GUSTO trials

Clinical trials One of the trials (ISIS-3) showed that streptokinase plus aspirin performed as well as recombinant tissue-type plasminogen activator (rt-PA) or complex formulations of streptokinase such as anistreplase (APSAC). The GUSTO trial showed a small advantage for the much more expensive t-PA over streptokinase, but with a significantly higher risk of hemorrhagic stroke. Nine clinical trials—each containing over 1000 patients with suspected acute myocardial infarction—... 

On the basis of the information derived from the GUSTO trial, Hathaway (1998a,b) reported a nomogram, for the quantification of involved area and to stratify the 30-day mortality risk, on the basis of the ST-segment abnormalities (elevation or depression) at the time of hospital admission (between 1 and 4 h from the onset of pain). Also, electrocardiographic (QRS complex width) and clinical (age, risk factors, Killip class, etc.) data were included (Table 8.4). From a practical point of view, an ST-segment deviation (upward or downward deviation)above 15 mm is supposed to indicate the existence of a large area of myocardium at risk (see Risk stratification ) (p. 257). 

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. 

Randomized comparison of direct thrombin inhibition versus heparin in conjunction with fibrinolytic therapy for acute myocardial infarction results from the GUSTO-lib Trial. Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO-lib) Investigators. J Am Coll Cardiol, 1998.31(7) 1493-8. 

In contrast to the putative superiority of abciximab in PCI, its role in medical stabilization therapy for ACS was seriously challenged by the findings of GUSTO-IV ACS trial, resulting in a Class III (contraindicated) recommendation. On the other hand, small molecules are recommended as Class II indication for medical management of ACS,... 

The GUSTO-IV ACS Investigators. Effect of glycoprotein llb/IIIA receptor blocker abciximab on outcome of patients with acute coronary syndromes without early revascularization the GUSTO-IV ACS randomized trial. Lancet 2001 357 1915-1924. 

Topol EJ, Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein llb/llla inhibition the GUSTO V randomized trial. Lancet 2001 357 1 905,... 

Efficacy and safety oftenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin the ASSENT-3 randomized trial in acute myocardial infarction. Lancet 2001 358 605. LincoffAM, Califf RM, Van De WerfE etal. Mortality at I year with combination platelet glycoprotein llb/llla inhibition and reduced-dose fibrinolytic therapy vs conventional fibrinolytic therapy for acute myocardial infarction GUSTO V randomized trial. JAMA 2002 288 2130. 

Savonitto S, Armstrong PW, Lincoff AM, et al. Risk of intracranial haemorrhage with combined fibrinolytic and glycoprotein llb/llla inhibitor therapy in acute myocardial infarction. Dichotomous response as a function of age in the GUSTO V trial. Eur Heart J 2003 24 1807. 

In the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-llb trial, the effects of UFH and hirudin in combination with either t-PA or SK were compared in 3289 patients with AMI (53), When dosed in combination with SK, the benefit of hirudin over UFH was observed in the clinical efficacy endpoint with the same levels of bleeding complications, In the TIMI 9b trial, 3002 patients with AMI were dosed with hirudin or UFH in combination with t-PA or SK, but no difference between the groups was observed in the clinical efficacy endpoint up to 30 days after administration (54). The administration of UFH or hirudin was not initiated... 

The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO I la) Investigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. Circulation 1994 90 1631-1637. 

Several direct thrombin inhibitors have been studied in NSTEMI and STEM I patients and were compared to unfractionated heparin. In the GUSTO lib- and OASIS-2 trial (42,43), hirudin was studied versus heparin in patients with ACS. Despite early benefits, no statistical significance could be demonstrated at 30 days. Together with the OASIS-1 data, a combined analysis indicated a 22% relative risk reduction in cardiovascular death or Ml at 72 hours, 17% at 7 days, and 10% at 35 days (42). 

Combination therapy with a thrombolytic agent and GPIIb/llla inhibitor has been studied in acute Ml. Various randomized trials (TAMI-8, IMPACT INTRO AMI, TIMI-14, SPEED, GUSTO V) in the coronary literature have shown that combination therapy reduced thrombolysis time and permitted a reduction of thrombolytic doses by 25% to 50% of the normal dose, This is explained by the fact that thrombus is composed of both fibrin and platelets. Thrombolytics only address the fibrin component of acute thrombus, Furthermore, thrombolytics may actually activate platelets directly resulting in additional thrombus formation, Therefore, the addition of GPIIb/llla inhibition facilitates the efficiency of the thrombolytic agent, It is also known that GPIIb/llla inhibition alone can actually dissolve platelet rich clot (41,42,43),... 

Crenshaw BS, Granger CB, Birnbaum Y, et al. Risk factors, angiographic patterns, and outcomes in patients with ventricular septal defect complicating acute myocardial infarction. GUSTO-1 (Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries) Trial Investigators. Circulation 2000 101(1 ) 27—32. 

GUSTO-1 and EPILOG, two different antithrombotic trials, GUSTO-1 and EPILOG, the first in acute myocardial infarction and the second during coronary stenting, compared the event rates in patients taking aspirin, an ACE inhibitor, or both (110). In each of these trials, events... 

Because of the significant correlation with age and a previous history of stroke, it is now widely considered that in patients over 75 years with a history of stroke other therapies, such as primary coronary angioplasty, must be considered. As reported in the GUSTO-1 trial, patients with very high systolic blood pressures have an increased risk of death or disabling stroke (26), and the pulse pressure has been reported to be the clearest predictor of the blood pressure as regards the risk of intracranial hemorrhage (27). 

Aylward PE, Wilcox RG, Horgan JH, White HD, Granger CB, Califf RM, Topol EJ. Relation of increased arterial blood pressure to mortahty and stroke in the context of contemporary thrombolytic therapy for acute myocardial infarction. A randomized trial. GUSTO-I Investigators. Ann Intern Med 1996 125(ll) 891-900. 

Tsang TS, Califf RM, Stebbins AL, Lee KL, Cho S, Ross AM, Armstrong PW. Incidence and impact on outcome of streptokinase allergy in the GUSTO-I trial. Global Utilization of Streptokinase and t-PA in Occluded Coronary Arteries. Am J Cardiol 1997 79(9) 1232-5. 

When it is suspected that there may only be small differences between active treatments, and when placebo controls are unavailable for clinical or ethical reasons, then it is often necessary to resort to large-scale studies ( mega-trials ). A good, famous example was the clinical trial known by the acronym GUSTO, where streptokinase and recombinant tissue plasminogen activator (t-PA) were compared for acute coronary thrombosis (for a commentary, see Hampton, 1996). 

Selected scores have been proposed for stratifying risk after MI. These scores have been derived either from clinical trials (TIMI, PURSUIT, GUSTO, etc.) or from registries and cohort studies (PREDICT, CCP, etc.). The majority of them divide the ACS into two groups with and without ST-segment elevation (STE-MI or STE-ACS vs NSTE-MI or NSTE-ACS). This classification is very useful for a better approach of treatment. The GUSTO score includes QRS duration and ECG (Hathaway et al., 1998a,b) prior MI (Table 8.4), and the PREDICT score uses other ECG parameters (ECG severity score) that include ST, Q wave and branch block criteria (Jacobs etal., 1999 Table 8.5). 

Lee KL, Woodlief LH, Topol EJ et al. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction results from an international trial of 41,021 patients. GUSTO Investigators. Circulation 1995 91 1659. 

EUROPA European trial On Reduction Of Cardiac Events With Perindopril In Stable Coronary Artery Disease GRACE Global Registry of Acute Coronary Events GUSTO Global Use of Strategies to Open Occluded Arteries HOPE Heart Outcomes Prevention Evaluation INR international normalized ratio... 

Berger R ElUs SG, Holmes DR Jr, et al. Relationship between delay in performing direct coronary angioplasty and early chnical outcome in patients with acute myocardial infarction Results from the Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-llb) trial. Circulation 1999 100 14-20. 

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