Role of antithrombotic therapy in unstable angina, myocardial infarction and sudden death

678

lACC Vol 8, No 6 December 1986 67B-75B

Role of Antithrombotic Therapy in Unstable Angina, Myocardial Infarction and Sudden Death CRAIG E. HJEMDAHL-MONSEN, MD,* H. DANIEL LEWIS, MD,t JOHN CAIRNS, MD,:l: JAMES H. CHESEBRO, MD, FACC,§ VALENTIN FUSTER, MD, FACC* New York. New York. Hamilton. Ontario. Canada and Rochester. Minnesota

The role of platelets and the clotting system in the initiation and progression of atherosclerosis has received significant attention. Most importantly, platelets and thrombosis playa pivotal role in the pathogenesis of the acute coronary syndromes of unstable angina, myocardial infarction and sudden death. In each stage of the development of coronary artery disease, from the early symptomatic stage through the growing lesion and finally to the complicated plaque that results in the precipitation of the acute coronary syndromes, platelets and the clotting system serve as a common link among them. Antithrombotic therapy aimed at halting the progression of these syndromes, preventing their occurrence or even reversing them (such as in the early stages of acute myocardial infarction), has provided exciting new modalities to treat these disorders. The use of aspirin in unstable angina in two well designed studies has clearly

Recent evidence suggests that platelets and thrombosis play an important role in the progression of coronary artery disease as well as in the pathogenesis of the acute coronary syndromes of unstable angina, myocardial infarction and sudden death. Progression of the ubiquitous raised fatty streaks in the coronary arteries and other vessels into an atherosclerotic plaque may, in part, be mediated by platelets and the clotting system. Most importantly, however. the acute coronary syndromes are frequently precipitated by events involving the formation of thrombus on a disrupted, preexisting atherosclerotic plaque. With a better understanding of the pathogenesis of these conditions, a new role for antithrombotic therapy has emerged. From the *DIVISlon of Cardiology, Department of MedICine. Mount Sinai School of Medicine of the City Univen.ity of New York, New York. New York; tCardlOlogy Division, Veterans AdminIstration, Kansab City, Missouri; tRegional Cardiovascular Program, McMaster University, HamIlton, Ontario, Canada and the §Division of Cardiovascular Diseases and Internal MedICine, Mayo Clinic, Rochester, Minnesota Address for reprints: Valentin Fuster. MD, DiVIsion of Cardiology, Department of Medicine. Mount Sinai Medical Center, One Gustave L. Levy Place, New York, New York 10029. © 1986 by the Amencan College of Cardiology

shown a reduction in fatal as well as nonfatal cardiac events compared with control groups not treated with aspirin. Although demonstration of a benefit of anticoagulant and antiplatelet therapy is difficult owing to a low event rate of thrombotic events (low sensitivity) and other nonthrombotic fatal events (low specificity) after myocardial infarction, pooled results have shown a favorable effect with their use. The usefulness of thrombolytic therapy in the early stages of acute myocardial infarction depends on the timing of initiation of therapy, the severity of the residual stenosis and possible use of agents that protect the ischemic myocardium. Other potential therapies for the acute coronary syndromes are also suggested. Further studies are in progress to establish the clinical benefits of antithrombotic agents in acute coronary syndromes. (J Am Coil CardioI1986;8:67B-75B)

Role of Platelets in Atherogenesis Stages in development of coronary atherosclerosis. The natural history of coronary atherosclerotic disease can be divided into five stages (I). In stage I. benign raised fatty streaks develop. These are found in most young persons and do not lead to symptoms. If these raised plaques grow (stage II), clinical symptoms of angina pectoris may develop. This stage is accelerated by certain cardiac risk factors as well as by racial and geographic influences. If a plaque undergoes a rapid change due to plaque rupture with or without thrombus formation (stage III), unstable angina, myocardial infarction or sudden death may be the result. Over time, the thrombus formed in stage III becomes organized, leading to growth of the plaque and possibly further symptoms of angina pectoris (stage IV). In stage V, infarcted myocardium resulting in significant ventricular dysfunction may predispose to ventricular arrhythmia and sudden death. The role of platelets and thrombosis is mainly limited to the first three stages. Therefore, the benefit of antithrombotic therapy should be geared to these areas. 0735-1097/86/$3 50

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HJEMDAHL~MONSEN ET AL ANTITHROM80TIC THERAPY IN ACUTE CORONARY SYNDROMES

JACC Vol X. No n Delemher 19XO 078-758

Coronary Atherosclerotic Disease Complicated leSion (ThrombosIs)

[ Pathology

I Early leSion

Normal

IClinical I

Asymptomatic

1-----------11

I

Angina

Myocardial Infarction (LV dysfunction) Unstable Angina Sudden Death Sudden death

-----------------1

Figure 1. Scheme of the five stages of evolution of coronary atherosclerotic disease. Early lesions (stage I) (lower left) tend to progress to a growing lesion (stage II) (middle) in those palien" with so-called risk factors of atherosclerotic disease. Some plaques may undergo rapid changes with thrombus formation (stage III) and subsequent fibrosis (stage IV) (upper right). Finally, extensive occlusive coronary disease and infarcted myocardium result in significant left ventricular (LV) dysfunctIOn (stage V) (lower right). (Modified with permission from Fuster V, et al. [I ].)

r-I

Risk factors .----~------.,----T7//-{-,---------.--, ----------"

10

20

40

50

60

Age (years)

Stages I and II: asymptomatic phase and stable angina phase (Fig. 1, Table 1). Platelets can attach to the endothelial surfaces of coronary arteries; that is, when the endothelial surface becomes damaged, platelets that contact these areas become attached. Branch points in the coronary arteries are the site of rapid turbulent flow that can lead to endothelial damage (2,3). Damaged endothelium exposes collagen fibers and von Willebrand factor, a protein related to factor VIII (4). Platelets that contact these areas become firmly attached by a process of "pseudopod" formation (5). Once attached to the vessel wall, the platelets release platelet-derived growth factor, which stimulates smooth muscle cells in the vascular intima to proliferate and which, in part, are responsible for the synthesis of collagen and uptake of cholesterol. This may ordinarily serve as a repair process, but in the coronary arteries, can contribute to atherosclerotic plaque development (6) of stages I and II. As mentioned, von Willebrand factor is responsible for platelets contacting injured endothelium to become firmly attached. The importance of von Willebrand factor in this stage is supported by a breeding colony of pigs with absence of von Willebrand factor that is resistant to both spontaneous and high cholesterol diet-induced atherosclerosis (7,8). There is no antiplatelet drug currently available that can completely prevent the adherence and activation of this single layer of platelets. If a drug was developed that totally inhibited platelet adhesion, the risk of bleeding might preclude its longterm use.

tinuously undergoing bending and twisting movements. In addition, these advanced plaques often have become relatively soft owing to the buildup of fats beneath their fibrous cap. Moreover, shear stresses or vasotonicity at the level of stenosis may act on the softened lesions, predisposing them to rupture or ulceration, exposing underlying collagen and promoting thrombus formation. The clinical result may be unstable angina, myocardial infarction or sudden death,

Table 1. Simplified Unified Concept of Probable Sequential Events in Coronary Atherosclerotic Disease: Role of Platelets and Thrombosis in Stages I, II and III

Stage III: acute and subacute coronary syndromes (Fig. 1, Table 1). In stage III, the atherosclerotic plaque

Stage I Early lesion,-a,ymptomatlc ,tage Hemodynamic factor,-endothellal damage Platelet deposition Smooth muscle cell migratIOn and proliferation Connective tls,ue syntheSIS Lipid transformation and deposition Stage II Growing leSIon-angina pectow, Progression of above (,low process) Organization of thrombus (rapid process)* Stage III Complicated plaques (that IS, plaque rupture) Un,table angina-thrombosis Myocardial infarction-thrombotic occlusion* Ischemic ,udden death Myocardial infarction-thrombosis* Myocardial ischemia ?Microemboli

undergoes a rapid change, which is due to plaque rupture with or without thrombus formation (l). Why does this occur? Sites of advanced atherosclerotic plaques are con-

*Events that may be prevented or dimmished by use of antithrombotic therapy. Bold face type 10dicates step, 10 whIch platelets and thrombosis playa role.

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HJEMDAHL-MONSEN ET AL ANTITHROMBOTIC THERAPY IN ACUTE CORONARY SYNDROMES

depending on the degree of obstruction caused by the thrombus and the duration and suddenness of the obstruction.

A Common Link Among the Acute Coronary Syndromes Plaque rupture and thrombus formation are important in the pathogenesis of the acute coronary syndromes; that is, there is evidence that the syndromes of unstable angina, myocardial infarction, and sudden death all share in the same pathophysiologic process (1,9, 10). Unstable angina. Moise et al. (II) found progression of coronary lesions in the majority of patients with unstable angina undergoing coronary angiography as compared with a smaller percentage in patients who had stable angina. Similarly, Ambrose et al. (12) showed progression of coronary stenoses in 76% of patients with repeat coronary angiography after the development of crescendo angina compared with 33% of patients who had repeat angiography with little or no change in symptoms. It has also been noted that patients with unstable angina are more likely to have a specific morphologic pattern of the coronary lesion consisting of an eccentric stenosis with irregular borders or a narrow neck, or both (13). Similar-appearing irregular lesions have been confirmed by pathologic examination to represent disrupted atherosclerotic plaques or partially occlusive thrombi, or both (14). Therefore, sudden progression in coronary stenoses as well as the development of a morphologically distinct pattern may represent the disruption of an atherosclerotic plaque with thrombus formation in patients with unstable angina. Myocardial infarction. DeWood et al. (15) showed that in the early hours after myocardial infarction, 87% of the infarct-related arteries are totally occluded. In a subgroup of patients who underwent emergency surgical revascularization, thrombus was retrieved from the coronary arteries in 88%. Reperfusion studies (16,17) have shown that thrombolytic therapy is effective in restoring perfusion to totally occluded infarct-related arteries in 60 to 90% of patients. Ambrose et al. (18) also showed that in patients with acute myocardial infarction with less than 100% occluded arteries or in patients receiving thrombolytic therapy with reperfusion of a totally occluded artery, the same eccentric and irregular-appearing coronary lesions seen in unstable angina are found in the majority of patients. Sudden death. Although a lethal arrhythmia is considered to be the terminal event in patients with sudden death, there is evidence from patients surviving an episode of sudden death that myocardial infarction or ischemia is involved in nearly two-thirds of patients (19,20). In addition, in twothirds of patients dying suddenly, pathologic evidence of plaque rupture and thrombus formation is found (21). Recurrent, layered mural thrombi overlying the plaque with or without peripheral embolization are also seen (22).

69B

Antithrombotic Therapy for the Acute Coronary Syndromes From the previous discussion, clinical and pathologic evidence suggests that thrombus formation occurring at the site of a disrupted atherosclerotic plaque is a mechanism linking the acute coronary syndromes. Therapy aimed at preventing, limiting or dissolving the thrombus implicated in these syndromes has recently gained interest (Table I). Antithrombotic therapy can be based on the use of platelet inhibitors, heparin, oral anticoagulants and thrombolytic agents. We will review the role of antithrombotic therapy in each of the clinical entities that make up the acute coronary syndromes.

Unstable Angina Aspirin. Aspirin therapy has an antiplatelet effect owing to its acetylation of the cyclooxygenase enzyme in platelets. Inhibition of this enzyme prevents formation of thromboxane A2 (23). Because this inhibition is irreversible, restoration of platelet function depends on release of new platelets into the circulation. Therefore, aspirin has a sustained antiplatelet effect. The use of antithrombotic therapy in unstable angina has been demonstrated by two randomized, placebo-controlled double-blind trials (24,25) involving the use of aspirin. Veterans Administration Cooperative Study (24). This randomized, placebo-controlled, double-blind clinical trial was designed to determine if aspirin could decrease the incidence of death and acute myocardial infarction in patients with unstable angina. The treated patients received 324 mg of aspirin in buffered solution (Alka-Seltzer) daily for 12 weeks; the control patients received the buffer without aspirin. From 1974 to 1981, the study of 1,266 men hospitalized with unstable angina was conducted at 12 Veterans Administration medical centers. To qualify for the study, a patient had to have unstable angina beginning within I month before and still present within the week before hospital admission, evidence of coronary artery disease and no baseline evidence of acute myocardial infarction. Unstable angina was defined as new onset or worsening of angina, manifested by frequency of one or more episodes per day, duration longer than 15 minutes or occurrence at rest or during minimal activity. Coronary arteriograms were not performed routinely. Patients were entered into the study within 51 hours of admission to the hospital. During the 12 week treatment period. death or acute myocardial infarction occurred in 10.1% of the placebotreated and 5.0% of the aspirin-treated patients (p = 0.00(5). Acute myocardial infarction and nonfatal acute myocardial infarction exhibited similar percent reductions with comparable p values. Death occurred in 3.3% of the placebotreated and 1.6% of the aspirin-treated patients (p = 0.54). This difference was not statistically significant. However,

70B

HJEMDAHL-MONSEN ET AL. ANTITHROMBOTIC THERAPY IN ACUTE CORONARY SYNDROMES

the 51 % reduction in mortality in the aspirin group was the same as that for acute myocardial infarction. Importantly, follow-up study at 1 year showed persistence of the beneficial effects of 12 weeks of aspirin therapy, with mortality still 43% less in the aspirin-treated patients (p = 0.008). The protective effects of aspirin treatment in unstable angina appeared to be additive to any effect of beta-adrenergic blocker therapy that may have been present. There was no evidence of gastrointestinal side effects from the study medicine. The occurrence of epigastric symptoms, hemoglobin decrease or occult blood in the stool at any time during follow-up was equally distributed between the treatment groups. Only 1.3% of the patients were withdrawn from study because of possible treatment side effects, and they were equally distributed between the placebo and aspirin groups. The lack of gastrointestinal adverse effects is probably a result of both the low dose of aspirin and its administration in a buffered solution. Canadian Multicenter Trial (25). The Canadian Multicenter Trial of aspirin or sulfinpyrazone, or both, in unstable angina was conducted in seven centers between 1979 and 1984. A total of 555 patients (73% men) entered the study, and after a mean follow-up of 18 months, there was a marked benefit from aspirin in the reduction of death and myocardial infarction. Sulfinpyrazone conferred no benefit. The target population consisted of patients admitted to a coronary care unit with a clinical (nonangiographic) diagnosis of unstable angina. These patients underwent a detailed interview to determine whether there was good clinical or electrocardiographic evidence of myocardial ischemia and whether there was an unstable pain pattern, either crescendo pain or prolonged pain at rest. The study criteria were satisfied by 85% of the 817 patients interviewed after the exclusion process, among whom 159 refused study entry, leaving 555 who entered the trial. Patients were randomly allocated to one of four treatment regimens: aspirin (325 mg four times a day) or matching placebo, plus sulfinpyrazone (200 mg four times a day) or matching placebo, for a total of eight tablets daily to be taken with meals or milk. Coronary angiography was not a prerequisite for study entry. However, it was performed at least once in 61 % of patients, most often within the first 3 months of study entry. Coronary artery lesions with stenoses of at least 50% of luminal diameter were present in one vessel in 16% of patients, in two vessels in 24%, in three vessels in 44% and in the left coronary artery in 6%; such lesions were absent in 9%. The primary analysis was to be one of efficacy, with outcome to be assessed only among patients who met certain criteria established at inception of the study and to be applied without knowledge of the treatment allocated or of clinical outcome. It was also decided in the design phase to report the outcome in every randomized patient, following an "intention to treat" approach. The outcome of greatest importance was considered to be that of the combined total of

JACC Vol R. No (, December 19R(, 67B-75B

zw

20

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I-

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w

.. .'

......... .,

'

.'

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5y

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l=
. ,.,

........ .......

NO ASA

I

I

3 mo.

6 mo.

1 yr.

(174) (180)

(137) (144)

18mo.

2 yr.

(107) (115)

(73) (80)

TIME

AT RISK ASA (263) NO ASA (274)

Figure 2. Efficacy of aspirin (ASAl versus no aspirin in reducing cardiac death or nonfatal myocardial infarction in patients with unstable angina. (Reproduced with permiSSIOn from Cairns lA, et al. [25].)

cardiac death and nonfatal myocardial infarction. It was also planned to evaluate cardiac death alone and death from any cause as important secondary outcomes. In the efficacy analysis, the primary outcome event of cardiac death or nonfatal myocardial infarction occurred in 53 patients. There was no overall benefit from sulfinpyrazone and no interaction with aspirin. Accordingly, in Figure 2, we have depicted a lifetable cumulative risk according to aspirin allocation. There were 36 events in the groups not given aspirin, and 17 in those taking aspirin, and by 2 years, the lifetable rate of these events was 17% versus 8.6%, representing a risk reduction of 50.8% (p = 0.008). The outcome event of cardiac death alone (Fig. 3) occurred in 22 patients not taking aspirin, and in 6 given aspirin, and by 2 years, the lifetable rate of these events was 11.7% versus 3%, representing a risk reduction of 71 % (p = 0.004). All deaths were cardiac in this analysis. In the intention to treat analysis, counting all randomized patients and all outcomes, the outcome of cardiac death or nonfatal myocardial infarction was observed in 70 patients, including 17 patients who were excluded from the primary

Figure 3. Efficacy of aspirin (ASA) versus no aspirin in reducing cardiac death in patients with unstable angina. (Reproduced with permission from Cairns lA, et al. [25].) I-

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3mo.

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(111) (123)

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(140) (154)

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lACC Vol. 8, No 6 December 1986.67B~75B

HJEMDAHL-MONSEN ET AL. ANTITHROMBOTIC THERAPY IN ACUTE CORONARY SYNDROMES

analysis of efficacy. Again, sulfinpyrazone had no significant effect and no interaction with aspirin. The risk reduction with aspirin was 30% (p = 0.072). With outcomes of cardiac death and death from any cause, the corresponding risk reductions with aspirin were 56.3% (p = 0.009) and 43.4% (p = 0.035), respectively. Gastrointestinal side effects occurred in 39% of patients and were 29% more common among the patients receiving aspirin. However, most of these were minor, including abdominal discomfort, indigestion, nausea, vomiting and constipation. Only seven patients had either occult blood in the stool, rectal bleeding or melena (one of these requiring transfusion), and eight had peptic ulcer. These potentially dangerous gastrointestinal side effects, observed in only 3% of patients, were not more common among those receiving aspirin, although among those receiving neither aspirin nor sulfinpyrazone, only one patient had such a complication. Differences in the studies. The greater protective effect of aspirin in the Veterans Administration Cooperative Study (24) and the Canadian Multicenter Trial (25) compared with the several trials after myocardial infarction is probably related to several differences. Patients with unstable angina often have an acute, potentially reversible thrombus (high specificity), and the frequency of complicating thrombotic clinical events in the form of myocardial infarction and sudden death is high (high sensitivity). Thus, when treated acutely, a patient with unstable angina has a greater potential for benefit than does a patient with a myocardial infarction in whom, as described later, the frequency of recurrent clinical events is low (low sensitivity) and some of the recurrent events such as sudden death related to myocardial dysfunction are not thrombotic (low specificity). Although most of the patients in these studies were men, the results of the Canadian study suggest that the conclusions hold true for women as well. Heparin and oral anticoagulants. Intravenous heparin therapy was shown to reduce the morbidity and mortality in a small group of patients with the intermediate coronary syndrome randomized to placebo, atenolol, heparin or a combination of heparin and atenolol (26). There was an 80% reduction in mortality or acute myocardial infarction in the heparin-treated group during the study period as compared with the control group. This benefit was continued for 8 weeks of follow-up. In addition, studies using intravenous heparin therapy followed by oral anticoagulant therapy have also been reported (27,28). A beneficial effect in terms of morbidity and mortality was seen in patients who received anticoagulant therapy. However, all of these studies on heparin alone or heparin followed by oral anticoagulants had either a large number of exclusions from the study or from analysis or were not properly randomized and controlled so that their conclusions may not be valid. Thrombolytic therapy. The use of thrombolytic therapy for unstable angina has been studied by several investiga-

7lB

tors. In patients with recent onset of severe unstable angina, streptokinase was given into the coronary artery responsible for the anginal syndrome at the time of catheterization (29). There was an improvement of the coronary lesions in terms of percent stenosis as compared with prestreptokinase percent stenosis. In another study (30), streptokinase was given by intravenous infusion over a period of 24 hours to a group of patients with unstable angina and was followed by oral anticoagulant therapy. This group was compared with a similar group that received oral anticoagulants alone. There was a statistically significant reduction in the incidence of myocardial infarction at 6 months in the streptokinase group compared with the group receiving only oral anticoagulants. These studies, however, were done in a small number of very selected patients. Therefore, the role of thrombolytic therapy in unstable angina is still uncertain.

Myocardial Infarction In assessing the benefit of antithrombotic therapy in myocardial infarction, it must be emphasized that the risk of dying from infarction is greatest immediately after the onset of symptoms. The risk decreases over a period of days and remains somewhat elevated for the first 6 months after the infarction, Deaths occurring immediately after the onset of symptoms are usually caused by arrhythmias, Deaths that occur somewhat later are usually a result of pump failure. Beyond 6 months, pump failure may also be a significant cause of death. Because most deaths are not caused by thrombotic events in the early phases at least, it is unlikely that antithrombotic therapy would have much impact at this stage. Thus, death is a nonspecific end point for thrombotic events. In addition, reinfarction tends to occur with a low incidence in the early phases after myocardial infarction. Thus, the large number of patients needed to reach a valid conclusion because of the low incidence of reinfarction makes studies of antithrombotic therapy insensitive. Oral anticoagulation. Despite the preceding considerations, the pathologic evidence combined with the results of a number of trials that were poorly designed by today's criteria led to the widespread use of short-term anticoagulant therapy for patients with myocardial infarction in the 1950s and 1960s. However, three large studies (Medical Research Council, Bronx Municipal, and Veterans Administration (31-33) reduced the enthusiasm for the short-term therapy. These studies failed to show the value of short-term anticoagulant therapy, and the treatment thereafter fell into disfavor. The relatively low intensity of anticoagulation in these trials has been stressed by Loeliger (34). Most patients underwent anticoagulant therapy to a point now considered appropriate for venous thrombosis (35), but not believed to be adequate for arterial thrombosis. This may have contributed to the poor results of the therapy. Other factors may

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HJEMDAHL-MONSEN ET AL ANTITHROMBOTIC THERAPY IN ACUTE CORONARY SYNDROMES

have made interpretation of the results difficult, such as the use of heparin therapy initially or the late initiation of therapy (up to 72 hours from the onset of symptoms). Long-term anticoagulant therapy. Therapeutic trials assessing the role of anticoagulant therapy beyond 6 months are more specific for possible thrombotic events. However, the event rate is low and, therefore, these studies have a low sensitivity. Three large studies (36-38) have assessed the benefit of long-term anticoagulant therapy given after myocardial infarction. While there seemed to be some reduction in mortality early on, there was no significant benefit over follow-up periods of 2 to 7 years. However, if the results of several studies are pooled (39), it appears that long-term anticoagulant therapy may be protective against recurrent infarction. In addition, the Dutch Sixty-Plus Reinfarction Study (40) showed a significant reduction in myocardial infarction and total mortality in patients older than 60 years of age. The greater benefit using anticoagulants in this trial over previous trials may be related to two factors in the Dutch trial: I) anticoagulant therapy was more rigidly controlled, and 2) randomization into treatment groups was

JACC Vol ~. No 6 December 1986 67B-75B

made at a median of 6 years after a previous myocardial infarction. Therefore, in this relatively stable group of patients, thrombotic events rather than myocardial factors dictated long-term prognosis so that the specificity for thrombosis was higher. Platelet inhibitors (Table 2). Anticoagulant therapy is relatively dangerous and exposes the patient to a significant risk of bleeding. More recently, drugs with antiplatelet effects that have been studied in patients recovering from myocardial infarction include aspirin, sulfinpyrazone and dipyridamole. It is unlikely that sulfinpyrazone or dipyridamole has a significant role in the long-term therapy of acute myocardial infarction. The discussion over the Anturane Reinfarction Trial (41) had clouded the use of sulfinpyrazone, and it is becoming unlikely that dipyridamole has a significant antiplatelet effect on other than artificial vascular surfaces. Eight large studies have been performed with aspirin (or aspirin combined with dipyridamole) in doses of 300 to 1,500 mg/day. These studies, when pooled (42), suggest that aspirin reduces the rate of reinfarction by 21 %. There is also a significant reduction in death rate of

Table 2. Comparison of Platelet-Inhibitmg Drugs After Myocardial Infarction in Eight Prospective Randomized, Double-Blind Placebo-Controlled Trials

Tnal (Reference)

Time Between MI and Entry (mean mol

Duration of Follow-Up (mean mol

Drug

Dosage (mg/day)

Total No. Patients

Results Therapy Favorable trend Favorable trend

Elwood et al. (50)

2 V3

12

ASA

300

1,239

Coronary Drug Project (51)

3

22

ASA

927

1,529

Breddin et al. (38)

I V3

24

1,500

946

V.

12

ASA. phenoprocoumon (Liquamar) ASA

900

1,682

Elwood and Sweetnam (52) AMIS (53)

25

38

ASA

1,000

4,524

Paris (53)

20

41

ASA

972

2.026

ASA

ART(4\)

2/3

ARIS (55) PARIS (56)

2

+D

972

+ 225

Favorable trend Favorable trend No benefit

Favorable trend Favorable trend

16

Sulf

800

1,558

Decreased SD only

19

Sulf

800

727

23

ASA

Decreased MIonly Decreased all end points

+ D

972

+ 225

3,128

End Point(s) Total mortality Total and CAD mortality. MI and other CY events SD, MI (fatal and nonfatal) Total mortality Total and CAD mortality, MI stroke Total and CAD mortality, CAD incidence Total and CAD mortality, CAD mcidence Total and CAD mortality, CAD incidence MI, SD, CAD total mortality Total and CAD mortality. MI, CAD incidence

AMIS = Aspirm Myocardial Infarction Study; ARIS = Anturane Reinfarction italian Study; ART = Anturane Reinfarction Trial; ASA = aspmn; CAD = coronary artery disease; D = dipyridamole; MI = myocardial infarction; SD = sudden death; Sulf = sulfinpyrazone

HJEMDAHL-MONSEN ET AL. ANTlTHROMBOTlC THERAPY IN ACUTE CORONARY SYNDROMES

JACC Vol 8, No 6 December 1986 67B-75B

the same magnitude as with the pooled results of anticoagulant therapy (39). Given the low risk of the lower dosage of aspirin used, a case can be made for its use as the preferred antithrombotic drug after acute myocardial infarction. Thrombolytic therapy. There has been much recent interest in thrombolytic therapy initiated within the first few hours after the onset of acute myocardial infarction. Streptokinase has been given to patients intravenously as well as directly into the infarct-related coronary artery at the time of catheterization performed immediately after the diagnosis of myocardial infarction was made. The procedure often recanalizes totally occluded vessels (16). Tissue-type plasminogen activator, a naturally occurring protease that has the ability to specifically dissolve fibrin clots, has also been used to recanalize acutely occluded vessels of patients within the first few hours after the onset of acute myocardial infarction (43). Factors in clinical outcome. Although successful recanalization of the infarct-related arteries has been shown to occur after thrombolytic therapy, the practical utility of this therapy depends on limitation of infarct size with preservation of ventricular function and a decrease in mortality. Spontaneous recanalization can occur. Therefore, the clinical end points of improvement in ventricular function and mortality are the ones most often studied. Several factors play a key role in the clinical outcome of thrombolytic therapy. These factors are the timing of initiation of therapy, the severity of the residual stenosis and the evolving concept of myocardial protection. The importance of early initiation oftherapy is borne out in a recent placebo-controlled trial performed in Italy (44), using intravenous streptokinase given to patients within 12 hours of the onset of acute myocardial infarction. The study group comprised nearly 12,000 patients. The results of the trial showed that hospital mortality was 10.7% in streptokinase recipients versus 13% in control patients (Table 3). This significant reduction in mortality was more striking as a function of time from onset of pain to streptokinase infusion. Table 3 shows that the extent of reduction in mortality was greatest in those patients receiving streptokinase less than 3 hours from the onset of pain.

Table 3. Mortality by Hours From Onset of Symptoms to Streptokinase or Placebo Therapy

738

Improvement in I year mortality after thrombolysis was shown in a trial by Simoons et al. (45), in which streptokinase was given within 4 hours from the onset of chest pain. The I year survival rate in the treated group was 91 % compared with a survival rate of 84% in the conventionally treated group. Ventricular function also appears to be preserved if thrombolytic therapy is initiated soon after the onset of symptoms. The study by Koren et al. (46), using early (average 1.7 hours) administration of intravenous streptokinase often initiated in a mobile care unit, showed a significantly higher left ventricular ejection fraction in the treated group (56%) than in the control group (47%). The Intravenous Streptokinase in Acute Myocardial Infarction (ISAM) Study (47) also showed a preservation of global and regional ejection fractions in patients treated with intravenous streptokinase within 6 hours of the onset of symptoms. The importance of residual stenosis is demonstrated by the Western Washington Trial (48). The 1 year survival rate in this study was only improved in a subset of patients who achieved complete recanalization with normal or nearly normal distal coronary flow. Those patients with p;rrtial reperfusion and, therefore, more severe residual stenoses had a mortality rate similar to that in patients without reperfusion. Further evidence to support the importance of residual stenosis has been shown in a study by O'Neill et al. (49). Patients undergoing successful coronary angioplasty within 12 hours of the onset of acute myocardial infarction had greater improvement in ventricular function than did those treated with thrombolysis alone. The residual stenosis after angioplasty (43%) was significantly less than that in patients receiving streptokinase (83%). Modalities that protect ischemic myocardium. Finally, there is interest in attempting to increase the amount of salvageable myocardium by modalities that protect the ischemic myocardium. Drugs such as calcium antagonists or beta-blockers may delay the point beyond which irreversible myocardial damage occurs. The second phase of the Thrombolysis in Myocardial Infarction Trial (TIMI II) will study the possible benefits of metoprolol, given to a subset of patients, on the 1 year mortality rate and left ventricular function. The role of thrombolytic therapy in acute myocardial infarction, therefore, depends on early initiation of therapy, achievement of complete reperfusion with minimal residual stenosis and, perhaps, the ability to protect the ischemic myocardium.

MortalIty (%) Hours

Streptokinase

Control

p

9.2

12.0 14.1 14.1 13.6 13

00005 0.03 NS NS 0.0002

<3 3t06 6 to 9 9 to 12 Total (0 to 12) NS = not SIgnificant.

11.7 12.6 15.8 10.7

Sudden Death In many cases of sudden death, the cause can be attributed to a rapidly progressive atherosclerotic plaque that undergoes disruption with thrombus formation. Patients dying soon after the onset of unstable angina are found to have a ruptured plaque and evidence of mural thrombosis with or

74B

HlEMDAHL-MONSEN ET AL ANTITHROMBOTIC THERAPY IN ACUTE CORONARY SYNDROMES

without microemboli or microinfarcts, or both, distal to the thrombosis (21,22). The reduction in sudden death previously discussed in patients receiving antithrombotic therapy for unstable angina is evidence for its potential use. In trials using anticoagulants for secondary prevention after myocardial infarction, as mentioned previously, sudden death occurring soon after infarction is more likely related to myocardial dysfunction. Therefore, these trials lack the necessary specificity to show beneficial result.

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