(Circulation. 1998;98:2829-2835.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports* |
Clinical Outcomes of Therapeutic Agents That Block the Platelet Glycoprotein IIb/IIIa Integrin in Ischemic Heart Disease
From the Duke Clinical Research Institute, Durham, NC (D.F.K., R.M.C., R.A.H., J.E.T., V.H.); the Cleveland Clinic Foundation, Cleveland, Ohio (D.P.M., D.J.M., A.M.L., E.J.T.); and Green Lane Hospital, Auckland, New Zealand (H.D.W.).
Correspondence to Robert M. Califf, MD, Duke Clinical Research Institute, 2024 W Main St, Durham, NC 27705. E-mail calif001{at}onyx.mc.duke.edu
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—Several platelet glycoprotein (GP) IIb/IIIa receptor antagonists have been evaluated in clinical trials. We conducted a systematic overview (meta-analysis) to assess the effect of these compounds on death, myocardial infarction (MI), and revascularization.
Methods and Results—ORs were calculated for 16 randomized, controlled trials of GP IIb/IIIa inhibitors. An empirical Bayesian random-effects model combined the outcomes of 32 135 patients. There was a significant mortality reduction by GP IIb/IIIa inhibitors at 48 to 96 hours, with an OR of 0.70 (95% CI, 0.51 to 0.96; P<0.03), equivalent to a reduction of 1 death per 1000 patients treated. Mortality benefits at 30 days (OR, 0.87; 95% CI, 0.74 to 1.02; P=0.08) and 6 months (OR, 0.97; 95% CI, 0.86 to 1.10; P=0.67) were not statistically significant. For the combined end point of death or MI, there was a highly significant (P<0.001) benefit for GP IIb/IIIa inhibitors at each time point. The 30-day OR was 0.76 (95% CI, 0.66 to 0.87), or 20 fewer events per 1000 patients treated. For the composite end point of death, MI, or revascularization, there was also a highly significant (P<0.001) benefit for GP IIb/IIIa inhibitors. At 30 days, the OR was 0.77 (95% CI, 0.68 to 0.86), or 30 fewer events per 1000 patients treated. The risk differences for death, death or MI, and composite outcomes were similar at 6 months, indicating a sustained absolute improvement. Similar benefit was seen when trials were subgrouped by therapeutic indication (percutaneous intervention versus acute coronary syndromes).
Conclusions—Application of this new therapeutic class to clinical practice promises substantial benefit for both indications.
Key Words: platelet aggregation inhibitors • meta-analysis • myocardial infarction • mortality • revascularization
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In 1983, Coller and colleagues1 described an antibody that blocked the platelet glycoprotein (GP) IIb/IIIa receptor. A chimeric monoclonal antibody,2 abciximab, was later developed for treatment of patients undergoing high-risk percutaneous intervention. Prompted by the benefit of abciximab in a randomized study,3 multiple peptide and nonpeptide antagonists of the IIb/IIIa receptor have been developed.4 5 Large clinical trials6 7 have evaluated these agents for unstable angina, acute myocardial infarction (MI), and percutaneous coronary intervention indications. This article provides a meta-analysis of available studies to evaluate the impact of intravenous GP IIb/IIIa antagonists on clinical outcomes.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Trial Selection
Randomized, blinded, controlled trials of parenteral GP IIb/IIIa antagonists were identified through a MEDLINE search. Records between 1980 and 1997 were searched for the words "platelet," "random$," and ("inhibi$" or "block$"), where $ is a wild card. Published results were included when available. Publicly presented data also represented several recent trials.
Studies were subgrouped on the basis of the indication for GP IIb/IIIa
inhibition. Trials of percutaneous coronary
intervention (Table 1
) included
any study in which the intent to perform a percutaneous
procedure was an entry criterion.3 8 9 10 11 12 13 14 15 16 Acute
coronary syndrome trials enrolled patients with symptoms of
acute coronary ischemia without ST-segment elevation on
the 12-lead ECG (Table 2).6 7 17 18 19 20 The overview
analysis evaluated the entire collection of trials as well as
each of the subgroups.
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Several of these studies had multiple dose arms, and different trials of the same agents used different dosing strategies. To capture all patients exposed to this compound class, our conservative overview included all treatment arms in the analysis. Two trials (PURSUIT, PRISM Plus) had treatment arms that terminated early. Furthermore, the placebo arm event rate increased as the trials progressed. These trials were evaluated using all patients enrolled before the arm was stopped and patients in the remaining treatment arm with contemporaneous controls after the termination of the stopped arm.
Adjunctive heparin regimens also differed among trials. All
percutaneous intervention trials permitted heparin
during the procedure to maintain an activated clotting time
between 200 and 400 seconds or an activated partial
thromboplastin time of 1.5 to 3 times the control value (Table 1
). Postprocedure heparin infusions were permitted in 5 of the
10 percutaneous intervention trials. Heparin was given
in all acute coronary syndrome trials except for PARAGON A,
PRISM, and PRISM Plus, which randomized patients to heparin or placebo
(Table 2).
Clinical End Points
Clinical outcomes studied included death, the composite of death
or MI, and the composite of death, MI, or
revascularization. Each outcome was evaluated at an
early time point (between 48 and 96 hours), at 30 days, and at 6
months. For percutaneous intervention trials, the early
end point occurred after the end of the study drug infusion. Patients
in acute coronary syndrome trials often received drug during
this period. Urgent revascularization events were
evaluated at the early and 30-day time points, and the occurrence of
any revascularization event was assessed at 6
months. The numbers of patients experiencing events at each time point
were compiled for treatment and control arms. Although limited numbers
of patients were lost to follow-up in several trials, the amount of
incomplete data was expected to be equal among randomized arms. The
event rates for each arm reflect the number of events observed divided
by the number of patients enrolled, according to intention to
treat.
Statistical Analysis
ORs summarizing the effectiveness of GP IIb/IIIa
inhibitors were calculated by use of Fast*Pro
software.21 These ORs were combined assuming an empirical
Bayesian model described by Hedges and Olkin.22 Risk
differences between control and treatment arms were also combined by
use of the same model. The empirical Bayesian random-effects model
reduces to a fixed-effects model when the studies are
homogeneous. The method accommodated
heterogeneity by assuming that the true effect differed
among studies and therefore must be represented by a
distribution of values instead of a single value. The result was a
wider range of uncertainty about the point estimate than was calculated
with fixed-effects models.
Although the random-effects model accommodated variability among
studies, the extent of heterogeneity in the trials was
examined by 2 methods. The Q statistic of DerSimonian and
Laird23 approximated a 
2
statistic to test a null hypothesis that all of the studies estimated
the same true value. To identify potential sources of
heterogeneity, Galbraith radial plots were
constructed.24 25 This method plotted the log OR divided
by the standard error against the reciprocal of the standard error.
Ninety-five percent of trials should fall within 2 units above or below
a line with slope equal to the overall log OR. Trials that exceed the
2-unit boundary deserve further exploration for
heterogeneity.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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A total of 32 135 patients were included in the analysis (Figure 1
). A significant mortality
reduction with GP IIb/IIIa inhibitors was observed at the
early time point (48 to 96 hours), with an OR of 0.70 (95% CI,
0.51 to 0.96; P<0.03) (Figure 2). The combined risk difference of
-0.001 (95% CI, -0.0026 to 0.0003) was equivalent to a reduction of
1 death per 1000 patients treated. Trends toward mortality benefit at
30 days and 6 months were not statistically significant. At 30 days,
the OR was 0.87 (95% CI, 0.74 to 1.02; P=0.08), equivalent
to 3 fewer deaths per 1000 patients treated (-0.0032; 95% CI,
-0.0063 to -0.0001) (Figure 3). At 6
months, the OR was 0.97 (95% CI, 0.86 to 1.10; P=0.67),
equivalent to 2 fewer deaths per 1000 patients treated (-0.0015; 95%
CI, -0.0059 to 0.0029).
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), combined
non–ST-segment elevation acute coronary syndromes trials
(
), and all collected trials (
). N indicates sample size; Dif,
risk difference. *P<0.05; 
P<0.01;
P<0.001.
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For the combined end point of death or nonfatal MI, there was a highly
significant (P<0.001) benefit for GP IIb/IIIa
inhibitors at every time point. For the early time point
(48 to 96 hours), the OR was 0.66 (95% CI, 0.56 to 0.78), equivalent
to 17 fewer events per 1000 patients treated (-0.017; 95% CI, -0.023
to -0.011). At 30 days, the OR was 0.76 (95% CI, 0.66 to 0.87), or 20
fewer events per 1000 patients treated (-0.020; 95% CI, -0.029 to
-0.012) (Figure 4). At 6 months, the OR
was 0.82 (95% CI, 0.74 to 0.91), or 20 fewer events per 1000 patients
treated (-0.020; 95% CI, -0.028 to -0.011).
|
For the composite end point of death, MI, or
revascularization, there was a highly significant
(P<0.001) benefit favoring GP IIb/IIIa
inhibitors. For the early time point (48 to 96 hours), the
OR was 0.66 (95% CI, 0.58 to 0.75), equivalent to 27 fewer events per
1000 patients treated (-0.027; 95% CI, -0.034 to -0.020). At 30
days, the OR was 0.77 (95% CI, 0.69 to 0.86), or 30 fewer events per
1000 patients treated (-0.030; 95% CI, -0.040 to -0.020) (Figure 5). At 6 months, the OR was 0.89 (95%
CI, 0.84 to 0.94), or 23 fewer events per 1000 patients treated
(-0.023; 95% CI, -0.033 to -0.012).
|
Percutaneous Intervention Trials
No significant difference in mortality was seen at any time point.
At 48 to 96 hours, the OR was 0.66 (95% CI, 0.34 to 1.31;
P=0.24). At 30 days, the OR was 0.77 (95% CI, 0.53 to 1.10;
P=0.15). At 6 months, the OR was 0.90 (95% CI, 0.70 to
1.16; P=0.41).
For the combined end point of death or nonfatal MI, there was a highly significant (P<0.001) benefit for GP IIb/IIIa inhibitors at all 3 time points. For the early time point (48 to 96 hours), the OR was 0.57 (95% CI, 0.45 to 0.71), equivalent to 27 fewer events per 1000 patients treated (-0.027; 95% CI, -0.037 to -0.017). At 30 days, the OR was 0.64 (95% CI, 0.51 to 0.80), or 27 fewer events per 1000 patients treated (-0.027; 95% CI, -0.040 to -0.014). At 6 months, the OR was 0.76 (95% CI, 0.64 to 0.91), or 23 fewer events per 1000 patients treated (-0.023; 95% CI, -0.037 to -0.009).
For the composite end point of death, MI, or
revascularization, there was also a significant
benefit favoring GP IIb/IIIa inhibitors. For the early time
point (48 to 96 hours), the OR was 0.56 (95% CI, 0.46 to 0.67;
P<0.001), equivalent to a reduction of 38 events per 1000
patients treated (-0.038; 95% CI, -0.049 to -0.028). At 30 days,
the OR was 0.65 (95% CI, 0.54 to 0.79; P<0.001), or 
37
fewer events per 1000 patients treated (-0.037; 95% CI, -0.52 to
-0.022). At 6 months, the OR was 0.87 (95% CI, 0.80 to 0.95;
P<0.003), or 28 fewer events per 1000 patients treated
(-0.028; 95% CI, -0.045 to -0.012).
Acute Coronary Syndrome Trials
No significant difference in mortality was seen at any time point.
At the early time point (48 to 96 hours), the OR was 0.71 (95% CI,
0.50 to 1.01). At 30 days, the OR was 0.90 (95% CI, 0.76 to 1.06). At
6 months, the OR was 1.00 (95% CI, 0.87 to 1.15).
For the combined end point of death or nonfatal MI, there was a significant (P<0.01) benefit for GP IIb/IIIa inhibitors early and at 30 days. At the early time point (48 to 96 hours), the OR was 0.81 (95% CI, 0.71 to 0.92), equivalent to a reduction of 10 events per 1000 patients treated (-0.010; 95% CI, -0.015 to -0.004). At 30 days, the OR was 0.88 (95% CI, 0.81 to 0.97), or 13 fewer events per 1000 patients treated (-0.013; 95% CI, -0.023 to -0.004). At 6 months, the OR was 0.88 (95% CI, 0.79 to 0.97), equal to 16 fewer events per 1000 patients treated (-0.016; 95% CI, -0.027 to -0.004).
For the composite end point of death, MI, or revascularization, there was a highly significant benefit favoring GP IIb/IIIa inhibitors. For the early time point (48 to 96 hours), the OR was 0.77 (95% CI, 0.69 to 0.86; P<0.001), equivalent to 19 fewer events per 1000 patients treated (-0.019; 95% CI, -0.027 to -0.011). At 30 days, the OR was 0.86 (95% CI, 0.80 to 0.93; P<0.001), or 22 fewer events per 1000 patients treated (-0.022; 95% CI, -0.034 to -0.010). At 6 months, the OR was 0.90 (95% CI, 0.83 to 0.97; P<0.01), or 20 fewer events per 1000 patients treated (-0.020; 95% CI, -0.036 to -0.004).
Heterogeneity Analyses
For percutaneous intervention trials, the
Q statistic revealed significant
heterogeneity for the death/MI end point at 30 days and
6 months and for death/MI/revascularization at 48
to 96 hours and 30 days. No significant heterogeneity
was detected in the acute coronary syndrome trials. The test of
heterogeneity for the entire trial collection reflected
the heterogeneity present within the
percutaneous intervention subgroup.
Galbraith plots (Figure 6) identified the
EPILOG trial's particularly pronounced effect in favor of GP IIb/IIIa
blockade. This finding corresponds to the quantitative results.
Q statistics calculated without the EPILOG trial are
consistent with homogeneity for all end points except early (48
to 96 hours) death/MI/revascularization. Thus,
EPILOG contributed substantially to the statistical
heterogeneity of the collected trials.
|
) and acute
coronary syndrome trials (
) for death (top row), death or MI
(middle row), and death, MI, or revascularization
(bottom row) 48 to 96 hours, 30 days, and 6 months after randomization
to a GP IIb/IIIa inhibitor or placebo. In a statistically
homogeneous sample, 95% of trials should fall within 2
units (dashed lines) of overall OR (solid diagonal line). |
Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This new therapeutic class promises a substantial benefit when applied to clinical practice. Patients undergoing percutaneous coronary intervention or presenting with an acute coronary syndrome can expect a significant reduction in critical clinical events, including nonfatal MI and the need for repeat procedures. Much of the benefit occurs early in the patient's clinical course and is maintained at 6 months.
The effect of GP IIb/IIIa inhibitors on mortality is small compared with the number of patients studied. One might infer that no mortality benefit exists, simply because the 6-month result is not statistically significant. Another explanation recognizes that the absolute benefit (lives saved per 1000 patients treated) remains constant between the early phase and 6 months. In the early phase (during drug infusion), the 35% relative mortality reduction and paucity of deaths overall make this difference borderline statistically significant. Afterward, the numbers of additional deaths in the treatment and control groups are similar, suggesting no further effect on mortality after the infusion ends. Because deaths accumulate equally in both groups over time, the relative effect (ORs and P value) declines and becomes nonsignificant. In addition, although the point estimates remain relatively constant, the CIs widen because fewer patients had 6-month data than had 48- to 96-hour data. Last, the 30-day mortality rate was only 2.7% for the combined control arms. Proof of a mortality difference given this event rate requires either a monumental treatment effect or an enormous sample size (145 618 patients to detect a 10% relative reduction with 90% power, or 21 872 patients for a 25% reduction.) The probability of a detrimental effect on mortality is <3% for GP IIb/IIIa inhibitors given intravenously for 1 to 4 days. Long-term dosing of oral formulations may extend this effect to a larger, durable mortality benefit.
Definitions of nonfatal MI and reinfarction varied among trials, with different enzyme, ECG, and clinical criteria. A majority of the trials used adjudication committees in addition to (often complex) formal descriptive rules. The disparity among investigators and sponsors is a limitation of the trial designs in this area. Although a consensus end-point definition is highly desirable for future trials, there is at present no feasible way to reconstruct a uniform definition for previous studies. Despite this limitation, any MI, however defined, constitutes an undesirable event for patients, and we have reported results consistent with primary-end-point definitions.
Ten of the 16 trials used a composite of death, MI, or revascularization as the primary end point. A larger reduction in relative odds exists for combined death/MI events than for composite death/MI/revascularization events. Applied to 1000 patients similar to the overview population, GP IIb/IIIa blockade would prevent 20 of 91 deaths or nonfatal MIs in the first 30 days, a 22% relative reduction. Under the same conditions, the agents would prevent 30 of 169 deaths, MIs, or revascularization procedures (a 17% reduction). From a treatment policy perspective, the triple end point better reflects the anticipated benefit to clinical practice.
Efforts to accumulate all available information inevitably increase the
potential for heterogeneity in pooled data. Formal
tests for heterogeneity have low power. Thus,
statistical failure to reject the null hypothesis of homogeneity does
not imply equality26 but rather a lack of unacceptable
heterogeneity. In this overview, the methods used to
calculate the combined ORs accommodate
heterogeneity.21 27 The overview combines
studies of 3 agents with those of abciximab, which has a longer
duration of action and cross-reactivity with the
Vß3
receptor.28 As previously mentioned, patient
characteristics, therapeutic regimens, end-point definitions, and
adjunctive drugs (heparin and aspirin) were nonuniform across trials.
The EPILOG trial contributed strongly to the statistical
heterogeneity of the collected trials. The pronounced
power of EPILOG may stem from its early termination,29 30
the patient population, the dosing regimen, or inherent drug
effects.
Whether differences in clinical benefit exist among the different compounds is speculative. The variability present among trials precludes indirect comparisons of individual agents. These differences can produce disparity among trials included in meta-analyses31 and cause discrepancies between meta-analyses and subsequent large, controlled trials. For example, Fox32 attempted indirect comparisons between anistreplase and alteplase using a fixed-effects model. The ISIS-3 randomized trial33 later showed no significant difference between the 2 agents. Although practice guidelines should be influenced most by large randomized trials, properly conducted systematic overviews of large trials can describe overall benefit and summarize past experience better than individual studies examined separately.
The general mechanism of benefit is undoubtedly the inhibition of platelet aggregation, a critical component of thrombotic coronary occlusion. At 30 days, the trials of percutaneous intervention had a significantly larger relative reduction in combined death and MI than the acute coronary syndromes trials (95% CI, 0.51 to 0.80 versus 0.81 to 0.97, respectively), although the 95% CIs overlapped at the other 2 time points. These agents may perform better during angioplasty, when delivered at a time of arterial trauma and platelet aggregation. This difference also may represent a reduction in postprocedure myocardial enzyme elevation. The lesser benefit for acute coronary syndromes may reflect the delay between the initial intimal insult and institution of therapy. The optimal degree and duration of GP IIb/IIIa inhibition remain to be established for each indication.
The GP IIb/IIIa inhibitors clearly show a consistent, substantial, and durable benefit as a therapeutic class. Future randomized, comparative clinical trials will undoubtedly refine these results and identify optimal applications for specific agents. The completion of definitive outcome studies before regulatory approval should speed assimilation of these agents into clinical practice and transformation of these promising results into new standards of care.
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Acknowledgments |
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We recognize the following investigators who contributed data: Keaven M. Anderson, PhD (Centocor, Malvern, Pa); Manjushri Bhapkar, MS (Duke Clinical Research Institute, Durham, NC); Sorin J. Brener, MD (Cleveland Clinic Foundation, Cleveland, Ohio); Spencer B. King III, MD (Emory University Hospital, Atlanta, Ga); Cynthia M. MacAulay, MS (Duke Clinical Research Institute); Frederic L. Sax, MD (Merck Research Laboratories, West Point, Pa); Kristina N. Sigmon, MA (Duke Clinical Research Institute); and Maarten L. Simoons, MD (Thoraxcenter, Rotterdam, Netherlands). We also thank Penny Hodgson and Pat Williams for their editorial assistance.
Received June 17, 1998; revision received September 4, 1998; accepted September 15, 1998.
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R. A. Harrington, P. W. Armstrong, C. Graffagnino, F. Van de Werf, D. J. Kereiakes, K. N. Sigmon, T. Card, D. M. Joseph, R. Samuels, J. Granett, et al. Dose-Finding, Safety, and Tolerability Study of an Oral Platelet Glycoprotein IIb/IIIa Inhibitor, Lotrafiban, in Patients With Coronary or Cerebral Atherosclerotic Disease Circulation, August 15, 2000; 102(7): 728 - 735. [Abstract] [Full Text] [PDF]
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W. S. Weintraub, T. D. Thompson, S. Culler, S. J. Boccuzzi, E. R. Becker, A. S. Kosinski, and E. Mahoney Targeting Patients Undergoing Angioplasty for Thrombus Inhibition : A Cost-Effectiveness and Decision Support Model Circulation, July 25, 2000; 102(4): 392 - 398. [Abstract] [Full Text] [PDF]
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C. P. Cannon, C. H. McCabe, R. G. Wilcox, A. Langer, A. Caspi, P. Berink, J. Lopez-Sendon, J. Toman, A. Charlesworth, R. J. Anders, et al. Oral Glycoprotein IIb/IIIa Inhibition With Orbofiban in Patients With Unstable Coronary Syndromes (OPUS-TIMI 16) Trial Circulation, July 11, 2000; 102(2): 149 - 156. [Abstract] [Full Text] [PDF]
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R. A. Harrington Cardiac enzyme elevations after percutaneous coronary intervention: myonecrosis, the coronary microcirculation and mortality J. Am. Coll. Cardiol., April 1, 2000; 35(5): 1142 - 1144. [Full Text] [PDF]
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D. B. Mark, R. A. Harrington, A. M. Lincoff, R. M. Califf, C. L. Nelson, A. A. Tsiatis, H. Buell, K. W. Mahaffey, L. Davidson-Ray, and E. J. Topol Cost-Effectiveness of Platelet Glycoprotein IIb/IIIa Inhibition With Eptifibatide in Patients With Non-ST-Elevation Acute Coronary Syndromes Circulation, February 1, 2000; 101(4): 366 - 371. [Abstract] [Full Text] [PDF]
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C. P. Cannon Overcoming thrombolytic resistance: Rationale and initial clinical experience combining thrombolytic therapy and glycoprotein IIb/IIIa receptor inhibition for acute myocardial infarction J. Am. Coll. Cardiol., November 1, 1999; 34(5): 1395 - 1402. [Abstract] [Full Text] [PDF]
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