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(Circulation. 1996;94:1233-1238.)
© 1996 American Heart Association, Inc.

Articles

One-Year Results From the Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries (GUSTO-I) Trial

Robert M. Califf, MD; Harvey D. White, MB, DSc; Frans Van de Werf, MD; Zygmunt Sadowski, MD; Paul W. Armstrong, MD; Alec Vahanian, MD; Maarten L. Simoons, MD; R. John Simes, MD; Kerry L. Lee, PhD; Eric J. Topol, MD; for the GUSTO-I Investigators

Duke University Medical Center, Durham, NC (R.M.C., K.L.L.); Green Lane Hospital, Auckland, New Zealand (H.D.W.); Institut Kardiologu, Warszawa, Poland (Z.S.); University of Alberta, Edmonton, Canada (P.W.A.); Hospital Tenon, Paris, France (A.V.); Thoraxcenter, Erasmus University, Rotterdam, the Netherlands (M.L.S.); National Health Medical Research Council Clinical Trials Centre, University of Sydney, Australia (R.J.S.); University Hospital Gasthuisberg, Leuven, Belgium (F. Van de W.); and the Cleveland (Ohio) Clinic Foundation (E.J.T.).

Correspondence to Robert M. Califf, MD, Box 31123, Duke University Medical Center, Durham, NC 27710.

	Abstract

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Background In the randomized Global Utilization of t-PA and Streptokinase for Occluded Coronary Arteries (GUSTO-I) trial, 41 021 patients received one of four thrombolytic regimens. Patients treated with accelerated tissue plasminogen activator (TPA) had a lower 30-day mortality rate (6.3%) than those treated with the other regimens (7.3%, combined streptokinase groups).

Methods and Results Each patient who was alive at 30 days was sent a return postcard to ascertain vital status at 1 year. If the postcard was not returned, the patient (or an alternate specified at randomization) was contacted by telephone. A locator service was used in the United States for patients who could not be located by these methods. Final follow-up was 96% worldwide. One-year mortality rates remained in favor of accelerated TPA (9.1%) over streptokinase with subcutaneous heparin (10.1%, P=.011) and streptokinase with intravenous heparin (10.1%, P=.009). Combination therapy had an intermediate 1-year mortality (9.9%); this outcome was statistically indistinguishable from that with streptokinase (P=.47) but was marginally different from that with accelerated TPA (P=.05).

Conclusions The 1-year results demonstrated a saving of 10 lives per 1000 patients treated with accelerated TPA versus streptokinase and subcutaneous or intravenous heparin. Combination thrombolytic therapy had an intermediate benefit but offered no advantage over accelerated TPA treatment alone.

Key Words: mortality • myocardial infarction • follow-up studies • thrombolysis

	Introduction

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The use of thrombolytic therapy to treat acute myocardial infarction produces a substantial reduction in mortality and morbidity in the first weeks after the acute event.^{1 2 3 4 5 6} In the several randomized trials evaluating long-term survival differences with thrombolytic therapy versus either placebo or management without thrombolytic therapy, the mortality benefit with thrombolytic therapy has persisted 1 to 5 years.^{3 5 7 8 9 10} The benefit has not increased over time, however, perhaps because of the benefits of coronary artery patency and left ventricular preservation versus the survival of more high-risk patients treated with thrombolytic therapy. Because no previous large trials have observed a difference in short-term survival among current thrombolytic strategies, long-term survival differences have not been addressed.

The Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries (GUSTO-I) trial¹¹ showed a 6.3% mortality rate at 30 days in patients treated with accelerated tissue-plasminogen activator (TPA*) and intravenous heparin compared with 7.2% with streptokinase and subcutaneous heparin and 7.4% with streptokinase and intravenous heparin. To determine whether this survival difference was maintained, the GUSTO-I Investigators included 1-year mortality as a secondary end point of the study.

	Methods

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Patients
Between December 27, 1990, and February 22, 1993, the GUSTO-I trial enrolled 41 021 patients with acute myocardial infarction who presented with ST-segment elevation within 6 hours of symptom onset. The design and data collection methods of the trial are described elsewhere.¹¹ The criteria for exclusion included a history of stroke, active or recent bleeding or major coagulation abnormality, recent trauma or major surgery, noncompressible vascular punctures, and previous treatment with streptokinase or anistreplase. There were no restrictions for reasons of age, presentation in cardiogenic shock, or prior bypass surgery.

Study Protocol
Qualifying patients were randomly allocated to one of four treatment strategies: streptokinase (Kabikinase, Kabi Vitrum) 1.5x10⁶ U over 60 minutes with subcutaneous heparin (heparin sodium, Sanofi, Paris) 12 500 U twice daily beginning 4 hours after the start of thrombolytic therapy; streptokinase 1.5x10⁶ U over 60 minutes with intravenous heparin in a bolus dose of 5000 U followed by 1000 U/h, with the dose adjusted to maintain an activated partial thromboplastin time of 60 to 85 seconds; accelerated TPA (alteplase, Genentech) in a bolus dose of 15 mg followed by an infusion of 0.75 mg/kg (up to 50 mg) over 30 minutes and 0.5 mg/kg (up to 35 mg) over the next 60 minutes, accompanied by the same intravenous heparin regimen; or a combination of intravenous TPA (1.0 mg/kg over 60 minutes, not to exceed 90 mg, with 10% given as a bolus) and streptokinase (1.0x10⁶ U over 60 minutes) given concurrently but through separate catheters, accompanied by the same intravenous heparin regimen.

All patients received 160 mg chewable aspirin (Bayer) as soon as possible and 160 to 325 mg/d thereafter. ß-Blockade with 10 mg IV atenolol (ICI Pharmaceuticals) was given in two divided doses to patients without contraindication, with 50 to 100 mg given daily by mouth thereafter. All other medications and procedures were left to the discretion of the investigator.

Follow-up Methods
Detailed demographic information was collected on enrollment, including the addresses and telephone numbers of the patient and a contact. Each patient who was alive at 30 days was sent a return postcard to ascertain vital status after 1 year had elapsed. If the postcard was not returned, the patient was called; if no response was elicited, the contact was called. A locator service was used in the United States for patients who could not be located by these methods. Because of the number of patients enrolled in the trial, finances and logistics prevented follow-up beyond survival status. Final follow-up was 96% worldwide: 98% follow-up in the United States and 95% outside the United States. One-year follow-up data were received for 96% of the patients in each treatment arm.

Statistical Analysis
We calculated the frequencies of discrete events and the median and 25th and 75th percentiles for continuous variables with regard to baseline characteristics and clinical outcomes of the 30-day survivors in each treatment group. We used ² testing to compare discrete characteristics and the Wilcoxon rank sum test to compare continuous characteristics. Survival rates for each treatment group were calculated to 1 year with Kaplan-Meier estimates and under the intention-to-treat principle, and the Cox proportional hazards model was used to perform statistical comparisons.

We wished to estimate the degree of potential bias caused by the missing information for patients lost to follow-up. We recalculated the 1-year survival curves by counting all patients lost to follow-up as dead (as of 1 day after the last follow-up), counting patients lost to follow-up as alive at day 365, and assigning the median time to death (or 1 day after last follow-up, whichever was later) to a subset of the patients lost in each treatment group on the basis of the overall mortality of the group (9.1% of the missing TPA-treated patients, 10.1% for both streptokinase groups, and 9.9% for combination therapy), with the remaining lost patients considered alive on day 365.

The hazard of death was calculated for each treatment group from the time of randomization to 1-year follow-up with standard life-table survival estimation techniques.¹² These rates show the instantaneous risk of death for a patient at each time point, given that the patient survived to that time.

To address the issue of whether the observed survival differences beyond 30 days could be explained by different underlying risk factors in patients who survived the first 30 days, we evaluated the baseline risk of 30-day survivors. Because the 30-day survivors in each treatment group had different combinations of risk factors, which would leave the summary estimate of risk uncertain, we used a validated statistical model¹³ to estimate the predicted risk of death in each treatment group in patients who survived. The predicted mortality risk for each patient was calculated, and the median predicted risk was calculated for all patients assigned to each treatment.

	Results

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The baseline characteristics and clinical complications of patients who survived the first 30 days are displayed in Tables 1 and 2, respectively. Patients who survived the first 30 days after treatment with TPA were at no higher risk at baseline, as evidenced by the finding that the predicted 30-day mortality rate of patients who were treated with TPA and survived 30 days was 2.7% compared with 2.7% in 30-day survivors treated with streptokinase and intravenous heparin and 2.6% for those treated with streptokinase and subcutaneous heparin. The surviving TPA-treated patients had significantly fewer major complications (shock, heart failure, AV block, ventricular tachycardia, or worst Killip class) during the hospital course. Surviving patients treated with TPA or combination therapy had a slightly (but nonsignificantly) higher rate of stroke; a large proportion of these patients with stroke (43.5%) died within 30 days.¹⁴

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of 30-Day Survivors

View this table: [in this window] [in a new window]   Table 2. Clinical Events and In-hospital Complications in 30-Day Survivors

Fig 1 shows the 1-year mortality results. (For comparison, the mortality rate at 30 days was 6.3% for patients who received accelerated TPA, 7.2% for those receiving streptokinase and subcutaneous heparin, 7.4% for those receiving streptokinase and intravenous heparin, and 7.0% for those on the combination therapy.¹¹ ) The overall 1-year mortality rate was 9.1% in patients randomized to TPA, 10.1% in those treated with streptokinase and subcutaneous heparin (P=.011 versus TPA), and 10.1% in those treated with streptokinase and intravenous heparin (P=.009 versus TPA; P=.003 for TPA versus both streptokinase groups). The mortality rate with combination therapy remained intermediate, 9.9% (P=.050 versus TPA), but was closer to that observed with streptokinase. Table 3 presents the results of recalculating the mortality estimates including the patients lost to follow-up. The significantly lower mortality rate observed with accelerated TPA treatment persisted whether missing patients were considered to be alive or dead or to have median mortality.

View larger version (14K): [in this window] [in a new window]   Figure 1. Overall 1-year mortality in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) trial by treatment assignment. SQ indicates subcutaneous; t-PA, tissue-plasminogen activator; and Combination therapy, streptokinase and t-PA with intravenous (IV) heparin.

View this table: [in this window] [in a new window]   Table 3. Mortality Estimates at 1 Year: Patients Lost to Follow-up

Fig 2 gives the 1-year mortality rates for 30-day survivors. The mortality rates were almost identical beyond 30 days regardless of treatment assignment. As Fig 3 shows, the hazard of mortality declined sharply as a function of time from randomization, reaching a plateau at 60 days; beyond 60 days, the hazard of death was almost identical in all treatment groups.

View larger version (16K): [in this window] [in a new window]   Figure 2. One-year mortality in 30-day survivors by treatment assignment. Abbreviations as in Fig 1.

View larger version (15K): [in this window] [in a new window]   Figure 3. Hazard of death as a function of time from randomization. Abbreviations as in Fig 1.

Fig 4 shows odds ratio plots of 1-year mortality for selected subgroups. These mortality patterns mirrored the 30-day patterns. Higher-risk patients achieved a greater survival benefit, as evidenced by the larger number of lives saved per 1000 patients treated among elderly and anterior infarction patients. No significant difference was observed in relative or absolute treatment benefit as a function of time from symptom onset to treatment, although a trend in that direction was present.

View larger version (23K): [in this window] [in a new window]   Figure 4. Odds ratios and 95% CIs for 1-year mortality in selected patient subgroups. SK indicates streptokinase (pooled groups); t-PA, accelerated tissue-plasminogen activator.

	Discussion

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The major finding of this investigation is that the greater benefit of accelerated TPA and intravenous heparin treatment of thrombolytic-eligible patients with acute myocardial infarction was sustained for at least 1 year. Furthermore, the nonsignificant difference in 30-day survival rates between the strategies of intravenous or subcutaneous heparin in conjunction with streptokinase diminished so that the two strategies had almost identical mortality rates at 1 year. As at 30 days, the combination therapy group showed a 1-year mortality rate similar to that of the streptokinase-treated patients.

The persistence of the survival advantage with accelerated TPA and intravenous heparin without widening after 30 days could have several explanations. Considerable evidence exists that the earlier reperfusion with accelerated TPA, coupled with the sustained perfusion afforded by intravenous heparin, leads to improvement in left ventricular function in the aggregate population.¹⁵ Preliminary data from the angiographic substudy show a widening survival curve in patients with Thrombolysis in Myocardial Infarction grade 3 flow compared with less than grade 3 flow.¹⁶ We hypothesized that if the curves did not widen after 30 days, the reason would be that TPA saved more high-risk patients, leaving a sicker cohort alive at 30 days among the TPA-treated patients. We did not find this to be the case; 30-day survivors were at equivalent risk at baseline regardless of treatment assignment. Thus, the reason for the parallel survival curves in this and all previous trials remains unknown.

These results are compatible with previous follow-up reports of clinical trials comparing thrombolytic therapy with placebo or conservative care or comparing thrombolytic agents; all demonstrated a maintenance of the result of the trial in the first 30 days. Simoons and colleagues⁷ have reported the longest follow-up from a clinical trial of thrombolytic therapy; in their study, the initial survival benefit of intracoronary streptokinase compared with conventional therapy was sustained to 5 years. The Gruppo Italiano per lo Studio della Streptochinasi nell' Infarto Miocardico (GISSI-1) study followed patients randomized to streptokinase or conservative therapy for 1 year.⁸ The survival benefit observed at 30 days was maintained to 1 year, with a 17.2% mortality rate in those treated with streptokinase versus a 19.0% mortality rate in those treated with conservative care. Similar results were reported over 4 years of follow-up by the second International Study of Infarct Survivors, which compared streptokinase with placebo.¹⁰ The APSAC Intervention Mortality Study initially observed a 6% mortality rate in patients treated with anistreplase compared with 12% in the placebo group at 30 days.⁵ At 1 year, this difference was sustained, with an 11% mortality rate with anistreplase compared with an 18% rate with placebo treatment. The Anglo-Scandinavian Study of Early Thrombolysis reported a benefit of alteplase at 1 month with a 7.2% mortality rate compared with 9.8% with placebo at 1 month.³ At 6 months, this benefit remained: 10.4% mortality with alteplase versus 13.1% with placebo.

The clinical complications in the 30-day survivors emphasize the point that early reperfusion results not only in better survival but also in fewer morbid events among the survivors. Thus, treatment with accelerated TPA and intravenous heparin not only reduced mortality but also resulted in a less complicated hospital course.¹⁷ Most notably, multiple markers of left ventricular dysfunction and electrical instability were less common in TPA-treated survivors.

The hazard functions provide an estimate of the time course of treatment benefit. The estimate of the instantaneous risk of death in a patient surviving to a given point in time is lower with accelerated TPA than with the other regimens. The benefit gradually narrows until 50 days after randomization. At this point, given that a patient is alive, no further additional advantage of accelerated TPA is evident. Although the general time course of the decline in hazard is similar to a previous report from the prethrombolytic era,¹⁸ the time course appears somewhat shorter; direct comparisons are not possible.

Patients at higher risk as evidenced by anterior infarction or advanced age derived more benefit from accelerated TPA in terms of the absolute benefit or the number of lives saved per 1000 patients treated. Patients with Killip class IV continued to show no improvement with accelerated TPA, just as in the first 30 days. Although this comparison is grossly underpowered, the similarity of this result to the GISSI-3 result^{11 19 20} leads to a concern that adequate hemodynamics are required for more effective lysis to occur with TPA.²¹ The relative benefit does appear to be greater with earlier treatment, although this effect was not statistically significant when formal tests for an interaction were performed. Beyond 6 hours from symptom onset, too few patients were included to draw valid conclusions about the choice of thrombolytic regimen. Mortality after 30 days was substantially higher in patients treated later rather than earlier, regardless of thrombolytic strategy.

Two other major issues that could have affected the 1-year survival rates—stroke and revascularization—have been discussed extensively in terms of the GUSTO-I outcomes. Although the accelerated TPA strategy led to a higher rate of stroke, this difference was attributable predominantly to hemorrhagic stroke.¹⁴ The high mortality rate among hemorrhagic stroke victims resulted in a very small rate of patients surviving with disabling stroke among 30-day survivors and no significant differences between treatment strategies among survivors (Table 2). The major impact of stroke was evident in the 30-day mortality results. The greater use of coronary artery bypass grafting^{22 23} during the initial hospitalization in the accelerated TPA group was not statistically significant and occurred only after the seventh day from randomization. By then, the difference in survival rate was already 1%, and no further differences in survival at 1 year could be attributed directly to bypass grafting.

We did not collect nonfatal end-point data for all patients in this trial. However, in a substudy of 2600 randomly selected patients from the US cohort of 23 105 patients, we did collect details of procedure use and hospitalization.²⁴ No significant differences in any of these end points were observed between 30 days and 1 year among the treatment groups.

In summary, the 1-year follow-up data from GUSTO-I indicate that the earlier reperfusion afforded by treatment with accelerated TPA reduced mortality by 10% on a relative scale and 1.0% on an absolute scale. Alternatively, these results could be portrayed as showing that 100 patients would have to be treated to save 1 life for at least a year or that 1 of every 10 deaths that occur in these patients over the first year could be prevented by the use of accelerated TPA instead of streptokinase. Patients who survived 30 days also had less complicated hospital courses if they had been treated with accelerated TPA. The heparin regimen given with streptokinase appeared to make no difference, and the combination regimen used in this trial produced a mortality profile more similar to that of streptokinase than of accelerated TPA. Collection of longer-term follow-up data will be important to confirm the hypothesis that early and sustained reperfusion correlates with lasting survival benefits.

	Acknowledgments

 
This study was funded by grants from Bayer (New York, NY), CIBA-Corning (Medfield, Mass), Genentech (South San Francisco, Calif), ICI Pharmaceuticals (Wilmington, Del), and Sanofi Pharmaceuticals (Paris, France).

	Footnotes

 
Presented in part at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 15, 1994.

*AHA uses the abbreviation TPA because t-PA is a trademarked name.

Received December 19, 1995; revision received June 11, 1996; accepted June 17, 1996.

	References

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