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A correction has been published: N Engl J Med 1994;331(4):277.
Volume 329:673-682
September 2, 1993
Number 10
Next
An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute
Myocardial Infarction
The GUSTO Investigators
ABSTRACT
Abstract
Background The relative efficacy of streptokinase and tissue plasminogen activator and the roles of intravenous as compared
with subcutaneous heparin as adjunctive therapy in acute myocardial infarction are unresolved questions. The current trial
Letters
was designed to compare new, aggressive thrombolytic strategies with standard thrombolytic regimens in the treatment of
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acute myocardial infarction. Our hypothesis was that newer thrombolytic strategies that produce earlier and sustained
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reperfusion would improve survival.
Methods In 15 countries and 1081 hospitals, 41,021 patients with evolving myocardial infarction were randomly assigned to
four different thrombolytic strategies, consisting of the use of streptokinase and subcutaneous heparin, streptokinase and
intravenous heparin, accelerated tissue plasminogen activator (t-PA) and intravenous heparin, or a combination of
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streptokinase plus t-PA with intravenous heparin. ("Accelerated" refers to the administration of t-PA over a period of 1 1/2
hours -- with two thirds of the dose given in the first 30 minutes -- rather than the conventional period of 3 hours.) The
primary end point was 30-day mortality.
Related Article
by Topol, E. J.
PubMed Citation
Results The mortality rates in the four treatment groups were as follows: streptokinase and subcutaneous heparin, 7.2
percent; streptokinase and intravenous heparin, 7.4 percent; accelerated t-PA and intravenous heparin, 6.3 percent; and the combination of both
thrombolytic agents with intravenous heparin, 7.0 percent. This represented a 14 percent reduction (95 percent confidence interval, 5.9 to 21.3 percent)
in mortality for accelerated t-PA as compared with the two streptokinase-only strategies (P = 0.001). The rates of hemorrhagic stroke were 0.49 percent,
0.54 percent, 0.72 percent, and 0.94 percent in the four groups, respectively, which represented a significant excess of hemorrhagic strokes for
accelerated t-PA (P = 0.03) and for the combination strategy (P<0.001), as compared with streptokinase only. A combined end point of death or disabling
stroke was significantly lower in the accelerated-t-PA group than in the streptokinase-only groups (6.9 percent vs. 7.8 percent, P = 0.006).
Conclusions The findings of this large-scale trial indicate that accelerated t-PA given with intravenous heparin provides a survival benefit over previous
standard thrombolytic regimens.
Since the landmark trial of intravenous streptokinase by the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) in
1986,1 there has been no confirmation that other thrombolytic regimens provide additional survival benefit in patients with acute myocardial
infarction, except for the important addition of aspirin2. Collectively, the large trials of thrombolytic therapy demonstrated a 25 percent reduction
in 30-to-35-day mortality in patients presenting to the hospital within six hours of the onset of symptoms3. Neither the GISSI-2/International trial
nor the Third International Study of Infarct Survival (ISIS-3) trial4,5,6 of more than 60,000 patients found a difference in associated mortality
between the use of streptokinase and the use of tissue plasminogen activator (t-PA)4,5 or between the use of these agents and that of
anistreplase6. Furthermore, the addition of subcutaneous heparin to the regimens did not significantly reduce mortality as compared with no use
of heparin5,6. Although clear differences between thrombolytic agents are evident in the speed with which the agents achieve reperfusion, the
similar survival rates in these previous trials suggested that factors other than rapid or sustained coronary reperfusion might be important in
reducing mortality.
Recent data suggest that more rapid and effective infarct-artery patency can be achieved with accelerated t-PA,7,8,9 that lower rates of
reocclusion are observed with the use of combination thrombolytic therapy,10,11,12 and that infarct-artery patency can be sustained longer with
the use of intravenous heparin as an adjunct to thrombolytic therapy13,14,15. ("Accelerated" t-PA refers to the rapid intravenous administration of
t-PA over a period of 1 1/2 hours -- with two thirds of the dose given in the first 30 minutes -- rather than the conventional period of 3 hours.)
The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial was conceived in 1989 to
test the hypothesis that early and sustained infarct-vessel patency was associated with better survival rates in patients with evolving myocardial
infarctions. To this end, we compared the effects of four thrombolytic strategies on mortality: streptokinase with subcutaneous heparin,
streptokinase with intravenous heparin, accelerated t-PA with intravenous heparin, and streptokinase with t-PA and intravenous heparin.
Methods
Study Organization
Before the trial began, the Food and Drug Administration requested a pilot study of 100 patients treated with a combination of t-PA and
streptokinase along with intravenous heparin. After the dose regimen was found not to be associated with excessive bleeding,16 enrollment in
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the main trial began on December 27, 1990, and was completed on February 22, 1993. A total of 1081 hospitals in 15 countries in North America
and Europe and in Israel, Australia, and New Zealand participated (see the Appendix).
Patient Population
Patients presenting to a participating hospital less than 6 hours after the onset of symptoms, with chest pain lasting at least 20 minutes and
accompanied by electrocardiographic signs of 0.1 mV of ST-segment elevation in two or more limb leads or
0.2 mV in two or more contiguous
precordial leads were eligible for enrollment. The criteria for exclusion were previous stroke, active bleeding, previous treatment with
streptokinase or anistreplase, recent trauma or major surgery, previous participation in the trial, or noncompressible vascular punctures. Patients
with severe, uncontrolled hypertension (systolic blood pressure 180 mm Hg, unresponsive to therapy) were considered to have a relative
contraindication to enrollment. Patients gave informed consent for participation, and the protocol was approved by the institutional review
board at each hospital.
Randomization and Treatment Strategies
The investigators and study coordinators telephoned a 24-hour-per-day, seven-day-per-week randomization center to review patient eligibility
and receive a treatment assignment to one of four intravenous thrombolytic strategies: (1) streptokinase (Kabikinase, Kabi Vitrum, Sweden), 1.5
million U over a 60-minute period, with subcutaneous heparin (sodium heparin, Sanofi, Paris) in a dose of 12,500 U twice daily, beginning 4 hours
after the start of thrombolytic therapy (the treatment regimen tested in ISIS-36); (2) streptokinase, 1.5 million U over a 60-minute period, with
intravenous heparin (porcine-derived) in a bolus dose of 5000 U and 1000 U per hour (a dose of 1200 U per hour was recommended for patients
weighing more than 80 kg), with the dose adjusted to raise the activated partial-thromboplastin time to between 60 and 85 seconds; (3)
accelerated t-PA (Genentech, San Francisco) in a bolus dose of 15 mg, 0.75 mg per kilogram of body weight over a 30-minute period, not to
exceed 50 mg, and 0.5 mg per kilogram, up to 35 mg, over the next 60 minutes with the same intravenous heparin regimen; or (4) the
combination of intravenous t-PA (1.0 mg per kilogram over a 60-minute period, not to exceed 90 mg, with 10 percent given in a bolus dose) and
streptokinase (1.0 million U over a 60-minute period), given simultaneously but through separate intravenous catheters, along with intravenous
heparin as described for the other treatment strategies. For subcutaneous heparin, the treatment was continued for seven days or until the
patient was discharged from the hospital; intravenous heparin was given for at least 48 hours or longer at the investigators' discretion. The
activated partial-thromboplastin time was monitored at 6, 12, and 24 hours for titration of the dose of intravenous heparin. Individual drug kits
for each patient were forwarded to each study site for use according to the random assignment; these were sealed and coded with a numerical
sequence, and the actual treatment was not identifiable until the seal was broken.
The trial began in December 1990 with only three groups but was modified in March 1991 after the first 1160 patients had been enrolled. At that
time, the ISIS-3 results were reported,6 and it was suggested that there would not be a reference group within the three groups of the GUSTO
trial for adequate comparison of the results with those of ISIS-3. Therefore, the Steering Committee unanimously decided to include a treatment
group receiving streptokinase and subcutaneous heparin, which had the most favorable results with regard to mortality, on the basis of the
preliminary results of ISIS-3 in March 1991, supported by the results obtained with a similar regimen in the GISSI-2/International trial4,5.
Additional Therapy
Chewable aspirin (Bayer, New York) was administered as soon as possible in a dose of
160 mg, followed by a daily dose of 160 to 325 mg per
day. For patients without a contraindication to beta-blockade, 5 mg of intravenous atenolol (ICI Pharmaceuticals, Wilmington, Del.) was given in
two divided doses, followed by oral therapy with 50 to 100 mg once daily. All other medications, including nitrates, antiarrhythmic drugs, calciumchannel blockers, angiotensin-converting-enzyme inhibitors, and digitalis were prescribed at the discretion of the attending physician. Similarly,
the use of coronary angiography, angioplasty, and coronary-artery bypass surgery was left to the discretion of the investigator.
End Points
The primary end point was death from any cause at 30 days of follow-up. Other related major clinical outcomes that were prospectively defined
and assessed were the combined end points of death and nonfatal stroke, death and nonfatal hemorrhagic stroke, and death and nonfatal
disabling stroke. In all cases of focal neurologic dysfunction, every attempt was made to determine the cause by computerized axial tomography
of the head, magnetic resonance imaging, or in the case of death, by autopsy. Strokes were classified as caused by a primary hemorrhage
(including cerebral hemorrhage and subdural hematomas), a cerebral infarct with conversion to hemorrhage, a nonhemorrhagic cerebral infarct,
or an unknown cause (in which case there was no brain imaging or autopsy). The stroke data were independently reviewed by a Stroke Review
Committee whose members were unaware of the treatment assignments. A patient who had a stroke was classified as disabled if at the time of
hospital discharge he or she had a moderate deficit (substantial limitation of activity and capabilities) or a severe deficit (inability to live
independently or work) or as not disabled if he or she had no sequelae or only a minor deficit (with the functional status unchanged). This
classification was validated by direct interviews with patients about their quality of life.
Bleeding complications were classified as severe or life-threatening if they were intracerebral or if they resulted in substantial hemodynamic
compromise requiring treatment. Moderate bleeding was defined by the need for transfusion. Minor bleeding referred to other bleeding, not
requiring transfusion or causing hemodynamic compromise. The lowest hematocrit during the hospitalization was recorded.
Data Management and Quality Assurance
A simplified three-page case-report form was used to enter the primary data, with additional one-to-two-page data-collection forms used for all
patients who had stroke, cardiogenic shock, or reinfarction. The case-report forms were forwarded to either the international coordinating
centers (Catholic University, Leuven, Belgium, and the National Health and Medical Research Council Clinical Trials Centre, Sydney, Australia) or
the main coordinating center (Duke University, Durham, N.C.) for data entry and the generation of queries about missing or inconsistent data.
Patients who survived the hospitalization were given a postcard to mail to the coordinating center at the 30-day follow-up. Missing data on
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follow-up mortality were obtained by telephone, by registered mail, at follow-up clinics, or through locator services, as well as by cross-checking
with national-registry indexes in countries where such data are promptly and accurately tabulated and available. The quality of the data was
ensured by auditing 10 percent of the data forms. The audits involved at least one visit to each enrolling site, during which cross-checks between
the case-report forms and the source medical records were made. In addition to this verification, similar audits were performed for all patients
who had strokes. For each patient randomized, a safety summary form was sent by facsimile transmission to the coordinating center at the time
of discharge from the hospital, on day 30, or at the time of death, whichever came first. This form provided details about whether there had been
a stroke or a life-threatening bleeding event. The electrocardiographic core laboratory, which was unaware of the treatment assignments, read
all electrocardiograms obtained at enrollment, before discharge, and at the time of any subsequent infarction. No investigator or sponsor had
access to any of the data until the trial was complete and the prespecified analyses had been performed by the two biostatisticians who
coordinated the data analyses. The data reported herein are based on a 99.9 percent level of completeness of 30-day mortality outcomes and a
99.8 percent level of completeness for other outcome data derived from case reports.
Statistical Analysis
The trial was designed to provide high power for detecting a 15 percent reduction in mortality or an absolute decrease of 1 percent, whichever
was larger, for the experimental treatments as compared with the controls. The two groups assigned to monotherapy with streptokinase were
considered the control groups. It was prospectively determined that if there was no difference in mortality between these two groups (P>0.10),
the analysis would proceed with these patients pooled together. If a difference was observed between the two streptokinase groups, the plan
called for a comparison of the two experimental groups with the streptokinase group that had the best results. With a projection that mortality in
the control patients would be approximately 8 percent, the target enrollment of 41,000 was chosen to provide at least 90 percent power for
detecting the desired differences if mortality among the controls was 8 percent or higher, and at least 80 percent power if mortality among the
controls was less than 8 percent. These calculations were based on an alpha of 0.05 and two-tailed testing.
Continuous data are summarized as medians with 25th and 75th percentiles unless otherwise indicated. Selected base-line characteristics and
clinical outcomes were compared between treatments by the chi-square test for discrete variables and by nonparametric analysis of variance for
continuous variables. Odds ratios and 95 percent confidence intervals were used to compare treatments with regard to major clinical outcomes.
Mortality during the 30-day follow-up period was characterized with Kaplan-Meier mortality curves. The consistency of treatment effects among
prespecified subgroups (interactions) defined according to age, location of infarct, and time to treatment was assessed with logistic regression.
Prespecified interim analyses of safety were performed when enrollment reached 11,274, 21,926, and 28,312 patients, with the data reviewed by
an independent Data and Safety Monitoring Board. Comparisons of efficacy at the interim analyses were monitored with two-sided, symmetric
O'Brien-Fleming boundaries generated with the Lan-DeMets approach to group-sequential testing17,18. All tests of significance were two-tailed,
and treatments were compared according to the intention-to-treat principle.
Relationship with Sponsors
When the study was designed, the Steering Committee undertook specific measures to avoid financial conflicts of interest, as reported
elsewhere19. All the members of the Steering Committee, the Data and Safety Monitoring Board, and the Data Coordinating Center declared in
writing that neither they nor their immediate family members had any financial relationship with any of the sponsors, including equity interest,
receipt of honorariums, consulting relationships, and reimbursement for travel expenses. Principal investigators at the enrolling hospitals were
required to acknowledge in writing that they had no equity interest in the sponsoring companies.
Results
Characteristics of the Patients
A total of 41,021 patients were enrolled between December 27, 1990, and February 22, 1993 (Table 1). The imbalance in the number of patients
assigned to receive streptokinase and subcutaneous heparin reflects the slight delay in initiating this group during the trial. There were no
differences in base-line characteristics among the four treatment groups. The time from the onset of symptoms to treatment, although not a
base-line variable, differed among the groups (P<0.001); it was five minutes longer for the group assigned to combined streptokinase and t-PA
because of the longer time required to prepare and initiate this treatment regimen. The diagnosis of acute myocardial infarction was confirmed
in at least 97 percent of the patients in each group.
View this table: Table 1. Base-Line Characteristics of the Four Treatment Groups.
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Study Medications
The rate of compliance with the randomly assigned thrombolytic regimens was 97 to 98 percent for all four groups. In each group, the initial
aspirin dose was given to 97 percent of the patients, and oral aspirin was administered subsequently to approximately 93 percent, with no
significant differences between treatment groups. In the three groups assigned to intravenous heparin, 99.5 percent of the patients received this
therapy on the first hospital day, and 86 percent received at least 40 hours of continuously infused intravenous heparin during the first 48 hours.
The median activated partial-thromboplastin times at 12 hours in the groups assigned to streptokinase and intravenous heparin, accelerated
t-PA and intravenous heparin, and the combination of t-PA and streptokinase with intravenous heparin were 82, 72, and 83 seconds,
respectively; at 24 hours the corresponding values were 62, 63, and 62 seconds. These data demonstrate that the target value of in vitro
anticoagulation was achieved in at least half the patients assigned to intravenous heparin throughout the first 24 hours. Lack of compliance with
subcutaneous heparin therapy, defined as failure to start this regimen in the first 24 hours, occurred in 11 percent of the patients, more often in
the United States (14 percent) than in the other countries (7 percent). Overall, 36 percent of the patients in this group received intravenous
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heparin at some point during their hospitalization. The predominant reason for switching to intravenous heparin was recurrent ischemia, in more
than 60 percent of the patients.
Beta-blockers were administered intravenously to 46 percent of the patients and orally to 71 percent. Prophylactic lidocaine was given to 18
percent of the patients, a calcium-channel blocker to 31 percent, preparations of digitalis to 14 percent, other inotropic agents to 19 percent,
intravenous nitroglycerin to 77 percent, and an angiotensin-converting-enzyme inhibitor to 21 percent.
Major Clinical Outcomes
The data on the principal end points are summarized in Table 2 for the four treatment groups. For 30-day mortality, there was no significant
difference between the streptokinase groups (P = 0.731). There was a significant reduction in mortality with accelerated t-PA as compared with
the two streptokinase strategies (10 lives saved per 1000 patients treated; risk reduction, 14 percent; 95 percent confidence interval, 5.9 to 21.3;
P = 0.001). In addition, comparing the accelerated-t-PA group separately with each streptokinase group demonstrated significant reductions in
mortality (t-PA vs. streptokinase with subcutaneous heparin, P = 0.009; t-PA vs. streptokinase with intravenous heparin, P = 0.003). There was no
difference in mortality between the combination strategy using both t-PA and streptokinase and the two strategies involving streptokinase
monotherapy (risk reduction, 4 percent; 95 percent confidence interval, -4.2 to 12.2; P = 0.352). There was a significant difference in 30-day
mortality between accelerated t-PA and the combination therapy (6.3 vs. 7.0 percent; risk reduction, 10 percent; 95 percent confidence interval,
0.8 to 19.2; P = 0.04). As shown in Table 2, there were similar statistically significant differences between accelerated t-PA and each of the
streptokinase strategies with regard to the combined end points of mortality and stroke. In Figure 1, the mortality data are plotted with an
actuarial analysis for the 30-day end point. Figure 2 shows the benefit in the accelerated-t-PA group as compared with either streptokinase
group with regard to reduction in mortality and the combined end point of death or disabling stroke. There were significant reductions in the risk
of this combined end point with accelerated t-PA as compared with the two streptokinase strategies together (P = 0.006) and as compared with
each streptokinase group separately (t-PA vs. streptokinase with subcutaneous heparin, P = 0.03; t-PA vs. streptokinase with intravenous
heparin, P = 0.01).
View this table: Table 2. Major Clinical Outcomes.
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Figure 1. Thirty-Day Mortality in the Four Treatment Groups.
The group receiving accelerated treatment with t-PA had lower mortality than the two streptokinase groups (P
= 0.001) and than each individual treatment group: streptokinase and subcutaneous (SC) heparin (P = 0.009),
streptokinase and intravenous (IV) heparin (P = 0.003), and t-PA and streptokinase combined with IV heparin
(P = 0.04).
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Figure 2. Odds Ratios and 95 Percent Confidence Intervals (CI) for Reduction in Mortality and Net Benefit,
Defined as Reduction in Mortality and Disabling Stroke, in the Group Assigned to Accelerated t-PA as
Compared with the Streptokinase Groups.
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Stroke and Bleeding Complications
In Table 3, the data on strokes, broken down according to the presence or absence of hemorrhage, show an approximate excess of 2
hemorrhagic strokes per 1000 patients treated (absolute excess, 0.2 percent) for t-PA as compared with streptokinase (P = 0.03) and an excess of
4 hemorrhagic strokes per 1000 for the combination of thrombolytic agents (P<0.001). With regard to all strokes, there was an excess of
approximately 2 per 1000 in the accelerated-t-PA group (P = 0.09) and of more than 3 per 1000 in the combination group (P = 0.02). The
incidence of other bleeding events or indexes tended to be more favorable with accelerated t-PA than with the other treatments. Although
differences between groups in the nadir hematocrit during hospitalization were statistically significant, the magnitude of the differences clinically
was small.
View this table: Table 3. Incidence of Stroke and Bleeding Complications.
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Clinical Outcomes Other Than Mortality and Stroke
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A consistent pattern of fewer complications was noted in the accelerated-t-PA group, particularly with respect to allergic reactions, clinical
indicators of left ventricular dysfunction, and arrhythmias (Table 4). No differences were observed in the rate of complications reflecting recurrent
ischemia, including reinfarction. The use of coronary revascularization procedures was similar in the four treatment groups (angioplasty in 15
percent of the patients and bypass surgery in 9 percent). Procedures to treat arrhythmia or heart failure were used less often in the patients
receiving accelerated t-PA.
View this table: Table 4. Other Complications.
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Prespecified Subgroups
Three groups of patients were prospectively defined according to age (>75 years vs. 75 years), infarct location (anterior vs. inferior), and the
time to randomization. The relative reduction in the mortality rate was lower in the patients over 75 who were given accelerated t-PA than in the
patients 75 who were given streptokinase, and the excess risk of hemorrhagic stroke or stroke of any type was higher in those over 75 (Table 5).
However, as shown in Table 5, the absolute net benefit with respect to mortality and disabling stroke was similar in both younger and older
patients. The results of the test to determine whether treatment varied according to age (interaction between treatment and age) were not
significant (P = 0.098). Both patients with anterior and those with inferior myocardial infarctions derived a mortality benefit from accelerated t-PA
as compared with streptokinase, although the benefit in those with anterior infarctions was greater (anterior infarction, 8.6 percent vs. 10.5
percent, respectively; odds ratio, 0.81; 95 percent confidence interval, 0.71 to 0.92; inferior infarction, 4.7 percent vs. 5.3 percent; odds ratio, 0.89;
95 percent confidence interval, 0.78 to 1.03). When the time to treatment was categorized in intervals of 0 to 2 hours, 2 to 4 hours, and 4 to 6
hours, there was a consistent benefit for accelerated t-PA as compared with streptokinase with respect to the extent of the reduction in mortality
(4.3 percent vs. 5.4 percent, 5.5 percent vs. 6.7 percent, and 8.9 percent vs. 9.3 percent for the respective intervals), although a significant
interaction was observed between time to treatment and reduction in mortality (P = 0.015), with a greater reduction in mortality associated with
early treatment with t-PA (Figure 3).
View this table: Table 5. Effect of Treatment According to Age.
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Figure 3. Odds Ratios and 95 Percent Confidence Intervals (CI) for 30-Day Mortality in the Prespecified
Subgroups Defined by Age, Infarct Location, and Time to Thrombolytic Therapy.
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Discussion
Our findings indicate that a thrombolytic strategy consisting of accelerated t-PA with intravenous heparin was superior to both of the
streptokinase regimens in reducing mortality and achieving a net clinical benefit, as defined by survival without a disabling stroke. As compared
with the streptokinase regimens, t-PA led to an actual benefit of 10 additional lives saved per 1000 patients treated, or the prevention of death
and disabling stroke in 9 patients per 1000 treated. There was also a significant reduction in the mortality rate with accelerated t-PA as compared
with the combination regimen including both t-PA and streptokinase. The superiority of the accelerated t-PA treatment was statistically robust
across all the comparisons of prespecified subgroups. Even though this regimen was associated with a small excess of strokes, the end points of
survival without a stroke, survival without a disabling stroke, and survival without a nonfatal hemorrhagic stroke all demonstrated the net
advantage of this treatment approach over either streptokinase regimen.
The patency rate of the infarct-related artery at 90 minutes with accelerated t-PA has been reported to be 85 percent in previous angiographic
trials7,8,9,20 and was confirmed to be significantly higher than with the other thrombolytic regimens in the current trial (these data will be
reported on fully in a subsequent paper). On the other hand, the combination of t-PA and streptokinase, in which there was less initial loading of
t-PA, has not been associated with a higher early patency rate10,11,12. We suggest that the superiority of accelerated t-PA over the combination
strategy is probably related to faster recanalization of the infarct-related vessel achieved by the more rapid administration of t-PA.
Even at 24 hours, the mortality rate was reduced significantly, by 19 percent, with accelerated t-PA as compared with the other regimens,
showing that fully half the absolute benefit in survival occurred very early. These favorable survival data were paralleled by a lower incidence of
arrhythmia, congestive heart failure, and cardiogenic shock. Although the importance of early infarct-artery patency has been a subject of
debate, the current trial supports the idea that in the setting of acute myocardial infarction, rapid restoration of myocardial blood flow improves
survival.
As compared with previous, placebo-controlled thrombolytic trials1,2 that collectively showed a 2.5 to 3.3 percent absolute reduction in mortality
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(relative reduction, 27 percent), the current study demonstrated an additional survival benefit with the accelerated-t-PA strategy that represents
an important additional step forward in thrombolytic therapy. Like our trial, future trials using an active-treatment control group cannot be
expected to demonstrate as extensive an incremental survival benefit as did earlier placebo-controlled trials.
The cost effectiveness of widespread use of the most favorable thrombolytic regimen in this trial (accelerated t-PA with intravenous heparin) is
likely to attract substantial interest. As compared with a regimen of streptokinase and aspirin (and no heparin), which has been thoroughly
evaluated in the GISSI-2 and ISIS-3 trials, accelerated t-PA is more expensive ($320 vs. $2,300, respectively, in the United States) and more
complex to administer, because it requires the titration of intravenous heparin according to the activated partial-thromboplastin time in addition
to weight-adjusted dosing of t-PA as specified in the current trial. Given the different margins of benefit in certain prespecified subgroups,
further analysis of this issue will be useful in determining the most cost-effective application of the survival benefit realized in the overall study
population.
On the basis of the survival advantage and net clinical benefit, along with the lower incidence of allergic reactions and other complications, the
GUSTO trial provides evidence that accelerated t-PA combined with intravenous heparin is the best thrombolytic strategy to date for patients
with acute myocardial infarction. This development, however, should not lead to complacency about further clinical investigation of better
therapeutic approaches to myocardial infarction,20 given the 6.3 percent mortality rate and the 1.5 percent incidence of stroke. It is possible that
even more aggressive strategies to promote earlier and complete coronary reperfusion will further improve these outcomes.
Supported by a combined grant from Bayer, CIBA-Corning, Genentech, ICI Pharmaceuticals, and Sanofi Pharmaceuticals.
Source Information
Dr. Topol, as chairman of the study, assumes full responsibility for the overall content and integrity of the manuscript.A list of the Global Utilization of Streptokinase and Tissue
Plasminogen Activator for Occluded Coronary Arteries (GUSTO) investigators appears in the Appendix.
Address reprint requests to Dr. Eric Topol at the Department of Cardiology, One Clinic Center, Cleveland Clinic Foundation, Cleveland, OH 44195.
References
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or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349-360. [Medline]
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8. Neuhaus KL, Von Essen R, Tebbe U, et al. Improved thrombolysis in acute myocardial infarction with front-loaded administration of
alteplase: results of the rt-PA-APSAC patency study (TAPS). J Am Coll Cardiol 1992;19:885-891. [Abstract]
9. Carney RJ, Murphy GA, Brandt TR, et al. Randomized angiographic trial of recombinant tissue-type plasminogen activator (alteplase) in
myocardial infarction. J Am Coll Cardiol 1992;20:17-23. [Abstract]
10. Topol EJ, Califf RM, George BS, et al. Coronary arterial thrombolysis with combined infusion of recombinant tissue-type plasminogen
activator and urokinase in patients with acute myocardial infarction. Circulation 1988;77:1100-1107. [Free Full Text]
11. Califf RM, Topol EJ, Stack RS, et al. Evaluation of combination thrombolytic therapy and timing of cardiac catheterization in acute myocardial
infarction: results of thrombolysis and angioplasty in myocardial infarction -- phase 5 randomized trial. Circulation
1991;83:1543-1556. [Free Full Text]
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and streptokinase with full-dose tissue-type plasminogen activator. Circulation 1991;84:540-549. [Free Full Text]
13. Hsia J, Hamilton WP, Kleiman N, Roberts R, Chaitman BR, Ross AM. A comparison between heparin and low-dose aspirin as adjunctive
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14. Bleich SD, Nichols TC, Schumacher RR, Cooke DH, Tate DA, Teichman SL. Effect of heparin on coronary arterial patency after thrombolysis
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15. de Bono DP, Simoons ML, Tijssen J, et al. Effect of early intravenous heparin on coronary patency, infarct size, and bleeding complications
after alteplase thrombolysis: results of a randomised double blind European Cooperative Study Group trial. Br Heart J
1992;67:122-128. [Free Full Text]
16. Granger C, Califf R, Woodlief L, et al. The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary
Arteries (GUSTO) Pilot Study: combined streptokinase and t-PA. Circulation 1991;84:Suppl II:II-573.abstract
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clinical trial of myocardial reperfusion. J Am Coll Cardiol 1992;19:1123-1128. [Abstract]
20. Lincoff AM, Topol EJ. Illusion of reperfusion: does anyone achieve optimal reperfusion during acute myocardial infarction? Circulation
1993;87:1792-1805.
Appendix
The following investigators collaborated on the GUSTO study. The numbers shown are the numbers of patients enrolled from each area or
country.
Steering Committee: E. Topol (Study Chairman), United States; R. Califf (Clinical Director, Coordinating Center), United States; F. Van de Werf
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(Director, Intermediate Coordinating Center), Belgium; P.W. Armstrong, Canada; P. Aylward, Australia; G. Barbash, Israel; E. Bates, United States;
A. Betriu, Spain; J.P. Boissel, France; J. Chesebro, United States; J. Col, Belgium; D. de Bono, United Kingdom; J. Gore, United States; A. Guerci,
United States; J. Hampton, United Kingdom; J. Hirsh, Canada; D. Holmes, United States; J. Horgan, Ireland; N. Kleiman, United States; V. Marder,
United States; D. Morris, United States; M. Ohman, United States; M. Pfisterer, Switzerland; A. Ross, United States; W. Rutsch, Germany; Z.
Sadowski, Poland; M. Simoons, Netherlands; A. Vahanian, France; W.D. Weaver, United States; H. White, New Zealand; and R. Wilcox, United
Kingdom.
Coordinating Center: Duke University Medical Center, Durham, N.C.: Clinicians: R. Califf and G. Granger; Statistical Director: K. Lee; Statisticians: K.
Pieper and L. Woodlief; Administrators: S. Karnash, J. Melton, and J. Snapp; Coordinators: L. Berdan, K. Davis, B. Hensley, C. Huffman, E. KlineRogers, J. Lee, I. Moffie, and D. Smith; Pharmacy: D. Christopher and M. Dorsey; Programmers: C. Blackmon, B. Moss, and J. Shavendar; On-call
Physicians: R. Califf, C. Granger, B. Harrington, B. Hillegass, and M. Ohman.
Executive Center: The Cleveland Clinic Foundation, Cleveland: E. Topol, V. Stosik, D. Shyne, A. Thomas, D. Passmore, R. Wagner, D. Debowey, B.
Keogh, and P. Brickenden.
Intermediate Coordinating Center: University of Leuven, Leuven, Belgium: F. Van de Werf, I. Anastassiou, R. Brower, A. de Clerck, E. Lesaffre, A.
Luyten, A. Meuris, P. Tenaerts, S. Van Dessel, and K. Verberckmoes.
Australian Coordinating Centre: National Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia: J. Simes, E.
Belles, S. Cho, J. Fabri, K. Farac, R. McCredie, and J. Sowden.
Data and Safety Monitoring Board: E. Braunwald (Chairman), M. Bertrand, M. Cheitlin, A. De Maria, D. De Mets, L. Fisher, P. Sleight, and L. Walters.
Stroke Review Committee: N. Anderson, G. Barbash, J. Gore, P. Koudstaal, W. Longstreth, M. Simoons, M. Sloan, R. Tadmor, W.D. Weaver, and H.
White.
United States, Northeast (4369) (Connecticut, Massachusetts, Maine, New Hampshire, Vermont, New York, and Rhode Island): G. Macina, K.
Salzsieder, C. Lambrew, R. Bishop, G. Gacioch, N. Jamal, J. Alexander, J. Layden, R. Grodman, J. DeSantis, H. Zarren, J. Cirbus, J. Morrison, D.
Urbach, M. Capeless, E. Davison, G. MacDonald, B. Zola, G. Ryan, J. DiCola, J. Babb, W. Andrias, A. Binder, J. Robbins, P. Zwerner, M. Weinberg, J.
Gore, C. Levick, A. Macina, R. Wallach, D. Miller, R. Kohn, A. Merliss, M. Falkoff, A. Sadaniantz, J. Greenberg, R. Parkes, W.H. Gaasch, S. Zeldis, L.
Pinsky, M. Bakerman, B. Gaffney, M. Kaulbach, S. Labib, M. Therrien, A. Riba, J. Hanna, N. Brandon, S. Jacoby, H. Cabin, R. Dewey, D. Miller, J.
Moses, A. Khan, V. LaDelia, R. Klare, H. Seidenstein, D. Losordo, M. Kukin, J. Strain, A. Rosenfeld, D. McCord, P. Bruno, P. Reiter, S. Blatt, A. Fass, A.
Thomas, R. Shulman, B. Lindenberg, M. Bleiberg, J. Holbrook, M. Dharawat, J. Tumolo, S. Sheikh, G. Farrish, N. Niles, J. George, A. Sgalia, D. Parikh,
E. Funk, C. Manning, E. Kosinski, R. Vince, H. Sanghvi, L. Sherman, J. Hsueh, F. Zugibe, L. Pisaniello, M. Sands, E. Pollak, Jr., E. Kehoe, M.
Abdel-Azim, and B. Platt.
Southeast (3447) (North Carolina, South Carolina, Virginia, and Florida): J. McBride, P. Goodfield, M. Frey, P. Micale, E. Alsbrook, G. Miller, W.
Maddox, R. Iwaoka, H. Morse, G. Pilcher, N. Trask, III, R. Jesse, M. Collins, J. Schrank, L. Howard, K. Sheikh, J. Puma, R. Califf, J. Barnes, B. Hearon, J.
Dorchak, J. Kenerson, M. Johnson, J. Pasteriza, A. Magee, R. Schneider, C. Ashby, J. Nobel, M. Goldberg, J. Morris, S. Mester, W. Stuck, A.
Rosenblat, G. Thomas, J. Smith, W. Ellison, W. Levy, M. Glover, D. Eich, P. Popper, K. Gibbs, R. Seagle, G. Lane, K. Popio, A. Blaker, A. Tse, D.
McMillan, R. Vicari, A. Whitaker, D. Mokotoff, S. Roark, D. Ike, A. Ghahramani, C. Davenport, J. Hoekstra, D. Givens, R. Dunkelberg, R. Schneider, M.
Clark, F. Lenz, M. Whisenant, M. Lopez, S. Schnider, J. Strickland, R. Palaniyandi, R. Stack, A. Bartel, T. Long, E. Hawkins, R. Everhart, R. Goulah, R.
Lewis, R. Thigpen, S. West, J. Anderson, M. Hajisheik, and D. Privette.
Great Lakes (3155) (Indiana, Kentucky, Michigan, and Ohio): R. Josephson, R. Schumacher, K. Mohan, G. Litman, J. Formolo, D. Besley, A. Klaus, L.
Calli, Jr., W. Duvernoy, J. Heinsimer, J. Schaeffer, R. Miller, R. Stomel, E. Papasifakis, M. Zande, J. Jacobs, J. Kazmierski, K. Holland, F. Griff, W.
Whitaker, S. Weinberg, J. VanGilder, J. Rogers, D. Dageford, P. Bacidore, M. Rubin, R. Reynolds, A. Razavi, J. Hodgson, R. Millsaps, F. Wefald, T.
Fraker, Jr., R. Vanderlaan, K. Scully, B. Morrice, J. Forchetti, R. Kurtz, W. Meengs, A. Weizenberg, M. Tejura, E. Bates, P. Fleisher, B. Perry, M.
Kreindel, D. Kereiakes, T. Vrobel, M. James, E. Basse, P. Andres, B. Lew, S. Zampani, M. Gheorghiade, C. Milford, W. Wilson, S. Bhatia, T. Doyle, S.
Traughber, W. Polinski, S. Brownstein, E. Topol, M. Meyer, T. Heft, K. Kuppler, B. Schilt, V. Mistry, and D. Booth.
Mid-atlantic (3130) (District of Columbia, Delaware, Maryland, New Jersey, Pennsylvania, and West Virginia): R. Bahr, A. Doorey, T. Krisanda, J.
Smith, R. Biern, J. Gregory, N. Strahan, A. Bramowitz, R. Gordon, J. Ibarra, A. Ross, S. Worley, W. Berkowitz, R. Fields, M. Effron, K. Lindgren, E.
Roseff, M. Avington, S. Sharma, J. Banas, W. Beckwith, V. Krishnaswami, T. Boyek, H. Dale, J. Zimmerman, J. Burks, L. Gehl, A. Meshkov, R.
Rubinstein, G. Groman, J. Ellis, IV, A. Popkave, D. Ferri, M. Santer, Jr., L. Konecke, K. Singal, J. Wertheimer, H. Selinger, M. Borsch, H. Starr, T. Parris,
M. Pecora, J. Patankar, W. Noble, G. Grossman, B. Clemson, D. Rosing, L. Denlinger, L. Adler, H. Goldschmidt, J. O'Toole, D. McCormick, J. Granato,
C. Naganna, E. Gerber, T. Little, R. Angeli, W. Markson, O. Randall, M. Kesselbrenner, K. Olsen, W. Esper, and K. Hawthorne.
Southwest (2584) (Arizona, Colorado, Idaho, Kansas, Montana, New Mexico, Texas, Utah, and Wyoming): M. Padnick, H. White, Jr., M. Stern, T.
Lombardo, J. Svinarich, P. Browne, J. Saini, N. Laufer, S. Ung, D. Rigby, J. Perry, A. Mattern, N. Shadoff, V. Aquino, A. Newton, L. Lancaster, D.
Gonzalez, G. Symkoviak, W. Falcone, N. Israel, R. Scott, G. Hui, J. Boerner, K. Nademanee, J. Sbarbaro, M. Kraus, H. Lee, D. Sellers, B. Owens, S.
Harris, D. Brown, M. Solovay, A. Damien, S. Woolbert, B. Call, M. McGuire, T. Glatter, R. Davis, E. Terry, C. Castle, R. Oliveros, J. Laser, C. Haws, R.
Park, F. Cecena, C. Dahl, S. Gollub, R. Heuser, G. Peese, M. Sanz, C. Brooks, C. Schechter, J. Gladden, R. Bond, M. Crawford, R. Loge, J. Moreland, L.
Faitelson, W. Lewis, R. Dattilo, M. Carbajal, R. Tabbaa, G. Rodgers, J. Morgan, M. Traylor, C. Unrein, R. Crossno, and C. Wilkins.
Midwest (2498) (Illinois, Wisconsin, Missouri, South Dakota, North Dakota, Nebraska, Iowa, and Minnesota): G. Hanovich, W. Hession, B.
Abramowitz, J. Thompson, S. Kopecky, L. Cook, J. Drozda, L. Swenson, P. Schmidt, A. Mooss, B. Anderson, D. Goldsteen, F. Ferrigni, A. Edin, C.
Santolin, J. Alexander, K. Fullin, J. McCriskin, G. Taylor, D. Shuster, L. Solberg, R. Menning, L. Abrahams, J. Epplin, S. Benton, B. Handler, N.
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Streitmatter, M. Saddin, W. Lam, I. Silverman, R. Dinter, W. Frank, D. Zwicke, D. Pfefferkorn, T. Matzura, D. Meyers, S. Bloom, C. Jones, P. Quandt,
M. Wheeler, C. Monroe, D. Jenny, H. Coleman, R. Holm, L. Shelhamer, Jr., G. Grix, P. Leutmer, R. Harner, C. Koeppl, R. Yawn, P. Anantachai, K.
Jaeger, B. Patel, M. Cinquegrani, T. Dynes, C. Campanella, D. Larson, S. Gill, C. Thompson, K. Kavanaugh, N. Harb, D. Dixon, J. Carr, J. Shanes, V.
Miscia, A. Hsieh, and R. Pensinger.
West (2198) (Alaska, California, Hawaii, Nevada, Oregon, and Washington): P. Lightfoot, R. Swenson, P. Sarkaria, R. Acheatel, J. Rudoff, R.
Anschuetz, E. Lapin, R. Spiegel, P. Lai, B. Strunk, W. Rowe, R. Finegan, B. Gross, J. Chappell, T. Berndt, B. Titus, R. Oikawa, R. Ashmore, D. Bayne, G.
Wesley, E. Quinn, K. Jutzy, G. Fehrenbacher, P. Kotha, P. Phillips, K. Ryman, J. Holmes, H. Kwee, D. Cislowski, R. Bream, T. Elder, III, H. Olson, R.
Trenouth, C. Wolfe, S. Raskin, J. Comazzi, K. Stokke, M. Nallasivan, D. Hogle, B. Kennelly, E. Wroblewski, J. Altamirano, E. Chesne, A. Choe, and A.
Brodersen.
Middle South (1724) (Alabama, Georgia, Louisiana, Oklahoma, Tennessee, Arkansas, Mississippi, and Florida): S. Sherman, E. Pickering, J.
Kalbfleisch, C. Williams, J. Dedonis, M. Silverman, M. Geer, K. Wright, D. Williams, W. Guest, R. Sinyard, Jr., Z. Baber, S. Howell, III, R. Ingram, D.
Morris, W. Beeson, R. Schlant, V. McLaughlin, H. Hanley, G. Olson, P. Gainey, D. Shonkoff, Y. Ong, G. Phillips, F. Kushner, C. White, J. Hoopes, P.
Breaux, J. Lam, M. Honan, R. Hill, M. Certain, H. Ba'abaki, T. Atha, H. Butler, L. Battey, J. Scott, G. Cash, P. Mullen, R. Wrenn, A. DeLeon, U. Thadani,
L. Price, E. Magiros, and P. Subramaniam.
Israel (2944): H. Hamerman, D. David, S. Sklerovsky, G. Barbash, B. Peled, S. Laniado, N. Rogin, S. Schlezinger, I. Zehavi, A. Caspi, E. Barash, Y.
Kishon, A. Keren, A. Palant, E. Avineder, T. Weis, L. Reisin, D. Zivony, L. Rudnik, B. Luis, A. Marmur, M. Gotesman, and E. Gelvan.
Canada (2898): S. Roth, D. Roth, M. Traboulsi, M. Henderson, K. Finnie, J. Burton, R. Trifts, J. McDowell, P. Klinke, R. Lesoway, M. Senaratne, B.
Lubelsky, E. Goode, M. Cheung, P. Bogaty, B. Burke, C. Morgan, M. Turek, A. Hess, C. Lefkowitz, J. Charles, P. Armstrong, A. Fung, G. Kuruvilla, D.
Langleben, B. Hrycyshyn, C. Kells, R. Delarochelliere, V. Sluzar, K. Kwok, M. Goddard, J. Fulop, J. Brophy, A. Zawadowski, B. Sahay, F. Ervin, C.
Thompson, A. Abdulla, K. Boroomand, C. McMillan, P. Carter, P. Laramee, R. Hathaway, M. O'Reilly, S. Vizel, D. Hilton, G. Jablonsky, P. Bolduc, L.
Simard, N. Ranganathan, D. Gould, L. Bate, D. Cameron, B. Mackenzie, P. Greenwood, D. Gossard, J. Blakely, J. Morch, R. Mildenberger, N. Racine,
and H. Baillie.
Netherlands (2299): A.E.R. Arnold, J.G. Engbers, B.J.L. DeRode, G.P. Molhoek, P.M. Van Kalmthout, L. Cozijnsen, C.L. Van Engelen, J.H.M.
Deppenbroek, S.K. Oei, J.B.L. ten Kate, M.J. de Leeuw, G.J. Laarman, J.V.C. Stevens, D. Haan, L. van Bogerijen, W.C.G. Smits, P.W. Westerhof, P.W.J.
Stolwijk, H.A.M. Spierenburg, E.J. Muller, B. Cernohorsky, J.J.J. Bucx, H.J.A.M. Penn, H. Fintelman, C. Van Rees, M.L. Simoons, J. Kerker, E.G. Faber,
R. Bergshoeff, H.W.O. Roeters Van Lennep, W. Muys v/d Moer, L. Relik-van Wely, F. van Bemmel, R.J. Bos, A. Zwiers, C.M. Leenders, P. Zijnen, D.G.
de Waal-Ultee, H. De Rebel-De Vries, S.A.G.J. Witteveen, and P. de Weerd.
Australia (2287): P. Aylward, B. Hockings, M. Brown, D. Cross, G. Lane, G. Aroney, D. Hunt, B. Singh, A. Tonkin, P. Thompson, G. Nelson, R.
Newman, J. Federman, T. Campbell, J. Healey, D. Ramsey, W. Ryan, J. Counsell, D. Coles, A. Thomson, S. Woodhouse, G. Simmons, P. Harris, P.
Caspari, A. Limaye, T. Donald, S. Coverdale, G. Smith, R. Walker, R. Harper, C. Gnanharan, P. Carroll, J. Woods, C. Hadfield, P. French, A. Groessler,
B. Morphett, G. Phelps, B. Quinn, K. Gunawardane, P. Kertes, C. Medley, A. Soward, T. Htut, A. Appelbe, J. Johns, I. Beinart, R. Hynes, M. Knapp, P.
Curteis, D. Owensby, P. Davidson, W. Renton, P. Windsor, L. Bolitho, B. Forge, R. Ziffer, R. McLeay, R. Cranswick, and L. Mollison.
Belgium (2030): H. De Geest, F. Van de Werf, G. Verstreken, J. Col, R. Beeuwsaert, J. Boland, A. Vanrossum, H. Lesseliers, R. Popeye, Ph. Dejaegher,
B. Pirenne, E. Van der Stichele, J. Chaudron, M. Castadot, L. Dermauw, G. Vanquickenborne, W. Van Meghem, H. Robijns, M. Vankuyk, C.
Emmerechts, D. Dendooven, H. Van Brabandt, E. Installe, S. Dierickx, C. Haseldonckx, H. Lignian, J. Beys, P. Noyens, A. Van Dorpe, Ph. Henry, Ph.
Van Iseghem, F. Gielen, D. Lanoy, P. DeCeuninck, J. Schurmans, L. Geutjens, M. Carlier, P. Surmont, Ch. Henuzet, P. Van Robays, R. Stroobandt, P.
Peerenboom, C. Mortier, X. Dalle, K. Mitri, U. Van Walleghem, J. Bonte, D. Koentges, A. De Paepe, L. DeWolf, Th. Sottiaux, J. Van Besien, P. Van den
Heuvel, H. Ulrichts, Y. Deheneffe, H. Jacobs, J. Croonenberghs, L. Pirot, J. Carpentier, R. Schreuer, L. Vermeersch, D. Stroobants, D. Missotten, E.
Marchand, S. De Schepper, B. Carlier, Ch. Doyen, A. Palmer, M. Jottrand, C. Gillebert, M. Bayart, A. Van Wylick, J. Leonard, and E. Benit.
Germany (1282): W. Rutsch, H. Topp, H. Simon, H. Ditter, P. Wylicil, H. Meyer-Hoffmann, H.P. Nast, R. Engberding, K. Caesar, U. Schmitz, W.
Jansen, H.R. Ewers, H.U. Kreft, D. Kaut, P. Schweizer, J. Cyran, U. Peters, E. Horstmann, R. Koch, R. Scheemann, J. Bolte, W. Berges, K.P. Schueren,
M.H. Hust, H.U. Koch, W. Overbuschmann, B. Henkel, S. Troost, R. Jacksch, W. Burkhardt, H. Loellgen, J. Schimanski, H. Callsen, P.W. Kummerhoff,
H. Hochrein, G.M. Mueller, H. Schulz, V. Hossmann, F. Voehringer, D. Boettcher, P. Glogner, K.H. Hohmann, H.J. Von Mengden, W. Krengel, B.
Maisch, P. Spiller, M. Adamczak, R. Wacker, W. Urbaszek, H.D. Bundschu, W. Ernst, R. Eisenreich, M. Konz, C. Dienst, J.G. Schmailzl, A. Gartemann,
W. Sill, C. Piper, J. Schiffner, N. Meyer-Guenther, D. Siebenlist, E. Chorianapoulos, R. Schroeder, P. Oehl, W. Lengfelder, J. Djonlagic, H.W. Hopp, W.
Weser, P. Kahl, P.H. Althoff, R. Hopf, R. Oberheiden, H.V. Lilienfeld-Toal, G. Schulte-Herbrueggen, and P. Doenecke.
France (1239): J. Valty, A. Py, J. Acar, A. Vahanian, G. Grollier, D. Barreau, K. Khalife, J.C. Quiret, X. Tran Thanh, J.P. Bourdarias, P. Besse, M. Hiltgen,
P. Bernadet, J. Boschat, C. Gully, J.M. Mossard, B. Charbonnier, F. Funck, M. Bedossa, R. Grolleau-Raoux, J. Cassagnes, J.C. Daubert, Ph. Beaufils,
J.M. Juliard, G. Bessede, B. Vitoux, C. Thery, G. Hanania, C. Mycinski, E. Brochet, C. Cassat, C. Socolovsky, R. Mossaz, J.L. Fincker, M. Lang, J.L.
Guermonprez, J.M. Demarcq, A. Page, C. Guerot, R. Barraine, Ph. Morand, A. Bajolet, J. Vedel, P. Dambrine, H. Lardoux, B. Veyre, A. Vacheron, F.
Latour, J.P. Normand, J.Y. Thisse, J. Machecourt, J.P. Bassand, B. Carette, C. Toussaint, J.P. Cebron, M.F. Bragard, Ph. Geslin, O. Leroy, G. AllardLatour, F. Fockenier, J. Gauthier, M. Escande, and M. Viallet.
United Kingdom (1050): R.G. Wilcox, R.D. Thomas, R.M. Boyle, R.H. Smith, E.T.L. Davies, J. Kooner, G. Terry, B. Gould, M.O. Coupe, J.E.F. Pohl, E.W.
Barnes, H. Simpson, A. Davis, J.A. Bell, I.N. Findlay, P. Wilkinson, G.C. Sutton, T.S. Callaghan, E.J. Wakely, D. Waller, G. Tildesley, and R.L. Blandford.
New Zealand (666): P. Leslie, H. Ikram, S. Foy, S. Mann, A. Mylius, S. Anandaraja, M. Singh, D. Friedlander, B. Bruns, L. Nairn, M. Abernethy, R.
Rankin, D. Durham, J. Doran, M. Audeau, H. White, S. Reuben, G. Lewis, H. Hart, and G. Wilkins.
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Spain (467): G. Froufe, X. Bosch, F.F. Aviles, C.M. Luengo, J. Corrons, L.L. Bescos, A. Loma, R. Masia, J. Figueras, V. Valle, L. Saenz, A. Betriu, E.
Alegria, and J. Eizaguirre.
Poland (360): T. Kraska, J. Kuch, A. Dyduszynski, J. Stepinska, K. Wrabec, E. Czestochowska, Z. Sadowski, K. Zawilska, Z. Kornacewicz-Jach, E.
Nartowicz, W. Piwowarska, G. Swiatecka, J. Wodniecki, T. Petelenz, and A. Kalicinski.
Switzerland (209): P. Urban, M. Pfisterer, O. Bertel, H.R. Jenzer, W. Angehrn, and H.R. Baur.
Ireland (185): K.M. Daly, J. Horgan, M. Walsh, J. Taaffe, D. Murray, D. Sugrue, P. Sullivan, B.C. Muldoon, D. McCoy, B. Maurer, G. Fitzgerald, T.
Pierce, and K. Balnave.
Luxembourg (22): R. Erpelding.
Related Letters:
Thrombolytic Therapy for Myocardial Infarction
Montgomery H., Speechly-Dick M.E., Pechlaner C., Lechleitner P., Ross A. M.
Extract | Full Text
N Engl J Med 1994; 330:1089-1090, Apr 14, 1994. Correspondence
Thrombolytic Therapy for Acute Myocardial Infarction: GUSTO Criticized
Friedman H. S., Chelluri L., Sirio C. A., Angus D. C., Ogunyankin K., Topol E. J., Califf R. M., Van de Werf F., Fuster V.
Extract | Full Text
N Engl J Med 1994; 330:504-506, Feb 17, 1994. Correspondence
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More on the GUSTO Trial
Topol E. J., Califf R. M., Lee K. L.
Extract | Full Text
N Engl J Med 1994; 331:277-278, Jul 28, 1994. Correspondence
Related Article
by Topol, E. J.
PubMed Citation
Thrombolytic Therapy for Myocardial Infarction
Frei S., Brophy J., Andreotti F., Thron C. D., Topol E. J., Califf R. M., Wilcox R., The GUSTO III Steering Committee , Van de Werf F., The COBALT
Investigators , Ware J. H., Antman E. M.
Extract | Full Text
N Engl J Med 1998; 338:545-548, Feb 19, 1998. Correspondence
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2009/4/23 下午 21:34