Role of blood platelets in coronary artery disease

Role of Blood Platelets in Coronary Artery Disease

JACOB I. HAFT, MD, FACC

Newark, New Jersey

From the Department of Cardiology, Saint Mi- chael’s Medical Center, Newark, New Jersey. Manuscript received October 30. 1978; revised manuscript received January 2, 1979. accepted January 3.1979.

Address for reprints: Jacob I. Haft, MD, De- partment of Cardiology, Saint Michael’s Medical Center, 308 High Street, Newark, New Jersey 07102.

Over the past decade, research in blood platelet physiology has led to the suggestion {hat platelets play an important part in the pathogenesis and complications of coronary artery disease. Occlusive intravascular platelet aggregates have been shown to cause ischemic myocardial damage in the experimental animal and to be present in soqe patients who die suddenly. The interplay between endothelial damage and platelet aggregation has been implicated in the etiology of atherosclerosis. Products released from platelets during aggregation may cause arterial spasm. Patients with overt ischemk h&art disease and with the risk factors associated with coronary artery disease have been found to have abnormally reactive platelets.

Clinical studies of drugs that intilblt platelet aggregation have been reported to show a beneficial effect in preventing cardiac deaths or myocardial infarction; other studies have been negative or shown only a trend toward benefit. This report reviews the theoretical and experimental basis for the platelet hypothesis and the current data on the use of antiplatelet drugs in patients with coronary disease.

In recent years, blood platelets and the possible role they play in the etiology and natural history of coronary artery disease have attracted increasing attention among researchers and cardiologists. The reasons for this interest have included theoretical considerations concerning platelet physiology and function, epidemiologic findings relating coronary risk factors with abnormalities in platelet function and clinical findings of an increased incidence of abnormal platelet function among patients with coronary artery disease. These data have been the stimulus for several clinical drug studies, one of which, the sulfinpyrazone study, has excited dramatic reports in the lay press of a breakthrough in preventing myocardial infarction. It is the purpose of this paper to review current thinking on the relation of platelets to coronary artery disease and to present the current status of antiplatelet aggregation therapy in the management of coronary artery disease.

Blood Platelet Physiology’

Blood platelets act as the first defense of the body against hemor- rhage. They circulate in the bloodstream as elliptical flat discs. When stimulated, usually by a break in the endothelial lining of a blood vessel, they are attracted to the defect, they round up, develop pseudopods, become sticky and adhere to the abnormal area, forming a plug that repairs the defect and reestablishes the continuity of the smooth endothelial surface. The platelet is a complex structure. Although lacking a nucleus it contains numerous organelles including granules, a microtubular system, a metabolically active membrane and contractile pro- teins.

After the platelets adhere to an area of damage, the reversible first stage of platelet aggregation, the adhering platelets undergo the release reaction associated with the second stage of aggregation, and additional platelets are attracted to the defect and join the aggregate, enlarging it. During this phase the substances within the granules are extruded through the microtubular system out of the platelets and into the sur- rounding area. The substances released include adenosine diphosphate (ADP), catecholamines, serotonin, enzymes and prostaglandins such

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BLOOD PLATELETS AND CORONARY DISEASE-HAFT

as thromboxane A2. These substances serve to stabilize the platelet aggregate in addition to stimulating additional platelets to aggregate. Thromboplastins are also released during this phase of aggregation and, if a sufficient number of platelets have been involved, the cascade system that results in the conversion of fibrin- ogen to fibrin is activated, and a typical clot develops. If the defect is large, a large amount of fibrin is formed, red cells become enmeshed in the fibrin strands and a recognizable red clot results.

Usually, it is collagen exposed to the bloodstream when there is a break in the endothelial surface that attracts platelets and stimulates them to adhere and to aggregate, but other stimuli can initiate the aggregation process. These include circulating catecholamines, ADP, prostaglandins, immune complexes and fatty acids. Excessive turbulence can also cause platelets to aggregate.

Platelets and lschemic Heart Disease

Currently, platelets are thought to participate in clinical coronary disease in two ways, in association with acute myocardial infarction and sudden death and by participation in the development of atherosclerosis.

Platelet aggregation and coronary occlusion: Theoretically, a platelet aggregate, stimulated by circulating catecholamines, immune complexes or excessive turbulence, might form inappropriately within the circulating blood. Such a platelet aggregate might lodge in an area of narrowing of an artery, close it off and lead to ischemia of the area fed by that artery. If such an aggregate were to occlude a narrowed coronary artery, myocardial infarction, possibly associated with a ventricular arrhythmia and sudden death, might occur. A platelet aggregate stimulated to form and cover a break in the endothelial lining of an artery might break off from the area of formation, travel in the bloodstream to a coronary artery and, lodging in an area of narrowing, then occlude it. Moreover, it is possible that rupture of the endothelial lining over an atherosclerotic plaque within a coronary artery might stimulate the formation, in situ, of a platelet aggregate that might grow to occlude the remaining lumen over the plaque.

The evidence that such events might indeed occur comes from several sources. First, it has been shown that platelet aggregates forming within the circulatory system can lead to myocardial damage in the experimental animal. Jorgensen et a1.2 infused ADP directly into the coronary arteries of pigs. All nine animals that died within 5 minutes of the onset of infusion had platelet aggregates in their coronary arteries. Among the 20 animals that lived beyond 2 hours, 16 were found to have gross infarcts and 17 had microscopic infarcts on histologic examination. This was a significantly greater incidence of infarction than among 17 pigs given in- tracoronary infusions of adenosine monophosphate (AMP), which does not stimulate platelet aggregation. In the two latter groups there was no difference in the incidence of arterial platelet aggregates found,

suggesting that platelet aggregates might form, do their damage, disaggregate and disappear before pathologic study.

In the early 1970’s we3 demonstrated that the intra- venous infusion of catecholamines in dogs caused intravascular aggregation of platelets in the small vessels, of the heart. Electron microscopy revealed platelet aggregates in the myocardial vessels of dogs infused for 4 hours with norepinephrine. The diffuse cardiac necro- sis4 known for years to occur after epinephrine infusion was found to be prevented by pretreatment with aspirin,5 dipyridamole5 or clofibrate,e drugs that have little in common other than inhibition of platelet aggregation. These findings suggest that the diffuse myocardial fi- brosis seen after extensive catecholamine therapy or in patients with pheochromocytoma is at least partially due to intravascular platelet aggregation.

In 1976 Felts et al7 demonstrated that spontaneously occurring platelet aggregates could cause occlusion of an experimentally narrowed section of a canine coronary artery. They showed that flow through a critically narrowed coronary artery was phasic, with periods of no flow alternating with near normal flow at rest. These changes were associated with sudden reductions in pressure distal to the narrowing that would suddenly revert to near normal pressure, suggesting that the compromised lumen was alternately being totally occluded and then opened. On sectioning the area of narrowing during the time of complete occlusion, they found a pure platelet aggregate plugging the lumen. They postulated that platelet aggregates were intermittently occluding the stenotic section of the coronary artery and that these plugs would break up and be flushed through the area of narrowing, intermittently opening the obstruction. They postulated that such events might not be uncommon in a human being with atherosclerotic heart disease, and that angina at rest or serious ventricular arrhythmias and sudden death might occur during the periods of occlusion. In further studies, these authors8 demonstrated that these phasic changes in coronary blood flow through a narrowed artery could be abolished by pretreating with drugs that inhibit platelet aggregation.

The extent of infarction after total occlusion of a coronary artery might also be affected by secondary platelet aggregates. Moschos et a1.g demonstrated that in the periphery of an infarct created by total experimental occlusion of a coronary artery, there was an increased concentration of platelets sequestered in the myocardial vasculature. In animals pretreated with aspirin these aggregates were not found and the re- sulting area of infarction was smaller. They postulated that the extent of an infarct might be influenced by the degree of platelet aggregation in the borders of the area of infarction.

Fatal arrhythmias and sudden death: Pathologic findings in patients who have died suddenly have supported the concept that an occluding platelet aggregate might be the event that triggers a fatal arrhythmia.lO Haerem” reported a significantly greater incidence of

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platelet microthrombi in patients with coronary artery disease who died suddenly than in patients who died from other causes. Forty-seven percent of 4’7 patients who died suddenly were found to have acute microthrombi in their coronary vessels compared with 15 percent of 13 patients who did not die suddenly and had no coronary artery disease.

Platelets and coronary spasm in myocardial infarction: Recently Oliva and Breckenridge12 presented data on patients with acute myocardial infarction that might implicate platelets as playing an important part in the acute event. They subjected 15 patients to coronary arteriography within a few hours after the onset of acute myocardial infarction and infused nitroglycerin directly into the occluded vessel that appeared to have led to the infarction. In almost half of the patients the nitroglycerin infusion caused the vessel to dilate and the area of occlusion to open and become less than total. These findings suggest that spasm may play a role in the acute occlusion that leads to infarction. The strongest vasoconstrictor produced endogenously is thromboxane A2,13 a prostaglandin that is released from the platelet as it undergoes the second stage of aggregation. It is conceivable that a platelet aggregate might lodge in an area of narrowing in a coronary artery, release thromboxane A2, and cause spasm of the artery, stabilizing the occlusion and maintaining the total blockage. Such an occlusion would be expected to open partially if the spasm were relieved. Although not yet proved, the findings of Oliva and Breckenridge can be interpreted to support the concept that inappropriate intravascular platelet aggregation may be the inciting event that leads to infarction.

Data from our laboratory14 have supported the findings of Oliva and Breckenridge. Of 106 patients with anterior myocardial infarction on electrocardiography and definite anteroapical dyskinesia or akinesia on left ventricular angiography, 23 patients were found on coronary arteriography to have a narrowed but patent left anterior descending coronary artery. It is possible that in these patients recanalization occurred or that a less than total occlusion caused infarction. More probably, however, a platelet aggregate, may have first totally occluded the stenotic area for sufficient time to result in infarction and then disbanded and passed downstream, opening the occluded. area or, alterna- tively, spasm played a role and, with release of the local spasm, the vessel regained partial patency. The report of Oliva and Breckenridge12 suggests that the latter two possibilities with the possible involvement of platelets might provide the more reasonable explanation.

Platelets and Atherosclerosis

Investigations into the biology of the arterial vessel wall have led to the concept that platelets may also play an important role in the initiation of atherosclerosis.15 Studies on the endothelial lining and vascular smooth muscle cells have suggested that injury to the vascular endothelium stimulates the proliferation of smooth


muscle cells and their migration into the intima where they actively absorb lipid and secrete fibrin, elastin and tissue matrix, the components that can become the typical atherosclerotic complex lesion. The trigger of this response of vascular smooth muscle cells appears to be a substance released from platelets as they undergo the second stage of platelet aggregation.

Platelets and endothelial trauma: The evidence for this theory comes from various sources. Experimental injury to the vascular endothelium by mechanical dis- ruption with a balloon catheter scraped across its surface,‘e by chronic exp osure to high levels of homocys- tine17 or cholesterol in the blood15 or by immune inju- ryi8 results in large areas of denudation of endothelial cells on the intimal surface. These areas are promptly covered by aggregated platelets. Within a few days after injury, smooth muscle cells have been demonstrated to be migrating from the muscularis layer into the intimal subendothelial parts of the vessel wall. In 1 to 3 months large numbers of these cells are found in the intima and have been demonstrated to form collagen fibrils, proteoglycans, mucopolysaccharides and elastin fibers. It may take 9 months for the endothelium to regenerate completely. If this occurs and further injury does not again stimulate the smooth muscle cells, the changes in the muscle cells in the intima regress and the vessel wall returns almost to normal. However, if the injury is re- petitive or there are large amounts of lipid in the serum, these vessel abnormalities may not regress and instead may degenerate into typical atherosclerotic 1esions.l”

Platelets and proliferative smooth muscle response: The pivotal role of platelets in this sequence of events has been suggested by several factors: (1) En- dothelial trauma induced in these ways is usually associated with a shortening of platelet survival time. (2) Inhibition of platelet function by drugs that block platelet aggregationlg or by making the experiment animal thrombocytopenic prevent the smooth muscle cell response. (3) It has been shown in vitro that there is a substance released from platelets as they aggregate that will stimulate and support proliferation of smooth muscle cel1s.l” The character of this substance is not yet clear, but it appears similar to a fibroblast, growth factor extracted from the pituitary gland. It is possible that the platelet does not produce this substance hut just carries it to be released at sites of endothelial damage.‘5 The source of the material, whether produced by t.he me- gakaryocte or elsewhere, remains conjectural. Other substances, especially low density lipoproteins, appear to play a supportive role in this proliferative smooth muscle cell response, perhaps providing the raw mate- rials for the cells to use as they proliferate and produce extracell matrix and collagen.

Role of risk factors: This theory of the origin of atherosclerosis is very attractive in that it is compatible with what is known about the risk factors for atherosclerosis. Endothelial injury induced by the mechanical hemodynamic stress of hypertension, the catecholamine response to cigarette smoking, the effect of serum car- bon monoxide from cigarette smoke, the chronic expo-



sure to high cholesterol levels and possible vessel abnormalities associated with diabetes may be the common characteristic of these risk factors that leads to atherosclerosis by means of the platelet aggregation that such injury induces.

Historical background: Although this theory is relatively new, the consideration that thrombosis may play a role in the development of atherosclerosis may be traced to Von Rokitansky20 in the 1850’s. He believed that vascular mural clots degenerated into atherosclerotic plaques. Duguid21 in the 1940’s demonstrated pathologic evidence that mural thrombi could acquire an endothelial covering, supporting Von Rokitansky’s concepts. Mustard’s laboratory2? has produced data suggesting that platelet clots themselves could damage vascular endothelium through enzymes released during aggregation and that such damage to the endothelial lining might make the surface more permeable to transudation of lipids into the intimal layer of the vessel wall, thereby bringing into accord the ultrafiltration theory of atherosclerosis with the thrombogenic concept. Thus evidence is accumulating that platelets and their function as the initiator of intraarterial thrombosis and as the first responders to endothelial injury may be a significant factor in the etiology of atherosclerosis.

Epidemiologic Data Linking Platelets With Coronary Artery Disease

In addition to the theoretical considerations concerning the platelet as a factor in the pathogenesis of clinical ischemic heart disease, numerous studies have demonstrated a large incidence of abnormally reactive platelets in patients with coronary artery disease. Ad- hesiveness of platelets was reported to be abnormal in patients with clinical coronary disease.23-27 Platelet aggregation studied with the aggregometer was shown to be significantly enhanced2s-31 and platelet survival time was shown to be significantly shortened26p30p32 among patients with clinical coronary disease. Hampton and Gorlin,33 using platelet electrophoretic techniques, also noted significant abnormalities in patients with coronary disease. Although all reports have not agreed with these findings, the majority of investigations have demonstrated a correlation between coronary artery disease and more responsive platelets regardless of the specific platelet function test utilized. The finding that patients with coronary disease have more reactive platelets can be interpreted either as evidence that these patients are more prone to mural vascular thrombi and occlusive vascular thrombi, and thereby to atherosclerosis and acute myocardial infarction, or as evidence that atherosclerosis is already present and the recurring stimuli to platelets caused by the areas of narrowing in the vascular tree may be manifested by more reactive platelets.

Risk Factors and Platelet Function

The effects of the presence of known coronary risk factors on platelet function have been extensively in- vestigated. Patients with hyperlipidemias, especially hypercholesterolemia, have been shown to have more

sensitive platelets.34 Carvalho et a1.35 found that the platelets of patients with type II hyperlipidemia re- sponded to significantly lower concentrations of epinephrine and collagen in the aggregometer than did platelets of control patients. A diet high in saturated fats leads to increased platelet aggregability, and even a high fat meal will cause acutely enhanced platelet reactivi- ty.25,36 Smoking cigarettes37p38 increases the activity of platelets acutely, and cigarette smokers have a shortened platelet survival time. Asymptomatic patients with a family history of, or relatives with, coronary artery disease have been shown to have a high incidence rate of platelet function abnormalities.33 Patients with diabetes have significantly more easily stimulated platelets than do control subjects.36v3g In a series of studies40p41 performed on normal house officers we recently showed that emotional stress has a potent effect on platelet function.

The observation that all these risk factors are associated with platelet abnormalities suggests that the risk factors may affect the vasculature through their platelet effects, and it indirectly supports the’ concept that platelets may play an etiologic role in clinical coronary artery disease. However, these findings can only be considered circumstantial evidence; the platelet abnormalities noted may be only coincidental events in the development of coronary disease rather than a causal factor.

Clinical Pharmacologic Studies

The experimental evidence and theoretical considerations linking platelet function with coronary artery disease have led to the logical conclusion that inhibition of platelet function might prevent acute myocardial infarction and the development or progression of coronary atherosclerosis. The availability of a large number of drugs42 that are used primarily for other purposes but that also have potent antiplatelet activity has led to a number of drug trials and reports. The drugs most studied have been aspirin, sulfinpyrazone, clofibrate and dipyridamole.

Aspirin Aspirin is a potent platelet aggregation inhibitor.43

It appears to work by inhibiting the production of prostaglandins.44 It blocks the second phase of platelet aggregation and the release reaction.

Aspirin in the prevention of myocardial infarction: The use of aspirin in the prevention of myocardial infarction is not new. In the early 1950’s, Craven45 suggested a trial of aspirin in middle-aged men. Some years later he46 reported the results in 8,000 men who had taken one or two aspirin tablets daily for about 6 years. There were no instances of myocardial’infarction in this treated group during the period of the uncon- trolled study. In 1951, an autopsy studti7 of 131 patients followed up in an arthritis clinic,and presumably taking large doses of aspirin over a prolonged period of time revealed only 4 percent to have died with myocardial infarction and only 2 percent with stroke,an incidence rate far below that expected for a similar population.


Over the subsequent years a number of reports4sl4g from arthritis clinics confirmed or denied this paucity of myocardial infarction among patients with arthritis.

More recently the results of two prospective studies on aspirin for prevention of infarction and death have been reported.50y51 Beginning in February 1971, the British group of Elwood et a1.50 randomized 1,239 men with history of recent myocardial infarction to treatment with either aspirin, 300 mg/day, or placebo and followed them up for a few months to 2 l/2 years. Analysis of the cumulative death rates showed a consistently lower mortality rate among the group receiving aspirin (7.6 versus 10.1 percent at 1 year, 9.0 versus 13.2 percent at 18 months, 12.2 versus 18.5 percent at 2 years). However, at no time did the difference achieve statistical significance. Separating the patients according to age did not improve the statistical significance, but classifying the patients according to the interval from infarction to entrance into the trial gave a somewhat more interesting result. Among the patients entering the study less than 6 weeks after infarction, 7.8 percent of the aspirin-treated men died compared with 13.2 percent of the control subjects. By applying the chi-square formula, chi-square equals 5.27, suggesting a statistically significant difference beyond the 0.025 level. Elwood et al. were reluctant to report any significant difference in this group because most of the patients came from one area, and it was not clear if this was an interval effect or a geographic aberration. In view of the positive findings in the sulfinpyrazone group in which all patients were entered into the trial within 35 days of infarction, these results in the study of Elwood et al. might be important. However, the investigators considered their findings “inconclusive,” although a trend toward a benefit for aspirin was clearly identi- fied.

The second reported prospective therapeutic trial of aspirin is the Coronary Drug Project Aspirin Trial.sl The Coronary Drug Project was designed to determine if any of a number of cholesterol-reducing drugs would decrease the mortality among patients who had survived at least one myocardial infarction. Three of the drug regimens being tested, D-thyroxine and large and small dose estrogen, were clearly found to be of no benefit and possibly harmful within a few years after recruitment was completed. Testing of these drugs was stopped. After at least 6 months on no active medication, 1,529 of these well worked-up patients were randomized to treatment with aspirin, 5 grains three times daily, or a placebo, and subsequently followed-up for 10 to 28 months. The total mortality rate in the aspirin-treated group was 5.8 percent, approximately 30 percent below the 8.3 percent rate of the placebo group, although the difference was not statistically significant. Using various end points other than mortality such as myocardial infarction or other coronary events and various com- binations of end points consistently showed a trend favoring aspirin, but no statistical significance was achieved. Unfortunately, funding was not available to continue the trial. Criticisms about the value of this study include the fact that most of the participants had

BLOOD PtATELETS AND CORONARY DISEASE-HAFT

had their infarction more than 3 years before entry into the aspirin trial and had been taking other medications for long periods before entry into the trial. Nevertheless, there was a trend, although not of statistical significance, toward benefit of aspirin therapy.

Data from the Boston Collaborative Drug Surveil- lance Group has supported the use of aspirin as preventive treatment for myocardial infarction.52These investigators interviewed patients in the hospital as to the drugs they had been taking before admission and correlated the diagnoses on discharge with the patterns of drug use and other habits. Two studies were simul- taneously reported. In the first study 0.9 percent of 325 patients with myocardial infarction reported long-term use of aspirin whereas 4.9 percent of 3,807 patients with other diagnoses gave such a history (P <0.003). Among 451 patients with myocardial infarction in the second study, 3.5 percent had a history of regular use of aspirin compared with 7.0 percent of 10,091 patients with other diagnoses (P <0.03). Multivariate analysis did not di- minish this negative association between regular use of aspirin and myocardial infarction, suggesting that aspirin may be protective against myocardial infarction.

Another epidemiologic study, carried out under the auspices of the American Cancer Society, x3 did not find any beneficial effect of aspirin in coronary artery disease. A 6 year follow-up study of more than 1 million men and women who answered a questionnaire concerning diet, habits and drugs revealed that among the approximately 43,000 men and 29,000 women who died with a diagnosis of myocardial infarction there was no significant difference in the number of persons who never used aspirin or used it often when compared with control subjects who had not had coronary disease. Analysis of the data according to age or sex did not affect these negative conclusions.

Implications: As yet no prospective studies have demonstrated a statistically significant benefit of aspirin in coronary artery disease. The two large studies reported both suggest a trend, and the Boston Collab- orative Drug study has been reported as positive. We are currently awaiting the results of the Aspirin-Myo- cardial Infarction Study sponsored by the National Institutes of Health and the aspirin-dypridamole (Persantin@) study sponsored by Boehringer Ingelheim. Both studies are in the process of following up large numbers of patients who have survived a myocardial infarction and have been randomized to treatment with aspirin or placebo (Aspirin-Myocardial Infarction Study) (AMIS) or to treatment with dipyridamole, dipyridamole and aspirin, or placebo groups (Persantin- Aspirin Reinfarction Study) (Paris). Results are expected in the next 1 to 2 years.

Sulfinpyrazone

The drug that has caught the interest of many in the past year has been sulfinpyrazone (Anturane@).54 Sul- finpyrazone, an antigout drug that was developed during research on butazolidin, has been known to have potent platelet-inhibiting effects for some years.“” It has


BLOOD PLATELETS AN0 CORONARY DISEASE-HAFT

been shown to be useful in maintaining patency of ar- teriovenous shunts used for hemodialysi@ and to have a beneficial effect in patients with transient cerebral ischemic attacks.57 In 1972, Blakely and Gents8 presented the results of a prospective double-blind trial of sulfinpyrazone, 600 mg/day, in 291 elderly institution- alized men. They followed up the patients for 4 years and found a statistically significant increase in survival among the patients with a previous history of atherosclerosis who had been treated with sulfinpyrazone in comparison with patients treated with a placebo, especially among those who died of vascular causes. The numbers were too small to separate those who died of myocardial infarction for separate analysis.

Multicenter randomized study: In 1975, a large multicenter therapeutic tria154 of sulfinpyrazone was organized to determine if the drug had any value in preventing death during the first 1 or 2 years after myocardial infarction. Data were accumulated on 1,475 patients who were randomized to treatment with either placebo or.sulfinpyrazone, 200 mg four times daily, starting 25 to 35 days after a documented acute myocardial infarction. By the time recruiting was completed in July 1977, it was apparent that there was a statistically significant benefit with sulfinpyrazone and the results of the study were reported. The appearance of the data in the New England Journal of Medicine” in February 1978 immediately stimulated headlines in the New York Times, the Wall Street Journal and other prestigious papers throughout the world, acclaiming that an important breakthrough in the therapy of heart attack had been achieved. Of the 69 deaths in the study group, 68 were cardiac; 44 occurred in the placebo group and 24 in the patients treated with sulfinpyrazone, a difference in cardiac mortality that was significant (P = 0.18). The biggest difference was among those who died suddenly, with 29 of the placebo group and 13 of the treated group having a sudden death during the study period (P = 0.015). The cardiac death rate cor- rected for exposure time (mean 8.4 months) was 9.5 percent for the placebo group and 4.9 percent for the treated group, a death rate reduction among the treated group of 48.5 percent. The annual sudden death rate was 6.3 percent in the placebo group and 2.7 percent in the treated group, a reduction of 57 percent associated with treatment with sulfinpyrazone. However, the number of deaths due to myocardial infarction-12 in the placebo group and 9 in the treated group-was not statistically significantly different. The occurrence of rehospitalization for myocardial infarction and cardiac arrhythmias tended to be lower among the treated patients but the difference was not statistically significant, whereas the frequency of admission for heart failure or angina tended to be greater among the treated patients.

Although it was originally planned to continue the study until all patients had been followed up for at least 1 year, because ongoing analysis of mortality demonstrated a statistically significant reduction in deaths among the sulfinpyrazone-treated patients the results were reported after a mean of 8.4 months follow-up. The investigators planned to inform the study patients of

the results and hoped to gain the cooperation of a sufficient number of these patients to continue the study with sufficient numbers to generate further significant follow-up data. Further reports from the investigational team are anxiously awaited.

Limitations of study: A number of criticisms were generated by the report. First, more patients in the placebo than in the treated group appeared to have had arrhythmias during infarction (P <0.05), and, although the difference was not statistically significant, there tended to be more patients with previous myocardial infarction, bundle branch block, angina, diabetes and claudication among the placebo group. This has raised the question whether, by multivariate analysis,5g the placebo group might not prove to be significantly sicker than the treated group, and the results therefore spu- rious. Second, the finding that the major beneficial effect of the drug was in the prevention of sudden death rather than the prevention of further myocardial infarction suggests that sulfinpyrazone may be acting primarily as an antiarrhythmic drug, possibly through an effect on prostaglandins,60 and that results may have little relation to the drug’s effect on platelets. Third, the mode of reevaluation of the data during the study has been criticized as possibly making a less significant difference appear more important than is justified.61 Furthermore, it remains unclear if the benefit noted in this short follow-up period will continue to remain significant as the patients are followed up further, and if the small incidence of side effects will also continue as the patients receive the drug for more prolonged periods.

It is expected that many of these criticisms will be more adequately resolved when the final report of the group is presented. Recent comments from members of the investigating team at meetings have suggested that a large number of participants in the study are con- tinuing in the protocol and that more data should be expected. A study similar to this American-Canadian study is currently underway in Italy62; confirmatory data will be of great value.

Other Antiplatelet Drugs

Clofibrate: This drug, used primarily for the lowering of serum lipid levels, is also an effective platelet aggregation inhibitor. 63p64 Several studies of its efficacy in preventing death in patients with coronary artery disease have been reported in recent years.65*66 A cooperative study performed in Newcastle-on-Tyness demonstrated a significant decrease in the incidence of death in patients with evidence of angina or myocardial infarction, or both, who were treated with clofibrate and followed up over a 5 year period. The beneficial effect of the drug in 497 randomly assigned patients did not appear to correlate with a specific effect of the drug on lipid levels. A similar study performed by the Research Committee of the Scottish Society of Physicians67 found similar results in patients followed up for 6 years, although they noted a significant decrease in death rate only in their patients who had angina with or without a previous infarction and not in those who had had a previous infarction but not angina. Again the beneficial

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effect of the drug did not appear to be related to a lipid-lowering effect.

A randomized study performed among United Air- lines’ personnel 66 demonstrated a significant decrease in the occurrence of myocardial infarction among men initially free of evidence of coronary disease and among men who had a history of myocardial infarction or angina, or both, who were randomized to treatment with clofibrate. These findings were not related to any lipid-lowering effect noted. The lack of correlation of benefit with serum lipid effects suggests that another mechanism, such as the platelet aggregation inhibition known to occur with the drug, might be operant. How- ever, the Coronary Drug Project study of clofibrate did not confirm the findings in these three studies.6s There was no significant benefit with regard to mortality noted among the patients with a history of at least one myocardial infarction who had been randomized to treatment with clofibrate. The reason for this disparity remains unclear but is probably related to patient selec- tion. The positive British studies included patients with angina alone, suggesting that possibly clofibrate is of greater benefit when begun earlier in the course of the disease.

A cooperative Edinburgh-Budapest-Prague Study of clofibrate in the prevention of ischemic heart disease in middle-aged men without manifest heart disease has been reported. 6g Approximately 30,000 men were screened and those with serum cholesterol levels in the top third of the cohort were separated into two groups. Approximately 5,000 men were randomly assigned to treatment with clofibrate (Group I) and 5,000 to receipt of placebo (Group II). These men were further compared with about 5,000 men randomly selected from those with cholesterol levels in the lower one third of the cohort who received placebo (Group III). The average follow-up period was 5.3 years. Cholesterol levels were decreased by approximately 9 percent below the initial cholesterol level in the treated group (Group I). Men in this group had 25 percent fewer nonfatal infarctions (P <0.05) than men in the high cholesterol-placebo group (Group II) but significantly more than men in the low cholesterol-placebo group (Group III) (P <O.Ol). The incidence rate of fatal infarction and sudden death did not differ significantly between Groups I and II but were significantly lower in Group III. These findings, coupled with further analysis of the data, led to the suggestion “ . . . that most of the reduction of nonfatal myocardial infarction in the clofibrate treated group is associated with reduction of cholesterol concentrations.” However, multivariate analysis revealed “ . . . that treatment (with clofibrate) may have some additional effect beyond that of cholesterol reduction. . . ” although “ . . . the excess effect is not itself significant.”

A number of disquieting results appeared in this study. First, there was a significantly higher death rate among the treated patients (P CO.05) than among the untreated high cholesterol patients, with a trend toward a greater incidence of deaths from cancer (although rates were similar to those in Group III and in the local population). Second, there was a greater incidence of disease of the liver, gall bladder and intestines and of


mortality due to disease of these organs in the clofi- bra&treated group than in either the high or the low cholesterol group treated with placebo.

These recent data support the conclusions of the earlier British studies and the United Airlines Study that clofibrate is effective in decreasing coronary artery disease morbidity although they disagree with previous findings by demonstrating that this effect is largely related to, rather than independent of, a cholesterol- lowering effect. Whether the platelet effects of clofibrate were of importance in this cooperative study is conjectural.

Beta adrenergic blocking drugs: These agents have also been demonstrated to have a significant platelet-inhibiting effect.37v70 In a prospective study of practolol,71 the investigators found a significant decrease in cardiac mortality and in combined nonfatal myocardial infarction and death (but not in infarction alone). Although these results are probably related to the ant&rhythmic and antiischemic effects of the drug, the antiplatelet effect may play a role. Practolol is not available, but it would be expected that propranolol would have a similar effect. A randomized study of propranolol in patients after infarction, sponsored by the National Institutes of Health is underway; the results will be of great interest.

Dipyridamole: This is another drug with antiplatelet activity72 that has elicited interest among cardiologists. Although studies suggesting its efficacy in the prevention of emboli associated with prosthetic valves have been reported,73 its value in the management of coronary artery disease has not yet been documented. In a current prospective trial (Persantin Aspirin Reinfarc- tion Study, PARIS) patients with a documented infarction are being randomized to treatment with either dipyridamole, dipyridamole and aspirin, or placebo and are being prospectively followed up. Results are expected to be reported within the next 2 to 3 years.

Negative Aspects of Antiplatelet Therapy

Two other aspects of the use of antiplatelet aggregation drugs must be taken into account when use of these agents is being considered. The first is related to a theoretical negative effect of these agents and the second to possible side effects.

Role of Prostaglandins

Recently a new prostaglandin has been discovered, prostacyclin 12.74 This agent appears to have properties almost directly opposite to those of thromboxane A2. Thus, instead of stimulating platelets to aggregate and blood vessels to constrict, prostacyclin 12 (PG 12) pre- vents or reverses platelet aggregation and relaxes and dilates blood vessels. Instead of being found in the platelet, it is synthesized in the walls of arteries and veins and is located primarily in the vascular endothelium. Teleologically, its function is probably to inhibit the formation of occlusive platelet aggregates and to maintain the patency of the vascular system. One reason that platelets do not normally adhere to the endothelial lining of vessels may be that endoperoxides released from the platelets may be converted to PG 12 by the



appropriate endothelial enzyme (prostacyclin synthetase) and adhesion and aggregation are inhibited. If there is a break in the endothelial lining, the loss of this newly formed prostacyclin and its attendant aggregation inhibition may be the reason that platelets aggregate on areas of damage and theoretically contribute to the formation of an atherosclerotic plaque. In addition, the presence of a plaque may inhibit the formation of the prostacyclin and thus favor the formation of a clot at the site of the atherosclerotic lesion that occludes the vessel or contributes to further growth of the plaque.

Prostacyclin 12 versus thromboxane A2 inhibition: The reason that the existence of prostacyclin I2 might complicate pharmacologic antiplatelet therapy is that at least some of these drugs, especially aspirin and drugs of the nonsteroidal antiinflammatory type (including possibly sulfinpyrazone), act through inhibition of cyclooxygenase. Natural synthesis of the prostagiandins is thought to proceed from arachidonic acid to the cyclic peroxides using cyclooxygenase as the catalytic enzyme. These cyclic peroxides are the pre- cursors of the other prostaglandins, being specifically converted in the presence of thromboxane synthetase in the platelet to thromboxane A2 and, in the presence of prostacyclin synthetase in the blood vessel lining, to prostacyclin 12. Thus the process that leads to the synthesis of both thromboxane A2, the platelet-aggregating agent and vasoconstrictor, and prostacyclin 12, the inhibitor of platelet aggregation and vasodilator, is repressed by these platelet-inhibiting drugs. Experi- ments with various blood levels of aspirin have not been successful in finding a dosage of aspirin that will inhibit production of thromboxane A2 without also inhibiting coronary vasodilation, 75 which is thought to be related to the production of PG 12. Theoretically then it is not known whether on balance the benefit of inhibition of thromboxane A2 outweighs the liability of inhibiting the production of prostacyclin 12.

Drug side effects: These drugs are potent pharmacologic agents and have known side effects. This is of especial importance because if they are to be used as preventive agents for coronary disease they must be given for prolonged periods of time; moreover, the side effects of years of drug use are largely unknown.

Aspirin: Among the patients considered for inclusion in the Coronary Drug Project Aspirin study, a significant number had to be excluded because of inability to tolerate aspirin or a history of peptic disease. Among those entered into the tria151 there was a significantly increased incidence of abdominal pain, though not ulcer, among those taking aspirin. Blood urea nitrogen and uric acid levels were slightly elevated in the treated group, and the incidence of gout and podagra were significantly increased among those receiving aspirin.

Sulfinpyrazone: The sulfinpyrazone study54 found no significant difference in the incidence of side effects in the treated versus the placebo group during the period of study; however, the mean follow-up period was only approximately 8.4 months. The manufacturer76 notes problems with increased sensitivity to sulfonyl- urea hypoglycemic agents, sulfa drugs and coumarin anticoagulant agents. The drug is a potent uricosuric

agent, and the possibility of precipitation of uric acid stones in the dehydrated patient must be considered. Peptic ulcers can be exacerbated with the drug, and severe blood dyscrasias, anemia, thrombocytopenia and agranulocytosis have been reported.

Dipyridamole: This agent is a vasodilator, and dizziness, headache, weakness and syncope occasionally result from its use.77 Because it seems to dilate selectively the large coronary arteries, a coronary steal syndrome may be precipitated with a worsening of angina pectoris. Occasional gastrointestinal disturbances have also been noted.

Clofibrate: A wide variety of side effects have been reported with clofibrate .76 Gastrointestinal problems, nausea, vomiting, dyspepsia, loose stools, flatulence and abdominal distress are the most common. Liver function tests may be affected. Results of the recent Coop- erative Studya suggest an increased incidence of liver, gall bladder and intestinal diseases related to use of the drug. Patients often become more sensitive to coumarin anticoagulant agents. Fatigue, dizziness, headache and “flu-like” syndrome have been reported, as have cardiac arrhythmias, alopecia, renal dysfunction, leukopenia, anemia and impotence. Barely, the cholesterol level may rise with the use of the drug. The litany of side effects with clofibrate is long, mainly because so many patients have been receiving the drug for long periods. In most patients clofibrate is well tolerated.

Beta adrenergic blocking agents: Side effects of the beta adrenergic blocking agents are well known and are primarily related to their antiadrenergic actions. These agents should be used with caution, if at all, in patients with diabetes, heart failure, asthma or chronic bronchitis or evidence of atrioventricular block.

Perspective on Antiplatelet Agents

In view of the theoretical benefit of antiplatelet aggregation therapy in the prevention of acute myocardial infarction and of progression of atherosclerosis, the suggestive data linking coronary risk factors with platelet abnormalities, the prospective studies that show a trend (although without statistical significance) toward benefit of aspirin in secondary prevention of infarction and the sulfinpyrazone study that has demonstrated a preventive effect in the short term, the disturbing data concerning a possible deleterious effect of these drugs because of inhibition of production of prostacyclin 12 and the possible side effects of long-term therapy with these drugs, the clinician is faced with the practical dilemma of whether and in what clinical cir- cumstances these pharmacologic agents should be prescribed. First, although not discussed in this review, it should be noted that these drugs are indicated or at least worthy of trial for therapy of transient cerebral ischemic attacks and amaurosis fugax.57*77 Second, it is considered appropriate to add these drugs to routine coumarin anticoagulation in a patient with a prosthetic valve who has had arterial emboli while on a well controlled anticoagulation regimen (not instead of coumarins but in addition to the coumarins).73

Recommended guidelines and indications for therapy: In patients with coronary artery disease the



indications for the use of these drugs are not yet proved beyond reasonable doubt, and the following recom- mendations are guidelines that I find useful while waiting for definitive data. I believe that the data tend to indicate that antiplatelet aggregating drugs have a beneficial effect. Although prostacyclin 12 inhibition theoretically may be detrimental, in no’study have the patients treated with aspirin or sulfinpyrazone appeared to do less well than untreated control subjects, and in most trials there has been a trend toward benefit, even if the effect has not achieved statistical significance. While we await data from the AMIS study, the PARIS study, the Italian sulfinpyrazone study and further data from the Anturane study group, I consider it appropriate to use these drugs. The following dosages are currently being used when an antiplatelet aggregation effect is the aim of therapy: aspirin, 5 grains (325 mg) two or three times daily; sulfinpyrazone, 200 mg four times daily; dipyridamole, 50 mg four times daily; clofibrate, 500 mg three times daily; and propranolol, 20 mg’four times daily.

The appropriate candidates for therapy are not known but, in order of priority, these are the patients for whom I consider therapy reasonable.

1. Patients with critical lesions on coronary arteriography who are not candidates for bypass surgery.

2. Patients who have had the intermediate coronary syndrome who do not undergo coronary arteriography.

3. Patients with a documented myocardial infarction who have recurrence of angina but who do not undergo coronary arteriography.

1. Weiss HJ: Platelet physiology and abnormalities of platelet function. N Engl J Med 293:531-539,1975

2. Jorgensen L, Rowgell HC, Hovfg T, Glynn MF, Mustard JF: Adenosine diphosphate induced platelet aggregation and myocardial infarction in swine. Lab fnvest 17:616-644, 1967

3. Haff JI, Kranz PD, Albert FJ,’ Fan1 K: Intravascular platelet aggregation in the heart induced by norepinephrine. Circulation 46:696-706, 1972

4. Haft Jk Cardiovascular injury induced by sympathetic catecholamines. Prog Cardiovasc Dis 17:73-66, 1974

5. Haff JI, Gerohengorn K, Kranz PD, Oestrelcher R: Protection against epinephrine-induced myocardial necrosis by drugs that inhibit platelet aggregation. Am J Cardiol 30:838-843, 1972

6. Haft JI, Kranr PD, Albert F, Oestrelcher R: Protection against epinephrine induced myocardial necrosis with clofibrate. Am Heart J 86:805-810, 1973

7. FoHs JO, Crowell EB, Rowe LL: Platelet aggregation in partially obstructed vessels and its elimination with aspirin. Circulation 54: 365-376. 1976

8. Folts JD, Rowe LL: Platelet aggregation in stenosed coronaries: mechanism of sudden -death? (abstr). Am J Cardiol 41:425, 1978

9. Moschos CB, Lahlrl K, Lyons M, Weisse AB, Oldewurtel HA, Regan TJ: Relation of microcirculatory thrombosis to thrombus in ths proximal ccmnary artery; effect of aspirin, dipyridamole, and thrombolysis. Am Heart J 86:61-68, 1973

10. Jorgensen L: Thrombosis, platelets and sudden death. In, Throm- bosis, Platelets, Anticoagulation and Acetylsalicylic Acid (Donoso E, Haft JI, ed). New York, Stratton Intercontinental Medical Book Corporation, 1976, p 131-142

11. Haerem JW: Mural platelet microthmmbi and major acute lesions of main epicardial arteries in sudden coronary death. Atheroscle- rosis 19:529-541, 1974

4. Patients with documented myocardial infarction, starting within 30 days of infarction.

5. Patients who have angina after coronary bypass surgery.

6. All patients with new angina. 7. All patients within 30 days of coronary bypass

surgery (less definite indication). 8. All patients with chronic angina (less definite in-

dication) . In these patients I try to make sure that one of the

platelet-active drugs is being administered. If the patient is not receiving propranolol for angina or clofibrate for a lipid abnormality, I tend to favor aspirin or sulfinpyrazone as therapy because most of the supportive studies have used these drugs. It is important to make it clear to the patient that these regimens are a reasonable and possibly effective means of prophylaxis but that they are not yet fully proved to be of definite beneficial effect. If side effects develop, I will switch to another regimen; if that is not tolerated I discontinue the drugs.

Future implications: As time passes and more definitive data become available, the indications for these drugs can be expected to change. One hopes that these drugs will in time be proved effective and provide an important treatment for the patient with coronary artery disease. Meanwhile, although I believe that use of these drugs for their antiplatelet aggregation effect is already tentatively justified, the clinician must maintain an open mind and realize that the definitive efficacy of these drugs in the management of coronary artery disease has yet to be fully demonstrated.

References

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1206 June 1979 The American Journal of CARDfGLOGY Volume 43

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Role of blood platelets in coronary artery disease