13 Fibrinolytic therapy in coronary artery disease J O H N B. GILL D A V I D MASSEL J O H N CAIRNS
RATIONALE OF THROMBOLYTIC THERAPY
The current use of thrombolytic therapy in acute myocardial infarction has occurred for three reasons. The first was the demonstration that coronary thrombi play an important role in acute, evolving myocardial infarction (DeWood et al, 1980). Second was the recognition of the importance of the extent of myocardial infarction (Sobel et al, 1972), and third the expectation developed that one might favourably alter a patient's prognosis by limiting infarct size (Rude et al, 1981). In experimental animals the extent of myocardial damage is directly proportional to the duration of coronary artery occlusion (Bergman et al, 1982). The modern era of thrombolytic therapy was ushered in when it was demonstrated that coronary thrombi could be lysed by various thrombolytic agents restoring perfusion to jeopardized myocardium (Rentrop et al, 1979). There is now an overwhelming body of evidence that thrombolytic therapy can lyse occlusive coronary thrombi, improve left ventricular function and reduce short and long-term mortality. As a result, thrombolytic agents are now indicated for most patients early in the course of acute myocardial infarction.
HISTORY OF THROMBOLYTIC THERAPY
In 1912, Herrick put forth the concept that coronary thrombosis was responsible for acute myocardial infarction (Herrick, 1912). In 1958, Fletcher and co-workers first attempted fibrinolytic therapy in acute myocardial infarction by the intravenous administration of streptokinase (Fletcher et al, 1957, 1958). Two years later Boucek and Murphy (1960) reported a small study of intracoronary streptokinase in patients with suspected acute myocardial infarction. Over the next 25 years, 24 randomized studies of intravenous thrombolytic therapy were conducted with mortality as an endpoint (Yusuf et al, 1985a). Treatment protocols varied widely, with long delays from the onset of acute myocardial infarction to treatment in some studies and the Bailli~re's Clinical Haematology-Vol. 3, No. 3, July 1990 ISBN 0-7020-1474-5
745 Copyright O 1990, by Bailli~re Tindall All rights of reproduction in any form reserved
746
J . B . GILL ET AL
results were largely inconclusive. However, five trials (European Working Party, 1971; Breddin et al, 1973; Brochier et al, 1975; Benda et al, 1977; European Co-operative Study Group, 1979) did show a statistically significant reduction in mortality, and several more showed trends favouring therapy (Lippschutz et al, 1965; Gormsan et al, 1973; Aber et al, 1976). Nevertheless, the enthusiasm for the use of thrombolytic therapy declined and there developed an increasing controversy as to the role of coronary thrombi in acute myocardial infarction (Ehrlich and Shinohara, 1964; Chandler et al, 1974). The current era of thrombolysis began when DeWood and colleagues demonstrated that 87% of patients with transmural myocardial infarction had an occluded coronary artery within the first 4 h, and that thrombus could be retrieved by Fogarty catheter in 88% of such patients (DeWood et al, 1980) (Figure 1). The renewed interest in thrombolytic therapy was initially directed at the intracoronary administration of streptokinase (Rentrop et al, 1979), with the hope that local administration would result in patency in a large percentage of patients without a marked systemic lytic state. Rentrop et al (1981) demonstrated that patients with acute myocardial infarction tolerate intracoronary administration of streptokinase and that acute coronary occlusions which had occurred less than 4 h before treatment could readily be lysed in about 80% of cases, resulting in restoration of coronary flow. Controversies surrounding the benefits of reperfusion were considerably resolved by the results of the Western Washington trial (Kennedy et al, 1983). This trial, with mortality as an endpoint, randomized 250 patients to I00
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4-6 6-12 Time interval (h)
No. of patients studied at each interval
12-24
after onset of symptoms Figure 1. Frequency of total occlusion in patient groups evaluated during discrete time intervals over 24 h after onset of symptoms. There is a significant decrease in total occlusion in both the 6-12-h group and the 12-24-h group as compared with the group studied 0-4-h after the onset of symptoms. *, P < 0 . 0 5 ; **, P < 0 . 0 1 . Modified from DeWood et al (1980).
FIBRINOLYTICS IN CORONARY ARTERY DISEASE
747
intracoronary streptokinase or conventional therapy following coronary angiography performed at a mean of 4.5 h after the onset of acute myocardial infarction. Thirty-day mortality was 3.7% in the streptokinase group and 11.2% in the control group (P~4 h
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30 40 50 60 70 80 t (time grade 2 or 3 first observed, rain)
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Figure 2. The proportion of successfully reperfused (grade 2, 3) infarct related arteries reperfused at time t (ordinate) versus time t in minutes at which grade 2, 3 reperfusion was first observed (abscissa) for rt-PA and SK groups at seven time intervals of angiographic observation up to 90 rain after the start of thrombolytic therapy. (a) Patients with baseline grade 0 (93 rt-PA and 103 SK-treated patients) and baseline grade 0, 1 (113 rt-PA and 119 SK-treated patients) perfusion. The reocclusion of four arteries in the rt-PA group and two in the SK group within 90 rain is not tabulated in this comparison. At each time interval, rt-PA reperfused at least twice as many arteries as SK. (b) Patients with baseline grade 0, 1 perfusion who were treated less than 4 h (41 rt-PA and 41 SK-treated patients) and 4 h or more (72 rt-PA and 78 SK-treated patients) from the onset of symptoms of myocardial infarction, Modified from Cheseboro et al (1987).
756
J . B . GILL ET AL
rt-PA patients had a patent infarct related artery as did streptokinase patients (42 versus 21% respectively, P
RATIONALE OF THROMBOLYTIC THERAPY
The current use of thrombolytic therapy in acute myocardial infarction has occurred for three reasons. The first was the demonstration that coronary thrombi play an important role in acute, evolving myocardial infarction (DeWood et al, 1980). Second was the recognition of the importance of the extent of myocardial infarction (Sobel et al, 1972), and third the expectation developed that one might favourably alter a patient's prognosis by limiting infarct size (Rude et al, 1981). In experimental animals the extent of myocardial damage is directly proportional to the duration of coronary artery occlusion (Bergman et al, 1982). The modern era of thrombolytic therapy was ushered in when it was demonstrated that coronary thrombi could be lysed by various thrombolytic agents restoring perfusion to jeopardized myocardium (Rentrop et al, 1979). There is now an overwhelming body of evidence that thrombolytic therapy can lyse occlusive coronary thrombi, improve left ventricular function and reduce short and long-term mortality. As a result, thrombolytic agents are now indicated for most patients early in the course of acute myocardial infarction.
HISTORY OF THROMBOLYTIC THERAPY
In 1912, Herrick put forth the concept that coronary thrombosis was responsible for acute myocardial infarction (Herrick, 1912). In 1958, Fletcher and co-workers first attempted fibrinolytic therapy in acute myocardial infarction by the intravenous administration of streptokinase (Fletcher et al, 1957, 1958). Two years later Boucek and Murphy (1960) reported a small study of intracoronary streptokinase in patients with suspected acute myocardial infarction. Over the next 25 years, 24 randomized studies of intravenous thrombolytic therapy were conducted with mortality as an endpoint (Yusuf et al, 1985a). Treatment protocols varied widely, with long delays from the onset of acute myocardial infarction to treatment in some studies and the Bailli~re's Clinical Haematology-Vol. 3, No. 3, July 1990 ISBN 0-7020-1474-5
745 Copyright O 1990, by Bailli~re Tindall All rights of reproduction in any form reserved
746
J . B . GILL ET AL
results were largely inconclusive. However, five trials (European Working Party, 1971; Breddin et al, 1973; Brochier et al, 1975; Benda et al, 1977; European Co-operative Study Group, 1979) did show a statistically significant reduction in mortality, and several more showed trends favouring therapy (Lippschutz et al, 1965; Gormsan et al, 1973; Aber et al, 1976). Nevertheless, the enthusiasm for the use of thrombolytic therapy declined and there developed an increasing controversy as to the role of coronary thrombi in acute myocardial infarction (Ehrlich and Shinohara, 1964; Chandler et al, 1974). The current era of thrombolysis began when DeWood and colleagues demonstrated that 87% of patients with transmural myocardial infarction had an occluded coronary artery within the first 4 h, and that thrombus could be retrieved by Fogarty catheter in 88% of such patients (DeWood et al, 1980) (Figure 1). The renewed interest in thrombolytic therapy was initially directed at the intracoronary administration of streptokinase (Rentrop et al, 1979), with the hope that local administration would result in patency in a large percentage of patients without a marked systemic lytic state. Rentrop et al (1981) demonstrated that patients with acute myocardial infarction tolerate intracoronary administration of streptokinase and that acute coronary occlusions which had occurred less than 4 h before treatment could readily be lysed in about 80% of cases, resulting in restoration of coronary flow. Controversies surrounding the benefits of reperfusion were considerably resolved by the results of the Western Washington trial (Kennedy et al, 1983). This trial, with mortality as an endpoint, randomized 250 patients to I00
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. . . . . . . . . . . . . . . . . . . . . . . . . . .
4-6 6-12 Time interval (h)
No. of patients studied at each interval
12-24
after onset of symptoms Figure 1. Frequency of total occlusion in patient groups evaluated during discrete time intervals over 24 h after onset of symptoms. There is a significant decrease in total occlusion in both the 6-12-h group and the 12-24-h group as compared with the group studied 0-4-h after the onset of symptoms. *, P < 0 . 0 5 ; **, P < 0 . 0 1 . Modified from DeWood et al (1980).
FIBRINOLYTICS IN CORONARY ARTERY DISEASE
747
intracoronary streptokinase or conventional therapy following coronary angiography performed at a mean of 4.5 h after the onset of acute myocardial infarction. Thirty-day mortality was 3.7% in the streptokinase group and 11.2% in the control group (P~4 h
E
605040-
20 10 0
(b)
"
0
I0
20
30 40 50 60 70 80 t (time grade 2 or 3 first observed, rain)
90
Figure 2. The proportion of successfully reperfused (grade 2, 3) infarct related arteries reperfused at time t (ordinate) versus time t in minutes at which grade 2, 3 reperfusion was first observed (abscissa) for rt-PA and SK groups at seven time intervals of angiographic observation up to 90 rain after the start of thrombolytic therapy. (a) Patients with baseline grade 0 (93 rt-PA and 103 SK-treated patients) and baseline grade 0, 1 (113 rt-PA and 119 SK-treated patients) perfusion. The reocclusion of four arteries in the rt-PA group and two in the SK group within 90 rain is not tabulated in this comparison. At each time interval, rt-PA reperfused at least twice as many arteries as SK. (b) Patients with baseline grade 0, 1 perfusion who were treated less than 4 h (41 rt-PA and 41 SK-treated patients) and 4 h or more (72 rt-PA and 78 SK-treated patients) from the onset of symptoms of myocardial infarction, Modified from Cheseboro et al (1987).
756
J . B . GILL ET AL
rt-PA patients had a patent infarct related artery as did streptokinase patients (42 versus 21% respectively, P
