Lincoff AM, Califf RM, Van de Werf F, Willerson JT, White HD, Armstrong PW, Guetta V, Gibler WB, Hochman JS, Bode C, Vahanian A, Steg PG, Ardissino D, Savonitto S, Bar F, Sadowski Z, Betriu A, Booth JE, Wolski K, Waller M, Topol EJ, for the GUSTO V Investigators . Mortality at 1 Year With Combination Platelet Glycoprotein IIb/IIIa Inhibition and Reduced-Dose Fibrinolytic Therapy vs Conventional Fibrinolytic Therapy for Acute Myocardial InfarctionGUSTO V Randomized Trial. JAMA. 2002;288(17):2130-2135. doi:10.1001/jama.288.17.2130
Author Affiliations: Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (Drs Lincoff and Topol and Mss Booth and Wolski); Duke Clinical Research Institute, Durham, NC (Dr Califf); University Hospital Gasthuisberg, Leuven, Belgium (Dr Van de Werf); Houston Medical Center, Houston, Tex (Dr Willerson); Green Lane Hospital, Auckland, New Zealand (Dr White); University of Alberta Hospital, Edmonton (Dr Armstrong); Chaim Sheba Medical Center, Ramat Gan, Israel (Dr Guetta); University of Cincinnati Medical Center, Cincinnati, Ohio (Dr Gibler); St Luke's Hospital, New York, NY (Dr Hochman); Medizinische Universitatsklinik, Freiburg, Germany (Dr Bode); Hopital Tenon, Paris, France (Dr Vahanian); Hopital Bichat, Paris, France (Dr Steg); Azienda Ospedaliera Di Parma, Parma, Italy (Dr Ardissino); Ospedale Niguarda Ca' Granda, Milan, Italy (Dr Savonitto); Academisch Ziekenhuis Maastricht, Maastricht, Netherlands (Dr Bar); National Institute of Cardiology, Warsaw, Poland (Dr Sadowski); University of Barcelona Hospital Clinic, Barcelona, Spain (Dr Betriu); and Centocor Inc, Malvern, Pa (Dr Waller). A complete list of the investigators and participating centers was published previously (Lancet. 2001;357:1905-1914).
Context Among patients with acute myocardial infarction, combination reperfusion
therapy with a platelet glycoprotein IIb/IIIa receptor inhibitor (abciximab)
and a half dose of a plasminogen activator (reteplase) did not significantly
reduce mortality at 30 days compared with a full dose of reteplase. Rates
of nonfatal ischemic complications were significantly diminished.
Objective To determine if the beneficial effects of abciximab and reteplase (combination
therapy) on early nonfatal complications would translate into a reduction
in the risk of death by 1 year.
Design, Setting, and Patients One-year follow-up of a randomized controlled trial (Global Use of Strategies
To Open Coronary Arteries [GUSTO] V). Of 16 588 patients who had been
treated in 820 community and referral hospitals in 20 countries between July
1999 and February 2001, mortality data were available for 16 453 (99.2%).
Intervention Patients were randomly assigned to receive (intravenously) a standard
dose of reteplase (two 10-U boluses, 30 minutes apart) or the combination
of a standard dose of abciximab (0.25 mg/kg bolus, 0.125 µg/kg per minute
infusion [maximum 10 µg/min for 12 hours]) and a half dose of reteplase
(two 5-U boluses, 30 minutes apart).
Main Outcome Measure One-year all-cause mortality rates.
Results All-cause mortality at 1 year occurred in 692 (8.38%) of 8260 patients
in the reteplase group and 698 (8.38%) of the 8328 patients in the combination
therapy group (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.90-1.11; P>.99). Reinfarction within the first 7 days occurred in
3.5% of patients in the reteplase group and 2.3% of patients in the combination
therapy group, and was significantly associated with 1-year mortality (22.6%
in patients with reinfarction vs 8.0% in patients without reinfarction; HR,
3.08; 95% CI, 2.53-3.75; P<.001). However, treatment
assignment did not significantly influence time of mortality regardless of
Conclusion Combination therapy (abciximab and reteplase) did not reduce mortality
over 1 year compared with fibrinolytic therapy with reteplase alone.
Myocardial reperfusion remains the foundation of early management of
acute myocardial infarction (MI). Although demonstrated to improve survival
in this setting,1,2 contemporary
pharmacologic reperfusion therapies appear to have reached a plateau in mortality
reduction.3,4 Interest has turned
to the development of adjunctive strategies that may enhance the effectiveness
of fibrinolytic agents. Pilot angiographic studies among patients with acute
MI indicated that potent inhibition of platelet aggregation with glycoprotein
IIb/IIIa receptor antagonists in combination with reduced doses of fibrinolytic
agents may increase rates of epicardial infarct vessel patency and improve
the quality of microvascular tissue reperfusion relative to conventional plasminogen
activator therapy.5- 7
The Global Use of Strategies To Open Coronary Arteries (GUSTO) V trial
evaluated the efficacy of abciximab and a half dose of reteplase (combination
therapy) compared with a full dose of reteplase during acute MI.8 Among
16 588 enrolled patients, combination therapy did not result in a significant
incremental reduction in the primary end point of mortality at 30 days: 5.9%
for reteplase alone vs 5.6% for abciximab and reteplase (P = .43). However, the combination regimen was associated with less
frequent need for percutaneous coronary revascularization during the first
6 hours (8.6% for reteplase alone vs 5.6% for abciximab and reteplase; P<.001), as well as lower rates of nonfatal reinfarction
(3.5% vs 2.3%, respectively; P<.001), recurrent
ischemia, and clinically important arrhythmias during hospitalization. The
analysis described in this article was performed to determine if the early
beneficial effects of abciximab and reteplase would translate into a significant
reduction in the risk of death during 1-year follow-up.
The design, methods, and primary results of the GUSTO V trial have been
described.8 Briefly, 16 588 patients were
enrolled at 820 hospitals in 20 countries between July 1999 and February 2001.
Inclusion criteria were continuous symptoms of chest discomfort for at least
30 minutes, but for less than 6 hours before randomization, associated with
electrocardiographic ST-segment elevation or new left bundle-branch block.
Patients for whom immediate catheter-based reperfusion was planned were excluded
from enrollment. Other exclusion criteria included age younger than 18 years;
active bleeding or known hemorrhagic diathesis; systolic blood pressure greater
than 180 mm Hg or diastolic blood pressure greater than 110 mm Hg; stroke
within the previous 2 years or hemorrhagic stroke at any time; structural
central nervous system abnormality; major surgery or trauma within the prior
6 weeks; ongoing warfarin therapy; noncompressible vessel puncture within
the prior 24 hours; use of a glycoprotein IIb/IIIa inhibitor during the previous
7 days; or documented thrombocytopenia (platelet count <100 000/µL).
The protocol was approved by the institutional review board at each clinical
site, and all patients provided written informed consent for participation
in the trial and 1-year follow-up.
Patients were randomized by central telephone hotline in a 1:1 ratio
to receive intravenously either a standard dose of reteplase (two 10-U boluses,
30 minutes apart) or the combination of a standard dose of abciximab (0.25
mg/kg bolus, 0.125 µg/kg per minute infusion [maximum 10 µg/min]
for 12 hours) and a half dose of reteplase (two 5-U boluses, 30 minutes apart).
Adaptive randomization was used to maintain an allocation ratio of 1:1 within
each site. Study drug kits were not distinguishable before opening, but reteplase
and abciximab were administered in an open-label manner.
All patients were treated with aspirin at the time of randomization
and daily thereafter for the remainder of the study period. Intravenous unfractionated
heparin was given according to a nomogram to maintain an activated partial
thromboplastin time between 50 and 70 seconds for 24 hours; initial doses
were a 5000-U bolus followed by a 1000 U/h (or 800 U/h for body weight <80
kg) infusion in the reteplase monotherapy group and a 60 U/kg (maximum 5000
U) bolus followed by 7 U/kg per hour infusion in the abciximab and reteplase
(combination therapy) group. Coronary angiography and revascularization could
be performed if indicated by the patient's clinical course. All other medical
therapies were left to the discretion of the treating physician.
The primary efficacy end point was all-cause mortality by 30 days after
randomization. Other early end points included the incidence of myocardial
reinfarction, as evidenced by new electrocardiographic changes or elevation
in cardiac enzyme levels with recurrent chest pain, during the hospitalization
or within 7 days (whichever came first). Mortality at 1 year was a prospectively
defined secondary analysis.
The protocol required that patients be contacted by the study sites
via telephone or written questionnaire at or after 365 days postrandomization
for assessment of vital status. For analysis purposes, confirmed vital status
information on or after day 335 postrandomization was accepted. The Kaplan-Meier
method was used to calculate event rates and treatment groups were compared
using the log-rank statistic. Treatment effects in subgroups are displayed
as hazard ratios (HRs) and 95% confidence intervals (CIs) calculated using
univariable Cox proportional hazards regression models. Analyses were conducted
according to the intention-to-treat principle using SAS statistical software
(Version 8; SAS Institute Inc, Cary, NC) and P<.05
was the level of significance.
The 1-year follow-up database was finalized on April 23, 2002. Mortality
status at or beyond 335 days after randomization was available for 8196 (99.2%)
of 8260 patients in the reteplase group and for 8257 (99.1%) of 8328 patients
in the abciximab and reteplase group (Figure
1). Baseline characteristics were balanced and did not differ between
the 2 treatment groups (Table 1).
The patients' mean (SD) age was 61.3 (12.1) years. Twenty-five percent of
the patients were women and 16% had diabetes mellitus. The mean (SD) time
from onset of symptoms to randomization was 2.7 (2.0) hours. Thirty-seven
percent of MIs were anterior in location and 98% of patients were classified
as Killip class I or II. Aspirin had been administered before randomization
to 71% of patients, β-adrenergic receptor blockers to 19%, and angiotensin-converting
enzyme inhibitors to 14%. Rates of revascularization by hospital discharge
were significantly lower in the combination therapy group, due entirely to
the reduced need for percutaneous intervention within the first 6 hours (8.6%
for reteplase alone vs 5.6% for abciximab and reteplase; P<.001).
All-cause mortality at 1 year occurred in 692 (8.38%) of 8260 patients
in the reteplase group compared with 698 (8.38%) of 8328 patients in the abciximab
and reteplase group (HR, 1.00; 95% CI, 0.90-1.11; P>.99).
The nonsignificant absolute mortality difference of 0.3% observed at 30 days
in favor of combination therapy (5.9% for reteplase vs 5.6% for abciximab
and reteplase) was maintained until approximately 90 days (6.9% for reteplase
vs 6.6% for abciximab and reteplase), after which the mortality curves converged
and remained superimposed beyond 180 days (Figure 2). One-year mortality rates at 30 days and 1 year in the
prespecified subgroups are compared in Figure
3. Although trends had been observed at 30 days for a mortality
advantage with abciximab and reteplase in patients aged 75 years or younger
or those with anterior infarction, diabetes, or time to treatment of more
than 4 hours, differences in outcome were less apparent in those subgroups
by 1 year.
Reinfarction within 7 days of randomization had occurred in 285 patients
(3.5%) in the reteplase group and 194 patients (2.3%) in the abciximab and
reteplase group (P<.001). The rate of subsequent
mortality by 1 year was significantly higher among patients who had experienced
reinfarction (22.6%) than among those who did not (8.0%) (HR, 3.08; 95% CI,
2.53-3.75; P<.001). When only those deaths occurring
after the 7-day period for assessment of the reinfarction end point were considered,
the excess risk of 1-year mortality associated with reinfarction was even
more marked (HR, 6.65; 95% CI, 5.43-8.16; P<.001).
Treatment assignment (reteplase vs abciximab and reteplase) did not significantly
influence time of mortality regardless of reinfarction status (reinfarction:
20.4% vs −25.8%; without reinfarction: 8.0% vs 8.0%, respectively).
The GUSTO V trial was the first large-scale study to test an alternative
strategy for pharmacologic reperfusion during acute MI, in which a reduced-dose
fibrinolytic agent was combined with a potent antithrombotic adjunct. Although
a mortality advantage of abciximab and reteplase relative to reteplase alone
had not been observed at 30 days, the combination regimen had been associated
with a decreased incidence of reinfarction and other nonfatal complications.8 In this follow-up analysis of GUSTO V, mortality rates
at 1 year were the same among patients treated with abciximab and reteplase
compared with reteplase alone, demonstrating that the combination regimen
does not lead to a superior long-term survival benefit despite the early protection
it affords from ischemic events.
The efficacy of fibrinolytic therapy for acute MI remains limited by
incomplete restoration of infarct vessel patency, persistent cyclical coronary
flow, reocclusion, or impaired tissue level reperfusion in a substantial proportion
of patients.9 Although bioengineered with improved
fibrin specificity, circulating half-lives, or resistance to inhibitors, the
"third generation" plasminogen activators have nonetheless failed to produce
incremental clinical benefit in large-scale mortality trials.3,4 Moreover,
pharmacologic reperfusion therapy continues to be associated with disturbingly
high rates of intracranial hemorrhage and other bleeding complications. Alternatively,
direct percutaneous coronary revascularization has been shown in randomized
trials to reduce composite end points of death, reinfarction, or stroke compared
with fibrinolysis.10,11 Mechanical
reperfusion strategies are subject to limited availability, the requirement
for institutional and operator expertise, and logistic barriers to mobilizing
catheterization laboratory teams during nonworking hours.
The unequivocal efficacy of aspirin among patients with acute MI suggested
that the clinical benefit derived from fibrinolytic therapy might be improved
by adjunctive use of more potent platelet inhibitors. In small pilot trials,
administration of a glycoprotein IIb/IIIa receptor antagonist during thrombolysis
appeared to increase the speed and completeness of infarct vessel recanalization
and reduce reocclusion.12- 14 Concerns
regarding the potential for bleeding with the combination of a potent platelet
inhibitor and a full-dose thrombolytic agent motivated the current investigation
of low-dose fibrinolytic regimens with glycoprotein IIb/IIIa blockade. Phase
2 studies provided preliminary evidence that doses of reteplase or alteplase
could be reduced by half when abciximab was also given, providing not only
better infarct vessel patency relative to conventional fibrinolytic therapy,
but also more complete resolution of electrocardiographic ST-segment elevations.5- 7 It was perhaps somewhat
surprising, then, that when tested in the large-scale GUSTO V mortality trial,
this reperfusion strategy resulted in only a nonsignificant 0.3% decrease
in the rate of death by 30 days relative to conventional reteplase monotherapy.8 More encouraging, however, was the finding of an apparent
improved stability of reperfusion with combination therapy, as evidenced by
significant reductions in rates of reinfarction, recurrent ischemia, and early
urgent revascularization procedures. The subsequent Assessment of the Safety
and Efficacy of a New Thrombolytic Regimen (ASSENT) 3 trial confirmed this
observation, wherein the combination of abciximab and half dose of tenecteplase
was associated with 37% to 51% relative reductions in the risks of reinfarction,
refractory ischemia, or urgent percutaneous revascularization compared with
Given that nonfatal ischemic complications, particularly reinfarction,
have been associated with increased long-term mortality following acute MI,16 it was anticipated that the early beneficial effects
of abciximab and reteplase in GUSTO V might translate to a significant reduction
in the risk of death over extended follow-up. The 1-year analysis of GUSTO
V failed to confirm this hypothesis. Rates of mortality were identical in
the 2 treatment groups at 1 year, with superimposition of the time-to-event
curves after the first 6 months.
Reasons for the lack of a survival benefit with combination therapy
in GUSTO V despite apparent improvements in epicardial vessel recanalization
and tissue level reperfusion in earlier trials remain unclear. It is possible
that the 13% increase in infarct vessel patency observed in the angiographic
pilot study with abciximab and reteplase compared with reteplase alone (55%
vs 48%, respectively)6 was not of sufficient
magnitude to produce an improvement in mortality. It may be relevant to note
that the significant reduction in mortality obtained with alteplase vs streptokinase
in the GUSTO I trial17 was accompanied by more
than a 74% relative increase in the rate of 90-minute angiographic coronary
patency (54% vs 31%, respectively; P<.001).18 The potential for modest improvements in angiographic
end points to influence mortality may have been diminished in GUSTO V by the
high use rates of other therapies (aspirin, β-blockers, and angiotensin-converting
enzyme inhibitors), which have been proven to enhance clinical outcome following
MI. It is also unknown if and how the difference in use of early percutaneous
interventions affected long-term survival. Moreover, baseline characteristics
suggest that the population of patients enrolled in GUSTO V may have been
at relatively low risk for mortality, further limiting the ability of the
trial to discriminate a benefit of combination therapy. Finally, the extent
to which any improvement in myocardial reperfusion can impact long-term survival
is likely to remain suboptimal when delays of approximately 3 hours between
the onset of symptoms and treatment have allowed substantial irreversible
myocardial necrosis to occur.
Should this therapy have any role in the contemporary management of
acute MI? Although a survival benefit cannot be expected, abciximab and reteplase
combination therapy may be a useful reperfusion strategy because of its effect
on nonfatal end points. Notably, the results of GUSTO V confirmed that in-hospital
reinfarction has an unfavorable long-term prognosis, with a 3- to 6-fold increase
in the risk of death by 1 year among patients who experienced reinfarction
compared with those who did not. Data regarding cause of death were not collected
within this trial format, and thus these findings do not elucidate the mechanisms
of mortality risk associated with reinfarction. Previous analyses of smaller
trials, however, have demonstrated that coronary reocclusion is associated
with impaired recovery of global and infarct-zone regional left ventricular
function,19 suggesting a potential hazard arising
from pump dysfunction or arrhythmias.
It is nevertheless remarkable that even with contemporary medical therapies,
nearly one quarter of patients who experience reinfarction can be expected
to die within the following year. However, the absolute reduction of 1.2%
in reinfarction rates observed with the combination therapy in this trial
would be extrapolated to reduce mortality at 1 year by only approximately
0.18% (derived from the 14.6% absolute mortality reduction per patient with
reinfarction), an effect that is too small to significantly influence overall
1-year mortality event rates. Nevertheless, prevention of reinfarction and
other ischemic events may be a worthwhile objective for an individual patient
and provides a rationale for considering combination therapy.
Potential benefits of the abciximab and reteplase combination therapy
must be weighed against the near doubling of rates of nonintracranial bleeding
observed in the primary analysis,8 especially
since other combination fibrinolytic regimens under investigation may entail
less hemorrhagic risk.15,20 Preliminary
analyses suggest that older patients are at particular risk for bleeding with
abciximab and reteplase, although clinically important hemorrhage in younger
patients appears to be infrequent with this regimen (unpublished data, 2002).
Moreover, multivariate modeling has demonstrated an interaction between the
risk of intracranial hemorrhage and age, whereby patients older than 75 years
are at increased risk, while those younger than 55 years may have significant
protection against intracranial bleeding with combination therapy relative
to reteplase alone.21 Although a formal economic
analysis of GUSTO V is under way, it is unlikely that drug acquisition costs
will prove to be a crucial factor in choosing between combination and conventional
fibrinolytic therapies. The cost of abciximab is largely offset by the savings
using a half dose of the thrombolytic agent reteplase.
The potential for combination therapy to unite the current dichotomy
between mechanical and pharmacologic means of reperfusion for acute MI remains.
Complementarity is suggested by the favorable trial experience with abciximab
during primary percutaneous coronary revascularization for acute MI.22- 24 The rationale for
pretreatment with the combination of abciximab and reteplase in patients undergoing
primary intervention would be to restore epicardial vessel patency and microvascular
reperfusion during the time delay inherent in mobilizing the cardiac catheterization
laboratory. GUSTO V did not test such an approach because early percutaneous
revascularization was reserved for clinical indications of failed reperfusion
and was not used routinely. Trials are currently under way to specifically
evaluate this concept of "facilitated" percutaneous coronary intervention.
In conclusion, the 30-day and 1-year results of the GUSTO V trial together
validate the regimen of abciximab with a half dose of reteplase as the first
alternative reperfusion strategy that is at least as effective as traditional
fibrinolysis for acute MI. Although the combination of this glycoprotein IIb/IIIa
receptor antagonist with a reduced-dose fibrinolytic is neither superior nor
inferior to reteplase monotherapy with regard to short-term or long-term mortality,
it represents an incremental therapeutic advance with regard to nonfatal outcomes.
Selection of combination therapy for clinical use must be based on the perceived
balance of benefit from reduced nonfatal ischemic complications vs risk of
increased bleeding in individual patients.