Thrombolysis mortality trials

With the failure of GISSIII and the International t-PA/SK Mortality Trial to show a clinical benefit of t-PA relative to SK and with the increased understanding of the importance of a period of antithrombin therapy in conjunction with thrombolysis, at least when a fibrin-specific agent was being used, another large international trial was undertaken, the first GUSTO study (28). In this trial, led by Topol and Califf, more than 40,000 patients presenting within 6 hours of onset of symptoms of AMI were randomized to one of four treatment arms ... 

Gore JM, Granger CB, Simoons ML, Sloan MA, Weaver WD, White HD, Barbash Gl, Van de Werf F, Aylward PE, Topol FJ, et al. Stroke after thrombolysis. Mortality and functional outcomes in the GUSTO-I trial. Global Use of Strategies To Open Occluded Coronary Arteries. Circulation. 1995 92 2811-2818. 

Antithrombotic therapy for acute peripheral occlusive disease is largely empirical. Thrombolytic therapy typically is reserved for patients in whom the occlusion is not amenable to surgery and for those in whom a possible delay between the initiation of therapy and thrombolysis would not jeopardize the viability of the limb. Evidence that antithrombotic therapy changes the natural course of the peripheral disease is sparse, but these patients are at an increased risk of cardiovascular mortality and should receive long-term aspirin therapy. Initial trials suggest that ticlopidine may improve the symptoms of chronic arteriosclerotic arterial insufficiency and also reduce fatal and nonfatal cardiovascular events, but further studies are needed. 

Pulmonary embolism. Thrombolysis is superior to heparin at relieving obstructed veins demonstrated radiologically. While a reduction in mortality is thus implied, the numbers of cases reported in clinical trials of thrombolytics have been insufficient to... 

Ischaemic stroke. There is little evidence of benefit and most trials have shown increased short-term mortality in patients treated with thrombolysis. 

Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet 1988 2(8610) 525-30. 

Based on this pilot data, three large multicenter randomized trials were performed to evaluate the safety and efficacy of IV SK alone or in combination with aspirin or heparin (Australian Streptokinase Trial (ASK) [39], Multicenter Acute Stroke Trial-Europe (MAST-E) [40], and Multicenter Acute Stroke Trial-Italy (MAST-I) [41]. ASK and MAST-E, the two double-blind randomized trials, were stopped prematurely because of excess mortality in the thrombolysis-treated group. MAST-I was stopped after randomizing only about a third of the intended number of participants due to similar safety concerns. Despite negative results, these trials contributed important information that was critical in the successful design of the later IV t-PA trials. 

Regardless of the nature of the endpoint used, the rapidity of coronary reperfusion was found to be of paramount importance (14,19,32-36,67-69). As much as 80% of the potential benefit conferred by coronary reperfusion via thrombolysis was found to be lost when reperfiision was delayed for as little as 3 hours following the onset of ischemic injury (32). Although some controversy exists with respect to file influence of early reperfusion on mortality after primary PCI (33,69), data from both multicenter trials and registries are consistent with increased mortality associated with delays in initiation of primary PCI (Fig. 1.4) (34-36,53). 

The third large trial was the Anglo Scandinavian Study of Early Thrombolysis (ASSET) (12). In this study, 5011 patients with AMI presenting within 5 hours were randomized to receive placebo or t-PA 100 mg infused over 3 hours. Mortality at 30 days was reduced by 27% in those receiving t-PA, from 9.8 to 7.2%. Heparin was given, but aspirin was not included in the treatment protocol. 

In the UAE, as well as many countries in western Europe and North America, primary PCI for treatment of patients with STEMI was and still is not readily available in many hospitals. We believe the case for performing primary PCI in most such patients is not yet compelling. The impact of time to treatment on mortality after prehospital thrombolysis or primary angioplasty (CAPTIM study) has shown that prehospital thrombolysis may be preferable to primary PCI for patients treated within the first 2 hours after onset of symptoms. Conversely, the DANish Multi-Center Randomized Study on Eibrinoljdic Therapy versus Acute Myocardial Infarction (DANAMI-2) report showed a reduction in cardiac events in patients treated with primary angioplasty compared with those treated with fibrinolytic agents for STEMI (13,14). The critics of that study have pointed out that the trial included only 37% of the population with STEMI and excluded patients with... 

Results from the Thrombolysis in Myocardial Infarction (TIMI) I study confirmed that prompt myocardial reperfusion decreased mortality (1). Results of several large-scale trials before and after TIMI I were consistent in establishing that treatment with intravenously administered thrombolytic agents to recanalize infarct-related arteries decreased mortality in patients with ST elevation myocardial infarction (STEMI) (2,3). However, despite the obvious benefits of thrombolysis, 30-day mortality in the GISSI-2 and ISIS-3 trials was as high as 8-10% (4,5). Because early restoration of myocardial blood flow was shown to... 

The GUSTO trial demonstrated that treatment of patients within 6 hours after onset of symptoms with the combination of a clot-selective thrombolytic agent [recombinant tissue type plasminogen activator (t-PA)] plus conjunctive treatment with aspirin and intravenous unfractionated heparin resulted in 30-day mortality of 6.3% (6). An angiographic substudy demonstrated that patency of the infarct-related artery was not the sole determinant of outcome. Restoration of normal coronary flow after thrombolysis was found to be critical in lowering mortality (7). Thus, angiographic analysis demonstrated that both induction of culprit artery patency and the extent of restoration of flow were determinants of outcome. 

Thus, overall in the three trials that assessed the potential benefit of a strategy in which thrombolysis was combined with PCI in the treatment of acute STEMI, no evidence of clinical benefit attributable to prompt PCI following thrombolysis was apparent. By contrast, complications occurred at an increased frequency. None of the trials had been powered to assess an impact on mortality. However, the lack of improvement in left ventricular ejection fraction, enzymatic estimate of infarct size, or the incidence of reinfarction was deemed to be discouraging. Moreover, the lack of apparent benefit was associated with an increased risk of bleeding. 

Section I of this book describes 1) the conceptual basis underlying pharmacoinvasive therapy, 2) the efficacy and limitations of each of its two components when used alone, and 3) the reductions in mortality that have been accomplished with each. Section II addresses the failure of early trials to demonstrate the benefit of combinations of balloon angioplasty coupled with antecedent coronary thrombolysis. 

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