REVIEW ARTICLE

Drugs 44 (3): 293-325, 1992 0012-6667/92/ 0009-0293/$16.50/0 © Adis International Limited. All rights reserved. DRUl187

Thrombolytic Therapy for Acute Myocardial Infarction

A Review

Christopher B, Granger, Robert M. Califf and Eric 1. Topol Duke University Medical Center, Durham , North Carolina, and The Cleveland Clinic Foundation, Cleveland, Ohio, USA

Contents 293 294 294 295 295 297 297 298 298 298 298 299 299 303 308

3/2 312 315 3/5 3/5 316 317 3/9

Summary

Summary I. Rationale for Use of Thrombolytics in Acute Myocardial Infarction 2. Mechanism of Action 3. Specific Thrombolytic Agents 3.1 Streptokinase 3.2 Urokinase 3.3 Tissue Plasminogen Activator 3.4 Anistreplase 3.5 Saruplase (Single-Chain Urokinase Plasminogen Activator; Scu-PA; Prourokinase) 3.6 BM-06022 (Recombinant Plasminogen Activator; rPA) 4. Other New Thrombolytic Agents 5. Clinical Trial Results 5.1 Mortality 5.2 Patency 5.3 Reocclusion and Reinfarction 5.4 Treatment of Reinfarction 5.5 Left Ventricular Function 5.6 Infarct Size 5.7 Composite Clinical End-Point 6. Tolerability, Complications and Contraindications 7. Stroke 8. Future and Ongoing Trials 9. Conclusions

In the past 10 years, thrombolytics have become standard therapy for acute myocardial infarction. Although the ability of streptokinase to lyse clot was first recognised in the 1930s, thrombolytic therapy was not used to treat acute myocardial infarction until the early 1980s, when the importance of thrombosis in the pathogenesis of acute infarction was fully recognised. In addition to streptokinase and urokinase, recombinant human tissue plasminogen activator (tPA) and anistreplase were developed and widely used in the 1980s. Saruplase (prourokinase) and BM-06022 (recombinant plasminogen activator) have also undergone human clinical studies. All of these agents are effective at achieving clot lysis and coronary patency. Large, randomised clinical trials have demonstrated that thrombolytic therapy reduces mortality in patients with ST

Drugs 44 (3) 1992

294

elevation treated within the first 6 to 12 hours of acute infarction, with an approximately 0.5% risk of intracranial haemorrhage. Recent data have more clearly identified which patients benefit from thrombolytic therapy. Efforts have been made to improve the speed of reperfusion, decrease reocclusion, simplify administration and reduce adverse effects. The characteristics of fibrin specificity and more rapid clot lysis with tissue plasminogen activator have not yet been translated into overall clinical benefit compared with the less expensive streptokinase. The lack of close association of improved early patency and improved global left ventricular function with improved survival challenges the very paradigm which led to the use of thrombolytic therapy for acute myocardial infarction. The need for development of additional methods for evaluation of new thrombolytic agents is evident.

The advent of thrombolytic therapy for treatment of acute myocardial infarction in the early 1980s has been followed by an era of extensive investigation leading to widespread clinical acceptance and a profound improvement in patient outcome. Based on the results of small studies documenting the specific effects of thrombolytic therapy, several groups, most notably the GISSI (1986, 1987, 1990) and ISIS (1988, 1992) investigators, proved the clinical benefits ofthrombolytic therapy in landmark trials enrolling tens of thousands of patients and efficiently collecting the most important end-points. This paper will describe the characteristics of thrombolytic agents, review the clinical studies, and discuss the implications for further investigation.

1. Rationale for Use of Thrombolytics in Acute Myocardial Infarction Although pathological studies, beginning with Herrick's description in 1912 (Herrick 1912), have demonstrated the importance of thrombosis in the pathogenesis of acute myocardial infarction, it was the angiographic studies in the early 1980s (DeWood et al. 1980) which convincingly dem,onstrated total coronary obstruction early in tl)e course of myocardial infarction in a large percentage of patients. Angiographic studies also demonstrated the ability of thrombolytic agents to suc~ cessfully achieve reperfusion in occluded coronary, arteries (Rentrop et al. 1979). The rationale for re~ perfusion therapy was based on the demonstratiQ~, in animal studies that early reperfusion of an artery

after a transient period of occlusion led to a smaller infarct size· than that obtained with a permanently occluded artery (Braunwald 1987). Animal experiments also provided important evidence that after coronary occlusion there is a 'wavefront of ischaemic cell death' which progresses over time from the subendocardium toward the epicardium (Reimer et al. 1977). The time frame for this process in models thought to represent the human situation was quite short, in the range of 3 to 4 hours. Thus, these studies provided the. basis for the rationale that recanalisation and reperfusion early in the course of myocardial infarction would limit myocardial necrosis, improve left ventricular function, and improve patient outcome.

2. Mechanism of Action Overall, thrombolytic agents act by converting the proenzyme plasminogen to the active enzyme plasmin, which lyses the fibrin clot (Sharma et al. 1982) [fig. 1]. Plasminogen is a single-chain glycoprotein, which in its native form has hn amino terminal glutamic acid ('glu-plasminogeb') but is easily converted to modified forms, called 'lysplasminogen'. Plasminogen is converted to plasmin by cleavage of the Arg-Val (resi~ues 560-561) peptide bond (Robbins et al. 1967). Plasmin, the active 2-chain polypeptide, is a nonspecific serine protease which is capable of breaking down fibrin as well as fibrinogen, and factors V and VIII. The plasmin(ogen) molecule has lysine binding sites, particularly in the homologous triple-loop structures ('kringle regions'), which bind to and degrade

295

Thrombolysis in AMI

Fibrin-specific

Non-fibrin-specific

SK + Plasminogen t-PA rPA Bat-PA Fibrin

Fig. 1. Non-fibrin- and fibrin-specific thrombolytic agents: effect on the conversion of plasminogen to plasmin. Abbreviations: SK = streptokinase; UK = urokinase; APSAC = anistreplase; t-PA = alteplase; rPA = BM-06022; scu-PA saruplase; Bat-PA = vampire bat plasminogen activator.

fibrin. In the circulation, however, its action is rapidly neutralised by circulating plasmin inhibitors (MacFarlane & Pilling 1947), primarily by the effects of c¥2-antiplasmin, which attaches at the lysine binding site to form a I : I complex with freely circulating plasmin (Wiman & Collen 1977). Thrombolytic agents are plasminogen activators which possess as a common characteristic the ability to activate plasminogen to plasmin, and result in fibrinolysis and varying degrees of depletion of circulating fibrinogen, factor V and factor VIII. In addition to the fibrinolysis itself, several other potential mechanisms of action have been proposed. Platelet function has been shown to be altered, as a result of a combination of direct effects of the thrombolytic agent, plasmin activity (Niewiarowski et aI. 1973), thrombin activity (Winters et aI. 1991), or due to the resulting fibrin degradation products (Stachurska et aI. 1970; Wilson et aI. 1968). Platelet activity after thrombolytic therapy has variably been shown to be enhanced (Fitzgerald et aI. 1988; Kerins et al. 1989; Vaughan et al.

=

1991) or inhibited (Bonnier et aI. 1991). Changes in blood viscosity (Bonnier et al. 1991; SchmidSchonbein et aI. 1978), prostaglandin and bradykinin levels, and haemodynamics (Lew et al. 1985a) may each play a role in the clinical effects of thrombolytic therapy.

3. Specific Thrombolytic Agents Table I outlines the major features of the thrombolytic agents currently in use. 3.1 Streptokinase In 1933, Tillet and Garner first described thrombolytic activity of streptokinase when they discovered that a filtrate of /3-haemolytic strains of Streptococcus could dissolve a human clot. Streptokinase is a nonenzyme protein which indirectly activates the fibrinolytic system by forming a 1 : 1 stoichiometric complex with plasminogen. This streptokinase-plasminogen activator complex then

296

Drugs 44 (3) 1992

Table I. Characteristics of thrombolytic agents Streptokinase

Urokinase

Alteplase

Anistreplase

Saruplase

BM-06022

streptococci

recombinant, human fetal kidney

recombinant, human

gp C streptococci plasminogen, anisoylated

recombinant, human

recombinant, human mutant

Mol. weight (kD) Fibrin specificity Metabolism Half-life (min) Mode of action Antigenicity Blood viscosity

47 No Hepatic 18-23 Activator complex Yes

35-55 No Hepatic 14-20 Direct No

63-70 Yes Hepatic 3-4 Direct

131 No Hepatic 70-120

47 Yes

39 Yes Renal 14 Direct

Decreased

Unknown

No No change

Estimated hospital cost per dose ($US)

$300/1.5mU

$2000/3mU

$2200/100mg

Source: gp C

converts noncomplexed plasminogen to plasmin (Davies et al. 1964). In addition to the activation of plasminogen, streptokinase has other effects, largely related to the antigenicity of the Streptococcus-derived molecule. Almost everyone has some level of circulating antibodies to streptokinase (Vaughan et al. 1991). Mild allergic reactions were reported in 4.4% of 8592 patients treated with streptokinase in the ISIS-2 trial (1988), versus 0.9% of controls. The ISIS-2 investigators found no reduction in reported allergic reactions in the 22% of patients receiving prophylactic steroids. Thus, the current recommendation is not to use prophylactic steroids in an effort to prevent allergic reactions. The incidence of true anaphylactic shock is very low «0.5%), with no confirmed cases in ISIS-2. Antibody development after treatment with either streptokinase or anistreplase (anisoylated plasminogen streptokinase activator complex; APSAC) has lead to the recommendation that retreatment with streptokinase or anistreplase be avoided for at least 6 to 12 months, and perhaps even indefinitely (White et al. 1990). After treatment with streptokinase, antibody activity measured either as IgG levels (Hoffman et al. 1988; Lynch et al. 1991) or by a functional in vitro assay assessing neutralisation of

Decreased

6-8 Direct No Unknown

$1800/30U

Not determined

Direct Yes

No Unknown Not determined

streptokinase activity (Jalihal & Morris 1990), remain elevated for at least 1 year, and in approximately half of patients for at least 4 years (Elliott et al. 1991). Whether the presence of these antibodies affects thrombolytic efficacy or safety following readministration of streptokinase is uncertain. In patients with high levels of circulating antibodies, administration of streptokinase has been shown to activate platelets (Vaughan et al. 1991). Hypotension as a result of thrombolytic administration is best described for streptokinase. With this agent, patients experience a decrease in systolic blood pressure of 35mm Hg on average (Lew et al. 1985a). Hypotension requiring vasopressor support has been reported in approximately 7 to 10% of patients treated with streptokinase (ISIS-2 1988; Lew et al. 1985a). Importantly, in the ISIS2 study, significant hypotension resulting from streptokinase administration was no more common in patients who presented with systolic blood pressure below 100mm Hg. Similarly, in spite of the possibility that patients in shock might have further haemodynamic compromise because of the hypotensive effect of streptokinase, the GISSI-2 investigators reported no worse outcome with streptokinase compared with alteplase for patients presenting with Killip class IV (pulmonary oedema

297

Thrombolysis in AMI

with hypoperfusion, or cardiogenic shock) [inpatient mortality 78.1% for alteplase vs 64.9% for streptokinase] (GISSI-2 1990). Among patients randomised to thrombolytic therapy versus control in ISIS-3 (1992), hypotension requiring drugs was significantly more common with any of the 3 agents (streptokinase, 5.8%; anistreplase, 5.9%; alteplase, 2.8%) than open control (1 %), suggesting that the hypotensive effect likely occurs with any thrombolytic agent, albeit more common with streptokinase and anistreplase. This effect is likely the result of kallikrein activation and the release of bradykinin (Lew et al. 1985a). More rapid administration of streptokinase is associated with a greater hypotensive effect, which is generally responsive to volume administration and to slowing the rate of administration (Lew et al. 1985a). Streptokinase is not specific for fibrin-bound clot, and therefore results in systemic conversion of plasminogen to plasmin, with resultant depletion of circulating fibrinogen, plasminogen, and factors V and VIII. Typically, circulating fibrinogen is reduced to less than 20% of pretreatment level after an intravenous dose of 1.5 million units (U) of streptokinase (Topol 1991). The conventional 1.5 million U dose over 60 minutes for intravenous administration of streptokinase has been derived empirically by Schroeder and colleagues (1983). Although definitive dosefinding study data are lacking, significantly lower doses or slower administration may be less effective (Gottlich et al. 1988; Lew et al. 1985b; Six et al. 1990). 3.2 Urokinase Urokinase is'a 2-chain serine protease which directly activates plasminogen without forming an activator complex and, like streptokinase, is not specific for fibrin-bound clot. First isolated from human urine in 1947 (MacFarlane & Pilling 1947), urokinase has generally been synthesised from human fetal kidney tissue culture (Bernick & Kwaan 1967), and is therefore not antigenic and lacks the problems of neutralisation due to antibodies. Allergic reactions

and hypotension are also not routinely encountered. The standard intravenous dose of 3 million U (Neuhaus et al. 1988; Wall et al. 1990a) was derived empirically. 3.3 Tissue Plasminogen Activator Native tissue plasminogen activator is a singlechain serine protease normally secreted by vascular endothelium (Loscalzo & Braunwald 1988). At first the material was only available in small quantities from a Bowes melanoma cell culture (Collen 1985). In 1983, Pennica and colleagues reported the cloning and expression of human tissue plasminogen activator. Although a 2-chain preparation was studied initially, the current clinically available agent, alteplase, is single-chain. There appears to be no significant difference in the activity of singleversus double-chain tissue plasminogen activator in vitro in the presence of fibrin (Rijken et al. 1982). It became apparent that the single-chain form was cleared 40% more rapidly, thus explaining the higher dose needed to achieve the same level of activity (Mueller et al. 1987). Duteplase is II nearly pure double-chain preparation of tissue plasminogen activator. During its development, the property of alteplase which was felt to be the most important difference between it and streptokinase or urokinase was the relative fibrin specificity; that is, fibrin strikingly increases the rate of conversion of plasminogen to plasmin by tissue plasminogen activator (Hoylaerts et al. 1982). The increased activity of tissue plasminogen activator in the presence of fibrin appears to be the result of a conformational change in tissue plasminogen activator (Loscalzo & Braunwald 1988), resulting from binding to fibrin, which causes a greatly increased affinity for plasminogen at the clot surface. In vivo, however, alteplase demonstrates only relative clotspecificity (Collen et al. 1986). Typically, after a 100mg dose of alteplase, circulating fibrinogen decreases to 30 to 40% of the baseline value (Topol 1991), and the amount of decrease in fibrinogen is inversely proportional to bodyweight (Topol et al. 1988). Race is also a factor, with greater fibrinogen

298

sparing in Whites compared with Blacks (Sane et al. 1991). Several circulating plasma factors inhibit the action of aIteplase on plasminogen, including cQ-plasmin inhibitor, plasminogen activator inhibitor-I (PAl-I) and -2 (PAI-2), which function to mediate the activity of naturally occurring tissue plasminogen activator. The clinical significance of these natural plasmin inhibitors is not known (Sane et al. 1991). A variety of dosage schemes have been used for alteplase, but the standard schedule has been 100mg given over 3 hours. Studies have demonstrated that higher doses and faster administration are associated with higher patency rates (Topol 1990), and higher and more prolonged doses with greater depletion of circulating fibrinogen and greater risk of bleeding (Bovill et al. 1991; Smalling et al. 1990). In response to the observation of increased bleeding complications in lower weight patients receiving a fixed dose (Bovill et al. 1991; Califf et al. 1988; GISSI-2 1990), weight-adjustment of alteplase dosage has been recommended. Thus, most studies with aIteplase support the use of a weightadjusted, rapid (90-min) infusion. 3.4 Anistreplase Anisoylated plasminogen streptokinase activator complex (APSAC) or anistreplase is a 'secondgeneration' agent consisting of streptokinase bound to Iys-plasminogen to form an activator complex, and therefore a direct plasminogen activator. The anisoylation both renders the activator inactive and protects it from plasmin inhibitors, resulting in a long half-life of nearly 100 minutes, allowing the agent to be administered as a single bolus over 5 minutes. Once in the circulation, the agent becomes active following deacylation. Although in vitro there is evidence of fibrin specificity, there is no evidence of this in vivo, with 60 to 80% depletion of circulating fibrinogen after a 30U dose. Because of the streptokinase moiety, anistreplase possesses the same antigenicity characteristics and problems as streptokinase. In the ISIS-3 study (1992), profound hypotension requiring vasopressor support was found in a similar propor-

Drugs 44 (3) 1992

tion of patients treated with either anistreplase (7.0%) or streptokinase (6.7%). 3.5 Saruplase (Single-Chain Urokinase Plasminogen Activator; Scu-PA; Prourokinase) Single-chain urokinase plasminogen activator is a short-lived, single-chain precursor of urokinase, which exhibits relative fibrin specificity, perhaps because a component in plasma competes with plasminogen for binding of this factor, a process which is inhibited by fibrin (Lijnen et al. 1986). Single-chain urokinase plasminogen activator has been tested as either a glycosylated form, or as the recombinant unglycosylated form saruplase. The PRIMI investigators (1989) demonstrated infarct vessel patency rates of approximately 70% 60 and 90 minutes after giving saruplase. 3.6 BM-06022 (Recombinant Plasminogen Activator; rPA) BM-06022 (recombinant plasminogen activator; rPA) is a novel agent which is a deletion mutant derived from tissue plasminogen activator, produced in E. coli using cDNA from a human melanoma cell line, similar to that used for production of commercially available alteplase. Compared with alteplase, BM-06022 has more potent fibrinolytic activity in animal models, similar fibrin specificity, and a longer half-life (Martin et al. 1991). In healthy human volunteers, no evidence of antibody formation to BM-06022 was found for up to 6 months after administration. In the initial clinical trial, GRECO (Neuhaus et al. 1991), a single bolus of BM-06022 10 to 15U led to 65 to 75% patency at 30 minutes in over 100 patients. This very rapid recanalisation rate is currently being further assessed in US and German muIticentre trials with single or double bolus therapy.

4. Other New Thrombolytic Agents A considerable amount of investigation has been and is being dedicated toward the further refinement of new thrombolytic agents in attempts to

Thrombolysis in AMI

improve efficacy, reduce risk, and provide for easier administration. Areas of investigation include the development of new synergistic combinations, hybrids, mutants, antibody-conjugated molecules, and nonhuman plasminogen activators (Bang 1991; Collen 1992). Because different thrombolytic agents may activate plasminogen or achieve fibrin specificity in .different ways, the combination of agents may provide additive or synergistic effects, while at the same time limiting dose-dependent bleeding complications (Ott & Fenster 1991). The combination of low dose alteplase and saruplase has been shown to be effective in clot lysis with limited effects on circulating fibrinogen in animals (Ziskind et a!. 1989) and in early human studies (Collen 1992; Kirshenbaum et a!. 1991). Chimeric or hybrid agents likewise may combine advantageous characteristics of different activators. Mutant tissue plasminogen activators, such as BM-06022 discussed above, have altered characteristics such as prolonged half-lives, which may provide an advantage with respect to potential for bolus administration, possibly resulting in less reocclusion. Recombinant vampire bat salivary plasminogen activator (Bat-PA) is another exciting new development. This potent, highly fibrin-specific plasminogen activator has been isolated from the salivary glands of the vampire bat Desmodus rotundus. The most unusual characteristic ofthis activator is the strong requirement offibrin as a cofactor, leading to much greater fibrin-specificity than other plasminogen activators (Gardell et a!. 1991), while at the same time demonstrating increased potency. Whether these theoretical advantages will translate into clinical benefits will be a subject of great interest in upcoming investigation.

5. Clinical Trial Results The rationale for thrombolytic therapy was based on sound pathophysiological theory, and basic and animal model investigation. However, particularly in light of recent experience that such reasoning may lead to poor clinical decision mak-

299

ing, as in the use of antiarrhythmic agents to treat ventricular ectopy after myocardial infarction (Echt et al. 1991), the need has become clear for clinical trials which examine clinically meaningful endpoints in evaluating new therapies. Trials evaluating thrombolytic therapy have used a variety of end-points, each with its own limitation. 5.1 Mortality Although mortality is commonly considered to be the most meaningful end-point and is highly objective, measuring mortality alone fails to take into account additional important outcome measures such as stroke with disability and overall quality of life. The effect of a treatment on mortality may be dependent on the time that mortality is measured. The use of early mortality as an end-point reflects the early risk of the therapy and may miss a longer term beneficial effect. In fact, thrombolytic therapy is known .to increase mortality in the first day after treatment (GISSI-l 1986; ISIS-2 1988), and therefore an end-point of very early (24 hour) mortality would lead to the conclusion that thrombolytic therapy is harmful. For this reason, measurement of both short and long term mortality is important. Survival benefit after thrombolytic therapy appears to be maximised 3 to 5 weeks after treatment, and persists over the next year (AIMS Trial Study Group 1990; GISSI-l 1987). Testing for relatively small differences in mortality between each new activator or variation on an old treatment is prohibited by the requirement for vast resources. For example, over 20 000 randomised patients would be needed in a study with sufficient power to detect a reduction in mortality from 8% to 7%. The need to develop alternative end-points for accurate clinical assessment of thrombolytic efficacy is therefore clear. The first large scale trial examining the effect of thrombolytic therapy on mortality was performed by the Gruppo Italiano per 10 Studio della Streptochinasi nell'Infarto Miocardico (GISSI-l 1986). The GISSI investigators randomised 11 806 patients who presented within 12 hours of symptom onset with ECG evidence of acute infarction

Drugs 44 (3) 1992

300

to streptokinase (1.5 million U over 60 minutes) or conventional care. This landmark trial was the first to show a definitive reduction in inpatient mortality with thrombolytic therapy, from 13.0 to 10.7%, with an almost 50% reduction in mortality for those patients treated within 1 hour of symptoms. This 2.3% absolute reduction in early mortality persisted to 1 year, at which time the mortality rate was 17.2% in the streptokinase-treated group, versus 19% in the control group (GISSI-1 1987). The second International Study of Infarct Survival (ISIS-2) investigators took a further step in extending the size and simplicity of thrombolytic trials. They randomised in a 2 x 2 factorial design 17 187 patients with suspected acute myocardial infarction and symptoms for less than 24 hours to streptokinase alone (1.5 million U over 60 minutes), aspirin alone (162.5mg), both, or neither. In contrast to GISSI, no ECG criteria were required, and indeed only 54% of patients had significant ST segment elevation. Five-week vascular mortality results confirmed the GISSI results, demonstrating a difference of 12.0% with placebo versus 9.2% with streptokinase in untreated patients (a 25% lower rate), and also revealing a similar 23% lower risk of death with aspirin, and an even more impressive additive effect (42%) of streptokinase plus aspirin (fig. 2). Similar to the GISSI results, those patients treated earlier with thrombolytic therapy had greater benefit, although the benefit from aspirin was similar regardless of time since symptom onset. The effect of alteplase on survival was tested in the Anglo-Scandinavian Study of Early Thrombolysis (ASSET) [Wilcox et al. 1988], in which 5011 patients with suspected myocardial infarction and symptom duration of up to 5 hours were randomised to alteplase (lOOmg over 3 hours) or placebo, both with intravenous heparin for 24 hours. The protocol did not call for aspirin administration. Patients over the age of 75 years were excluded, and there were no ECG entrance requirements. At 1 month, overall mortality was 26% lower in the alteplase group (7.2% vs 9.8% in the placebo group). The APSAC Intervention Mortality Study

(AIMS 1988) randomised patients aged under 71 years with less than 6 hours of symptoms of acute myocardial infarction and ST elevation to anistreplase 30mg or placebo. Heparin (followed by warfarin) was given to both groups, and aspirin could be administered according to normal practice. The trial was stopped early, when a substantial beneficial effect of anistreplase was evident on interim analysis of 880 patients. With 1004 patients randomised, anistreplase resulted in a 47% (95% confidence interval 21 to 65%) reduction in 30-day mortality, and unlike the findings in GISSI and ISIS-2, the reduction was similar in those groups given the thrombolytic after 0 to 4 hours and after 4 to 6 hours. As in GISSI, the beneficial effect persisted through at least 1 year of follow-up (AIMS 1990). The pooled patient data from these 5 studies in patients with up to 6 hours of symptoms are shown

500

U)

.s::::

1ii

400

CD

'0

~

::; u

U)

ro

>

300

'0

Streptokinase and aspirin:

Q;

343/4292 (8%)

.0

E ::>

c:

200

CD

>

:;

::; E ::>

u

100

04-----~--~----~----~----r

o

7

14

21

28

35

Days from randomisation

Fig. 2. Cumulative early vascular mortality in the ISIS-2 trial: aspirin results in nearly the same benefit as streptokinase, and the effects of aspirin and streptokinase are additive (reproduced from ISIS-2 with permission from R. Collins).

301

Thrombolysis in AMI

Agent Streptokinase

Trial name GISSI ISAM

Deaths/patients active control 495/4865

623/4878

50/842

61/868

ISIS-2

471/5350

648/5360

Anistreplase

AIMS

32/502

61/502

Alteplase

ASSET

182/2516

245/2495

Overall: any fibrinolytic

.•

Odds ratio (& 95% CI)

-I

•

I I I I I I

Odds reduction

(± SO) 23% ± 6 16% ± 18 30% ± 5 50% ± 16 28% ± 9

I I



1230/14075 1638/14103 0.0

27% ± 3

2.0 1.0 1.5 0.5 Fibrinolytic worse Fibrinolytic better

Fig. 3. Reductions in the odds of early death among patients treated within 6 hours: overview of currently available data from the 5 largest randomised controlled trials of thrombolytic versus control (reproduced from the ISIS-3 protocol with permission from R. Collins).

in figure 3, and demonstrate a consistent, marked beneficial effect of thrombolytic therapy on early survival. Analysis of pooled data (Muller & Topol 1990) also showed that this effect is consistent across all major subgroups, including the elderly (Grines & DeMaria 1990; Sherry & Marder 1991a), different myocardial infarction location (Midgett et al. 1990; Muller & Topol 1990), bundle branch block, and those with ST elevation or bundle branch block presenting between 6 and 12 hours after symptom onset. Figure 4 illustrates a diminishing but continued beneficial effect of thromoblytic therapy and aspirin on early survival when treatment was begun after 6 and 12 hours in the ISIS2 study. The ISIS-2 investigators. also demonstrated that the elderly derive cl,ear benefit from thrombolytic therapy, with a greater absolute reduction of mortality of 3.4% (18.2%mortality rate with streptokinase vs 21.6% in controls) in patients over age 70, versus 1.6% (4.2% mortality rate with streptokinase vs 5.8% in controls) in patients aged less than 60 years (p < 0.01). A beneficial effect on mortality has not been demonstrated, however, for patients with ST segment depression or a normal ECG. Patients with contraindications to thrombolytic therapy, including those who present later than 12 to 24 hours after symptom onset, have a higher mortality than

those who qualify for thrombolytic therapy (Cragg et al. 1991). Two trials, GISSI-2 (1990) [with International Study Group 1990] and ISIS-3 (1992), have recently compared the effect of different thrombolytic agents on mortality. Similar in design, these 2 trials randomised a total of over 60 000 patients to streptokinase or alteplase (GISSI-2), and to streptokinase, duteplase or anistreplase (ISIS-3), with both studies having a second randomisation to either no heparin or to subcutaneous heparin 12 500U twice daily. All patients received aspirin, and the primary end-points were inpatient (GISSI2) or 5-week (ISIS-3) mortality. The results revealed no difference in mortality, nor in mortality plus nonfatal stroke among the different thrombolytic agents. The GISSI-2 trial randomised almost 21 000 patients to alteplase 100mg over 3 hours or streptokinase 1.5 million U over 1 hour. Inclusion criteria included symptoms of less than 6 hours duration and ST elevation. A second randomisation assigned patients to either heparin 12500U subcutaneously twice daily, beginning 12 hours after thrombolytic therapy, or to no heparin. No therapeutic monitoring of anticoagulation status with heparin;was reported. All patients without contraindications were given aspirin and ,a-blockers. No significant differences for inpatient mortality

302

Drugs 44 (3) 1992

Hours from pain onset

Vascular deaths/patients (% dead) streptokinase and aspirin

placebo infusion and tablets

0-1 2 3 4 Subtotal: 0-4

11/178 31/476 41/617 36/590 119/1861 (6.4%)

25/179 62/480 84/617 74/590 245/1866 (13.1%)

5-12 13-24 Subtotal: 5-24

179/1823 45/608 224/2431 (9.2%)

25?/1820 71/614 323/2434 (13.3%)

Total: 0-24

343/4292 (8.0%)

568/4300 (13.2%)

Odds ratio & 95% CI placebo streptokinase and aspirin better better

,

---. ! •!

----t-

-----+-

-=i

53% S08

t--:.

F

33% S07

t 0.5

42% S05 odds reduction 1.0

1.5

Fig. 4. Reductions in the odds of early vascular death in the ISIS-2 trial in patients who received streptokinase and aspirin versus placebo: diminished but continued beneficial effect after 6 and 12 hours (reproduced from ISIS-2 with permission from R. Collins).

were found between alteplase and streptokinase (8.9 vs 8.5%) or between subcutaneous heparin and no heparin (8.5 vs 8.9%). These results, which demonstrate that an agent associated with a significantly higher early patency rate (alteplase) may not result in a survival advantage, led to considerable controversy and speculation (White 1990). These data challenged the commonly accepted premise that early patency is a clinically useful means of evaluating and comparing thrombolytic agents. Sherry and Marder (1991) argued that early in the course of acute myocardial infarction, when maximal myocardial salvage may be obtained and the thrombus is fresh, streptokinase and alteplase have similar effects with respect to clot lysis (Chesebro et a1. 1987). Later in the course, when the fibrin is more organised and alteplase is more effective at clot lysis, less myocardial salvage is possible. Another possible explanation for this inconsistency arose from the results of 3 studies which have shown that without heparin, patency after alteplase administration is lower at a mean time of 18 hours (Hsia et al. 1990), 57 hours (Bleich et a1. 1990) and 81 hours (European Cooperative Study Group-6 1990) compared with alteplase plus intravenous heparin (pooled patency rates 67% vs 82%). Thus, heparin appears to be important in the mainten-

ance of infarct vessel patency, and alteplase administered without adequate heparinisation may be associated with a high rate of reocclusion, which would nullifY any early patency advantage. However, even with intravenous heparin, randomised trials have demonstrated that alteplase is associated with a higher rate ofreocclusion [13.5%; 95% confidence interval (CI) 11 to 16%] than the non-fibrin-specific agents streptokinase, urokinase or anistreplase (8%; 95% CI 3 to 10%). It may also be, as the ISIS group has argued, that with adequate aspirin admInistration, intravenous heparin does not playa major role in optimising vessel patency with alteplase. The ISIS-3 investigators, in the largest thrombolytic trial to date, randomised patients with suspected or definite myocardial infarction and definite indications for thrombolytic therapy to streptokinase 1.5 million U over 60 min, duteplase 0.6 million U /kg, or anistreplase 30U bolus, and a second randomisation (3 X 2 factorial) to subcutaneous heparin 12 500U twice daily beginning at 4 hours, or to no heparin. A second group of patients, those with 'uncertain' indications for thrombolytic therapy (as defined by the investigator), were randomised to either thrombolytic or no thrombolytic. As in ISIS-2, patients with suspected or definite myocardial infarction and less

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303

than 24 hours' symptom duration were eligible. Approximately two-thirds of the patients had less than 6 hours of symptoms and ST elevation. Consistent with the results of GISSI-2, ISIS-3 demonstrated no significant mortality differences among the 41 299 patients enrolled according to thrombolytic assignment. The addition of anistreplase, which like alteplase results in a higher earlier patency than streptokinase (see section 5.2), provides further evidence of a dissociation between early patency and survival. Although the form of tissue plasminogen activator used in the 2 trials differed, the singlechain alteplase in GISSI-2 versus the 2-chain preparation duteplase in ISIS-3, the consistency of the results in the 2 trials supports patency data that the 2 agents are similar in activity. There was no significant difference in 35-day mortality between patients assigned aspirin plus subcutaneous heparin versus aspirin alone, either in ISIS-3 (10.3 vs

10.6%) or in GISSI-2 and ISIS-3 combined (10.0 vs 10.2%). As in GISSI-2, more strokes, and more haemorrhagic strokes, occurred in the tissue plasminogen activator and anistreplase groups than the streptokinase group (table II). Assignment to subcutaneous heparin was associated with more presumed intracranial haemorrhages, but with fewer other strokes. Overall, tissue plasminogen activator and anistreplase were associated with a statistically significant higher risk of stroke than streptokinase, and alteplase with a statistically insignificant lower mortality. With regards to which therapy results in the greatest benefit to patients, the rate of death plus nonfatal stroke was similar in the 3 groups, at approximately 11%. If in the future more potent thrombolytic regimens are shown to decrease overall mortality at the expense of increased risk of intracranial haemorrhage, an important task for all physicians using thrombolytic therapy will be to

Table II. Incidence of stroke and intracranial haemorrhage [% (n)] in large randomised trials of intravenous thrombolytic therapy Studies comparing thrombolytic with control Trial Agent All strokes

GISSI·1

SK

ISAM ISIS-2

SK SK

ASSET

t-PA

AIMS

APSAC

Pooled:

95%CI:

Probable ICH8

thrombolytic

control

mortality

thrombolytic

control

mortality

0.84% (49/5860)

0.68% (40/5852)

47% (47/99)

0.71% (61/8592) 1.1% (28/2516) 1.3% (8/624) 0.83% (146/17 592) 0.70-0.96%

0.78% (67/8595) 1.0% (25/2495) 0.63% (4/634) 0.77% (136/17576) 0.64-0.90%

39% (50/128) 32% (17/53) 58% (7/12) 41% (121/292) 36-47%

0.46% (23/5860) 0.47% (4/859) 0.31% (27/8592) 0.28% (7/2516) 0.32% (2/624) 0.34% (63/18451) 0.26-0.43%

0.13% (6/5852) 0% (0/882) 0.15% (13/8595) 0.08% (2/2495) 0.15% (1/634) 0.12% (22/18458) 0.01-0.17%

75% (6/8) 50% (2/4) 86% (6/7) 78% (7/9)

Studies comparing SK with t-PA SK Trial

ISIS-3 GISSI-2 Pooled:

75% (21/28) 59-91%

t-PA

n

stroke

ICH

n

stroke

ICH

13607 10396 24003

1.0% (141) 0.9% (98) 1.0% (239)

0.2% (32) 0.3% (30) 0.3% (62)

13569 10372 23941

1.4% (188) 1.3% (138) 1.4% (326)

0.7% (89) 0.4% (44) 0.6% (133)

a Includes patients with stroke of uncertain type on day 0-1 10 GISSI-l and ISIS-2. Abbrevietions: SK = streptokinase; t-PA = alteplase or duteplase; APSAC = anistreplase; ICH = intracranial haemorrhage.

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Table III. Patency without thrombolytic therapy Study

Baseline Anderson et al. (1984) TIMI-1 (1987) Timmis et al. (1987) 1h Collen et al. (1984) Topol et al. (1987) Cribier et al. (1986)

n

23

Time to treatmenta (min)

Mean cath time b

168

o min o min o min

289 40 Pooled: 352

285

14 25 23 Pooled: 62

284 228 208

186

Heparin

Patency

95%CI

9% (2.23) 20% (57/289) 28% (11/40) 20% (70/352)

45 min 68 min 74 min

Yes Yes Yes

7% 13% 22% 15%

(1/14) (2/23) (5/23) (9/60)

16-24%

6-24%

90 min ECSG-1 (1985) 2-3h

65

198

75-90 min

Yes

21% (13/62)

11-31%

Guerci et al. (1987)

66

192

2.5h

Yes

24% (15/62)

14-35%

56 29 Pooled: 85

180

17h 35h

Yes

29% (7/24)

Low dose

12.5% (3/24) 21% (10/48)

119 71 56 177 366 112 71 55 Pooled: 1027

188 195 180 210 168 180 114 190

1d TPAT (1989) Durand et al. (1987) 3-21d Bassand et al. (1989) NHFA (1988) TPAT (1989) Kennedy et al. (1988) ECSG-4 (1988) White et al. (1987) O'Rourke et al. (1988) Bassand et al. (1987)

149

4.1d 5-7d 10d 10d 10-21 d 21d 21d 21d

Yes Yes Yes Variable Yes Yes Yes Yes

36% 41% 59% 45% 78% 54% 63% 68% 61%

(38/105) (26/64) (17/29) (47/105) (259/334) (50/92) (40/63) (31/46) (508/838)

9-32%

57-64%

a Time from symptoms onset until initiation of thrombolytic or control treatment. b Mean time from initiation of treatment until coronary angiography. Abbreviations: cath = catheter; min = minute; h = hour; d = day; CI = confidence interval. See glossary on page 318 for full references to studies.

define the appropriate trade-off of increased stroke with decreased mortality. 5.2 Patency Approximately 80% of patients undergoing cardiac catheterisation within 4 hours of acute myocardial infarction symptom onset are found to have total occlusion of the infarct vessel. Early studies demonstrated that most patients with coronary occlusion who received intracoronary streptokinase experienced reperfusion, usually within approximately 1 hour of treatment (Anderson et al.

1983; Kennedy et al. 1983; Rentrop et al. 1984). Because establishment of patency is believed to be the primary mechanism of benefit from thrombolytic therapy, measurement of patency has been a primary focus in the evaluation of effectiveness of different thrombolytic agents. Moreover, based on the pathophysiological model, and supported by data (GISSI-l; ISIS-2) that those patients treated earlier in the course of their myocardial infarctions experience a greater reduction in mortality, more rapid achievement of infarct vessel patency would be a logical advantage. In the Thrombolysis in

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305

Myocardial Infarction (TIM I) [Dalen et al. 1988] trial of intravenous alteplase versus streptokinase, reperfusion at 90 min was associated with a 92% I-year survival, compared with 85% for patients with occlusion. Data from the TAMI (Thrombolysis and Angioplasty in Myocardial Infarction) trials likewise demonstrate improved survival in patients with angiographically documented early

patency compared with patients without early patency (Ohman et al. 1990). Angiographic data may be reported as 'reperfusion' rates, or 'patency' (,perfusion') rates. Reperfusion rates are determined by selecting patients with angiographically documented coronary occlusion, administering the thrombolytic agent, and measuring the rate of subsequent recanalisation.

Table IV. Intravenous streptokinase patency studies Study

n

Dose (mU/h)

1h PRIMI (1989) Cribier et al. (1986) 90 min ECSG-2 (1985) Stack et al. (1988) TIMI-1 (1987) Lopez-Sandon et al. (1988) Hogg et al. (1990) PRIMI (1989) Charbonnier et al. (1989)

2-3h TEAM-2 (1991) Monnier et al. (1987) Six et al. (1990) Vogt et al. (1988) 1d PRIMI (1989) Hogg et al. (1990) Lopez-Sandon et al. (1988) Durand et al. (1987) Ribeiro et al. (1991) 3-21d PAlMS (1989) Kennedy et al. (1988) Lopez-Sendon et al. (1988) White et al. (1987) White et al. (1989) Bassand et al. (1987)

203 21 Pooled: 224

1.5

65 216 159 25 63 203 58 Pooled: 789

1.0 1.5 1.5 1.5 1.5 1.5 1.5

182 11

1.5 1.5 1.5 1.5

56 31 Pooled: 280

1.5

203 63 25 35 50 Pooled: 376

1.5 1.5 1.5 1.5 1.2

85 191 25 107

1.5 1.5

135 52 Pooled: 543

a,b See table III. Abbreviations: See table III. See glossary for full references to studies.

1.5 1.5 1.5 1.5

95% CI

Time to treatmenta

Mean cath time b

Patency

140 min 115 min

61 min

48% (82/171)

74 min

52% (11/21) 48% (93/192)

41-56%

55% 44% 43% 60% 53% 64% 51% 51%

48-55%

156 min 180 min 286 min < 6hr 209 min 140 min 168 min

158 min 135 min 150 min 138 min

14-36h 24h 24h 39h 48h

4d 10d 15-21d

75-90 min 90 min 90 min 90 min 90 min 91 min 93 min

126 150 168 176

min min min min

140 min 209 min < 6hr 149 min 180 min

127 min 210 min

21d

< 6 hr 180 min

21d 21d

150 min 210 min

(34/62) (95/216) (63/146) (15/25) (31/58) (124/194) (27/53) (411/799)

73% (129/176) 64% 60% 72% 70%

(7/11) (32/53) (21/30) (189/270)

65-75%

88% 87% 75% 82% 80% 86%

(160/181) (49/56) (18/24) (27/33) (40/50) (294/344)

82-89%

74% (57/74) 69% (89/130) 90% (17/19) 75% (74/99) 75% (87/116) 68% (32/47) 74% (324/438)

70-78%

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Table V. Intravenous tPA patency studies (studies with 1-1.5 mg/kg or 70-100mg single-stranded, or ~ 40mg double-stranded tPA) Study

1h ECSG-5 (Simoons et al. 1988) Smalling et al. (1990) RAAMI (1990) Topol (1987) 90 min ECGS-2 (1985) TIMI-2A (1988) TIMI-I (1987) RAAMI (1990) ECSG-1 (1985) TAMI-4 (Topol & Ellis 1989) TAMI-5 (1991) Topol & Morris (1987) Topol & Bates (1987) Johns et al. (1988) CRAFT (1991) Smalling et al. (1990) TAMI-3 (1989) KAMIT (1991) GAUS (1988) 2-3h Topol (1987) Guerci et al. (1987) 1d TPAT (1989) GAUS (1988) TEAM-3 (abs) TIMHIA (1988) TIMHI (1989) 3-21d ECSG-6 (1990) PAlMS (1989) Bassand et al. (1989) NHFA (1988) TIMI-IIA (1988) Thompson et al. (1991) TPAT (1989) GAUS (1988) Rapold et al. (1989) ECSG-5 (1988) White et al. (1989) O'Rourke et al. (1988)

a,b

n

183 91 138 75 Pooled: 487

Dose

Time to treatmenta

Mean cath time b

Patency

100 mg/3h

156 min

42 min

60% (108/180)

1.25 mg/kg/3h 100 mg/3h 1.25 mg/kg/3h

228 min < 6h 216 min

56 min 60 min 68 min

45% 62% 57% 62%

(40/89) (53/86) (40/70) (2~1/425)

0.75 mg/kg/90 min 100 mg/6h 80 mg/3h 100 mg/3h 0.75 mg/kg/90 min 100 mg/3h

180 min 168 min 287 min < 6h 204 min 243 min

75-90 min 84 min 90 min 90 min 90 min 90 min

70% 75% 70% 75% 61% 52%

(43/61) (98/131) (100/143) (92/122) (38/62) (26/50)

95 75 142 68 206 91 134 107 124 Pooled: 1648

100 mg/3h 1.25 mg/kg/3h 1 mg/kg/h, 100-150 1 mg/kg/90 min 100 mg/3h 1.25 mg/kg/3h 1.5 mg/kg/4h 100 mg/3h 70 mg/90 min

200 min 216 min 190 min 180 min 10d

71% (59/83)

See table III.

Abbreviations: See table III. See glossary for full references to' studies.

(data contained in tables III to IX). Because the patients who 'drop out' are more unstable or may have died, and because such patients are more likely than those left alive to be occluded (Ohman et al. 1990b), the reported patency rates may overestimate true rates. The later the assessment of patency, the more similar all agents appear, which may be because the true effects on late patency are similar, or because the patients with occluded arteries are more likely to have dropped out, making the rates only appear similar. Finally, it is important to consider not only the rates of patency and reocclusion, but also the confidence intervals, which are often not reported, and which may be wide in studies with small numbers of patients. Rates of patency at various times after initiation of thrombolytic regimens are listed in tables III to IX. Figure 5 illustrates the pooled results of studies evaluating standard dose streptokinase, tissue plasminogen activator, anistreplase, and rapidly administered alteplase, as well as the pooled data of patients randomised to heparin alone, representing a total of over 13 000 angiographic observations.

The available data demonstrate that the early patency rate (60 and 90 min after initiation of thrombolytic therapy) is lowest with streptokinase, strikingly similar for tissue plasminogen activator and anistreplase, and higher for alteplase given rapidly. These differences are highly statistically significant, with narrow confidence intervals. By 2 to 3 hours, however, there is little difference in patency between the various agents. Likewise, at I day and beyond, the 'catch-up' phenomenon has occurred, and the patency rates are not different between streptokinase, aIteplase, or anistreplase. In fact, by 2 to 3 weeks after presentation, the difference in patency between thrombolytic and no thrombolytic is much less striking, with approximately 60% of control or heparin-treated patients exhibiting infarct vessel patency. 5.3 Reocclusion and Reinfarction Reocclusion after thrombolytic therapy has been shown to be associated with adverse clinical outcome, with approximately twice the mortality among those with reocclusion compared to those without (Ohman et al. 1990b). Therefore, the rate of reocclusion is considered an important measure in evaluating thrombolytic regimens.

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The definition of reocclusion is variable across different studies, and apparent differences in rates of reocclusion may reflect differences in the methods of reporting rather than the true rates. The denominator from which reocclusion rates are calculated may be based on all patients treated, all patients who were angiographically occluded before treatment, patients found at acute post-treatment angiography to be patent initially or after intervention, or on only that subset of patients who undergo follow-up angiography. The numerator may include only patients found to be angiographically occluded, or may also include patients who die or suffer reinfarction without follow-up catheterisation. If this latter group are counted as 'patent,' the true rate of reocclusion is underestimated. An agent or early intervention which results in a higher early patency will ironically provide more vessels with the opportunity for reocclusion. Several studies have indeed demonstrated a higher incidence of reocclusion in patients who have an initially occluded infarct artery managed with acute angioplasty (Anderson et al. 1991; Califf et al. 1991; Grines et al. 1991; Neuhaus et al. 1988; Ohman et al. 1990b). In assessing reocclusion, comparison of

agents between different nonrandomised studies should be regarded with caution because of these substantial differences in study design. Alteplase has generally (Califf et al. 1991; Chesebro et al. 1987; Neuhaus et al. 1988; Vogt et al. 1991) but not always (Whitlow & Bashore 1991) been shown to have higher reocclusion rates than the non-fibrin-specific plasminogen activators. Combining the randomised trials where alteplase (all with intravenous heparin) has been compared with streptokinase, anistreplase or urokinase, the reocclusion rate is nearly twice as high with alteplase [13.5% (95% CI 11 to 16%) vs 8% (95% CI 3 to 10%); p = 0.002] (fig. 6). The combination of alteplase with either urokinase (Califf et al. 1991; Topol et al. 1988; URALMI 1991; Wall et al. I990b) or streptokinase (Bonnet et al. 1989; Granger et al. 1991; Grines et al. 1989, 1991) has resulted in early patency rates comparable to alteplase alone (70 vs 82%), and low rates of reocclusion (2 to 10%). In randomised trials, the combination of alteplase with either urokinase (Califf et al. 1991) or streptokinase (Grines et al. 1991) has resulted in a reduction of reocclusion rates, compared with alteplase alone. Coronary collateral blood flow may attenuate

100 90 80 70

~ ,., u

60

cQ)

50

0.

40

0;

~.---

• None

30

! • Streptokinase

! .l Alteplase

20 10 0

I

I.:; Anistreplase I 0 Accelerated alteplase : .

~

I

I

I

0 60min 90min 2-3h

. I

It.

/ /~--~I---~J~~/------

1 day

3-21 days

Time after initiation of therapy

Fig. 5. Pooled analysis of angiographic patency rates over time after various thrombolytic agents: patency rates are highest following accelerated t-PA, early rates with conventional t-PA and anistreplase are strikingly similar, and the patency rate following streptokinase has 'caught up' to conventional t-PA and anistreplase within 2 to 3 hours. Includes 13 728 angiographic observations.

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311

Table IX. Intravenous combined t-PA with urokinase (UK) or streptokinase (SK) patency and reocclusion studies Study

Thrombolytic agents and doses

TAMI-2(1988) TAMI-5 (1991) TAMI-7 (1990) URALMI (1991)

t-PA 1 mg/kg/60 min 1 mg/kg/60 min 1 mg/kg/30 min 50 mg-1 mg/kg/60 min

UK 0.5-2.0 mU/h 1.5 mU/h 1.5 mU/h 1-2 mU/h

Pooled: t-PA KAMIT Pilot (1989) KAMIT (1991) Bonnet et al. (1989) GUSTO Pilot (1991)

50 mg/h 50 mg/h 50 mg/30 min 1 mg/kg/h

SK 1.5 mU/h 1.5 mU/h 1.0 mU/30 min 1/0 mU/h

Pooled:

90-min patency

76% 78% 74% 71%

Reocclusion 8

(85/112) (76/97) (33/44) (55/78)

9% 2% 5% 8%

(10/110); 7d (2.94); 5-10d (2/44); 5-7d (5/65); 5-7d

85% (249/331) (95% CI: 71-80%)

6% (19/313) (95% CI: 3-9%)

75% 79% 82% 70%

8% (3/37); 7d 3% (3/89); 7d 7% (2/28); 24h 10% (4/51); pre discharge 6% (12/195) (95% CI: 3-10%)

(30/40) (81/102) (28/34) (33/47)

77% (172/223) (95% CI: 72-83%)

% of patients with coronary occlusion (at follow-up angiogram) of infarct vessel patent at the end of the acute coronary angiography; mean time of second angiogram. Abbreviations: See table III. See glossary for full references to studies. a

the negative impact of coronary occlusion. Analysis of data from the TIMI-2 trial shows that in patients in whom thrombolytic therapy failed to induce reperfusion, there was an association of collateral flow at the onset of myocardial infarction with limitation of enzymatically determined infarct size and improved left ventricular function at the time of hospital discharge (Habib et al. 1991). Of those who experience reocclusion, approximately one-half also experience clinical reinfarction (Ohman et al. 1990b). Rates of reinfarction, generally as defined by the individual investigators in the large randomised trials are listed in table X. Aspirin is associated with· a highly significant reduction in reinfarction compared with placebo (ISIS-2 1988), and subcutaneous heparin with a nonsignificant trend towards lower reinfarction rates (GISSI-2 1990; ISIS-3 1992). In contrast, studies comparing streptokinase, alteplase or anistreplase with placebo have found a higher rate of

18 16 14 '0' 12

e:.