to note that increased thrombxane synthesis has been thought to play an important
'
role in the evolution and propagation of myocardial ischemia.2 Although initially it was believed that prostacyclin deficiency may also participate in the evolution of myocardial ischemia, subsequent studies have shown that prostacyclin synthesis by blood vessels may not be diminished in atheroscler~sis.~ It was suggested earlier that aspirin in small doses may selectively inhibit thromboxane while sparing prostacyclin f ~ r m a t i o nRecent .~ studies, however, have not shown such selectivity at any dose of a ~ p i r i n . ~ Therefore, it can be said that aspirin inhibits both thromboxane and prostacyclin formation equally by blocking the enzyme cyclooxygenase. Aspirin also reduces cathecholamine-induced vasoconstriction and lipolysis.6 While platelet aggregation and thromboxane release in the atherosclerotic coronary arteries may contribute to the evolution of ischemia-related arrhythmias, aspirin also reduces arrhythmias in plateletdepleted animals by other mechanism^.^ Recent studies indicate that aspirin also reduces vascular growth following de-endothelialization,' which may be a basis of long-term closure of vascular grafts and progression of atherosclerosis in coronary arteries subjected to angioplasty. A relatively recent study suggests that aspirin increases interleukin-2 and interferon production in human lymphocyte^.^ This very important study provides a basis for the efficacy of aspirin in viral infections, some of which may also be pathogentically related to atherosclerosis.
Rials of Aspirin in Secondary Prevention of Myocardial Ischemia Aspirin in Myocardial Infarction Dr. J. L. Mehta is a Clinical Investigator of the V A . Central Office. Address for reprints:
'.I-. Mehta, M.D. hofessor of Mcdicine University ofFlorida 'OX 1-277, JHMHC Gainesville.Florida 32610, USA
Deceniher 28. 1988 " 9 t e d with revision: k b r u a r y 7, 1989
There have been several major trials of aspirin and other antiplatelet drugs in patients with previous myocardial infarction (Table I). These trials were conducted in several different countries and employed several thousand patients.7I-'' Despite several limitations of these trials, such as variabilities in the protocols employed and different doses of aspirin used, it became quite obvious that aspirin therapy reduced mortality by 3-30% compared with
Clin. C:trdiol. Vol. I ? . April 198')
1x0
T,ABI.E I Trials o f antiplateh therapy in patients with MI
Year
Study (Ref.)
Drug ~
Elwood ef d.( 10) CDP (11) Elwood and Sueetnam (12) German-Austrian ( 13) AMIS (141 PARIS I (15) ART (16) PARIS I1 (17)
1974 1076 1979 1980 1980 1980 1980 1086
Mortality
Number of patients
Placebo
Drugs
10.9 8.3 14.8 11.6 9.7 12.8 7.9 7.3
8.3 5.8 12.3 9.3 10.8 10.5 5.5
~
I239
ASA ASA AS A ASA ASA ASA/ASA+ DP Anturane DP + ASA
1529
1682 626 4424 1216 1558 3128
Mori redu (5 -
-
Z1
Abhre\iafioris: ASA, aspirin; DP. dipyridaniole; CDP, coronary drug project: AMIS, aspirin myocardial infarction study; P/ persnntine aspirin reinfarction study: MI, myocardial infarction.
placebo in all but one trial. In the Aspirin Myocardial Infarction Study, l4 treatment with aspirin increased mortality by 11% compared with placebo. It is noteworthy, however. that even in the Aspirin Myocardial Infarction Study, frequency of recurrent niyocardial infarctions (definite, probable, or suspect) was reduced by 22%. Need for hospitalization for myocardial infarction was reduced by 33% and prolonged hospitalization (over 14 days) for myocardial infarction was reduced by 49%. It is to be noted that the reduction in mortality with aspirin did not achieve statistical significance in any of these trials. As mentioned earlier, variations in the study protocol as well as in the entry window after myocardial infarction ( I week to 5 years) may have affected the statistical significance of the results. Although subject to question, a recent analysis compiling the data from multiple trials shows a favorable effect of aspirin in the secondary prevention of mortality in patients with previous niyocardial infarction.
'*
Aspirin in Unstable Angina Pectoris
There are three niajor trials of aspirin in patients with unstable angina. In the V A . Cooperative study,''' 625 patients were given aspirin 324 mg daily and 641 patients received identical placebo. After a mean follow-up of 12 weeks, frequency of death and fatal as well as nonfatal acute myocardial infarction, were reduced by greater than 50% (Table 11). The Canadian Multicenter Trial'" used a high dose of aspirin (325 nig q.i.d.) in similar patients. The patients were followed for a mean period of I9 months. As in the VA. Cooperative Study, cardiac death and frequency of myocardial infarction were reduced by over 50%. It is interesting to note that in the Canadian Multicenter Trial, administration of su 1fin pyrazone , which also inhibits enzyme cyclooxygenase i n the arachidonic acid cascade,
TABLEI1 Small dose aspirin (324 mg daily) in unstable a VA cooperative study Placebo n=641 Death Nonfatal AM1 All AM1 Death or AM1
21 44 50 65
ASA n=625
(3.3%) (6.9%) (7.8%)
10 (1.6%) 21 (3.4%) 22 (3.5%)
(10.1%)
31 (5.0%)
Decre. 5 5 5 5
Adapted from Ref. 19. Abbreviations same as in Table I.
had no beneficial effect on mortality or evolution of cardial infarction in patients with unstable angina did it have any additive effect when given in combir with aspirin. These data with the use of sulfinpyr. suggest that inhibition of enzyme cyclooxygenase not be, or may be only one, mechanism of the bene effect of aspirin. In a recent study, aspirin, heparin, or combinati both. were cornpared in patients with unstable ang In this study, patients were given 325 rng of aspirin daily and followed for 6 days. The frequency of reci angina was reduced by 29% with aspirin therapy ( I in aspirin group and 22.9% in placebo group). frequency of myocardial infarction was reduced by (3.3% in aspirin group and 11.98 in placebo group patients died in the placebo group and none in the a group. Based on these trials in patients with unstable ar it can be concluded that aspirin in any dose (32 once. twice, or four times a day) is effective ar smallest dose is as effective as the largest dose.
J . L. Metita
;iiid
C . R . Coiiti: Aspii-in
Aspirin in Coronary Artery Bypass Grafting
MI
18 I
Aspirin Following Angioplasty
In several animal models. an interaction between platelets and subendothelial collagen resulting in intense platelet deposition at the site of angioplasty has been amply demonstrated. Although i n the animal models aspirin and other antiplatelet drugs have been shown to reduce platelet deposition, no definite evidence of beneficial effect of aspirin has been shown in patients with angioplasty. In a study by Thornton et d.,3i aspirin was compared with Couniadin i n 248 patients undergoing angioplasty. The follow-up of patients was for at least 9 months. Although coronary restenosis occurred i n 27%) of patients given aspirin and 36% of patients given Coumadin (p = NS). frequency of restenosis was significantly reduced by aqirin compared with Coumadin (21 vs. 447+, p
