(Circulation. 2001;103:201.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Increased Mortality With Oral Platelet Glycoprotein IIb/IIIa Antagonists
A Meta-Analysis of Phase III Multicenter Randomized Trials
From the Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Eric J. Topol, MD, Department of Cardiology, Cleveland Clinic Foundation, Desk F25, 9500 Euclid Ave, Cleveland, Ohio 44195. E-mail topole{at}ccf.org
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Abstract |
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Background—Numerous clinical trials have established the benefits of intravenous glycoprotein IIb/IIIa inhibition in the management of coronary artery disease. In contrast, the recent large-scale, placebo-controlled, randomized trials of the oral glycoprotein IIb/IIIa antagonists have failed to provide commensurate reductions in late composite ischemic end points despite potent inhibition of platelet aggregation.
Methods and Results—The ORs for death, myocardial infarction, urgent revascularization, and major bleeding from the 4 large-scale, placebo-controlled, randomized trials with oral glycoprotein IIb/IIIa inhibitors were calculated and combined. Stratification by low-dose or high-dose therapy and the use of concurrent aspirin was also undertaken. In 33 326 patients followed for >30 days, a consistent and statistically significant increase in mortality was observed with oral glycoprotein IIb/IIIa therapy (OR, 1.37; 95% CI, 1.13 to 1.66; P=0.001). This effect was evident regardless of aspirin coadministration and treatment with either low-dose or high-dose therapy. Although a reduction in urgent revascularization was observed with oral glycoprotein IIb/IIIa inhibition, pooled analysis favored an increase in myocardial infarction that did not demonstrate statistical significance.
Conclusions—Although we found a highly significant excess in mortality consistent across 4 trials with 3 different oral glycoprotein IIb/IIIa inhibitor agents, this was associated with a reduction in the need for urgent revascularization and no increase in myocardial infarction. These findings suggest the potential for a direct toxic effect with these agents and argue against a prothrombotic mechanism. Further investigation to elucidate the cause of this increased fatality risk is warranted.
Key Words: mortality • glycoproteins • trials
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Collectively, the efficacy of the intravenous glycoprotein IIb/IIIa antagonists as adjunctive therapy for percutaneous coronary intervention (PCI) and as empiric therapy for acute coronary syndromes is well established.1 Nevertheless, ongoing ischemic events continue to occur in these patient populations and represent an important contributor to the morbidity and mortality from coronary artery disease. After episodes of coronary instability, heightened platelet activity persists and correlates with ongoing ischemia and mortality.2 3 In addition, relatively weak platelet antagonists, such as aspirin and the thienopyridines, have provided an
25% relative risk reduction in
vascular events when administered as secondary
prevention.4 5
These observations have persuasively argued that ongoing platelet
activation plays an integral role in the pathophysiology of these late
ischemic outcomes. By blocking the fibrinogen receptor, the final common pathway of platelet aggregation,6 the intravenous glycoprotein IIb/IIIa antagonists provide potent platelet inhibition and have led to commensurate declines in ischemic events after spontaneous or mechanical coronary vascular injury. This success has spurred interest in the development of oral agents with the intention of extending these initial benefits to long-term care. To date, the experience with >33 000 patients in 4 large-scale, double-blind, placebo-controlled, clinical trials has been compiled. Individually, each trial has failed to document a reduction in long-term ischemic outcomes with the respective oral glycoprotein IIb/IIIa receptor antagonist studied, while a worrisome suggestion of increased mortality has been observed.7 8 9 Therefore, this article represents a meta-analysis of all the completed randomized clinical trials evaluating the impact of oral glycoprotein IIb/IIIa antagonists on mortality and myocardial infarction (MI).
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Methods |
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Trial Selection
Randomized, double-blind, placebo-controlled trials of the oral glycoprotein IIb/IIIa antagonists were identified through a MEDLINE search. Records between 1990 and 2000 were searched for the words "platelet," "oral," "random$," and "inhibit$ or block$," where $ is a wild card. Trials were included if the total number of patients enrolled exceeded 1000 and the duration of clinical follow-up was
30 days. Data from more recent trials presented at
major cardiology meetings were also included. Results from phase II
dose-ranging studies were not included in this analysis.
Four trials were identified and included: 3 enrolling
patients presenting with acute coronary syndromes and 1 with patients
undergoing PCI. Three different agents have been studied: xemilofiban,
orbofiban, and sibrafiban, although each agent is a prodrug with the
active compound mediating inhibition via the Arg-Gly-Asp (RGD) peptide
binding sequence, one of several binding domains on the glycoprotein
IIb/IIIa receptor (the
Table
).
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The Evaluation of Xemilofiban in Controlling Thrombotic Events (EXCITE) trial8 studied xemilofiban 10 or 20 mg compared with placebo administered 3 times a day for 2 weeks followed by twice-daily dosing for an additional 2 weeks in 7232 patients undergoing PCI. All patients received concurrent aspirin therapy, and stented patients were randomized to ticlopidine or xemilofiban. The primary end point was death, recurrent MI, and urgent intervention and was reported at 30 and 182 days. The 30-day outcomes were used in this analysis.
The Orbofiban in Patients With Unstable Coronary Syndromes Thrombolysis in Myocardial Infarction (OPUS TIMI) 16 trial7 randomized 10 302 patients presenting with acute coronary syndromes to 50 mg orbofiban twice daily for 6 months, 50 mg orbofiban twice daily for 30 days followed by 30 mg twice daily for 5 months, or placebo. All patients received concurrent aspirin, whereas patients receiving stents were randomized to orbofiban or ticlopidine. This trial was stopped prematurely because of a statistically significant increase in mortality observed with orbofiban therapy. The primary end point was death, MI, recurrent ischemia requiring rehospitalization or revascularization, and stroke and was reported at 30 days and 10 months. The 30-day outcomes were used in this analysis.
The Sibrafiban Versus Aspirin to Yield Maximum Protection From Ischemic Heart Events Post Acute Coronary Syndromes (SYMPHONY)9 and 2nd SYMPHONY trials studied sibrafiban individualized by weight and serum creatinine in acute coronary syndrome patients. SYMPHONY randomized 9233 patients to low-dose sibrafiban, high-dose sibrafiban, or aspirin therapy for 90 days. Patients receiving sibrafiban did not receive concurrent aspirin, but patients undergoing coronary stenting were administered ticlopidine concurrently if randomized to the low-dose sibrafiban arm. The 2nd SYMPHONY trial compared the same low-dose regimen of sibrafiban with aspirin or high-dose sibrafiban without aspirin to aspirin therapy alone for 90 days. This trial was terminated prematurely at 6637 patients (planned enrollment, 9000) when the results of the SYMPHONY trial were known. For both studies, the primary end point was death, MI, and severe recurrent ischemia requiring revascularization at 90 days.
Each study included a low-dose and high-dose trial design. Because the range of target inhibition determined by ADP-induced platelet aggregometry for low-dose therapy (30% to 60%) and high-dose therapy (50% to 80%) was comparable among the respective studies,10 11 12 13 the event rates in the low-dose treatment arms were pooled, as were the high-dose treatment arms, and each was compared with aspirin alone. However, both the low- and high-dose treatment groups of the OPUS TIMI-16 study were included in the high-dose analysis because all patients in this study received the high-dose orbofiban for the first 30 days, and this end point was used in the analysis.
The protocol of each trial varied with respect to the use of concurrent aspirin therapy. To determine whether a potential effect of combined aspirin and oral glycoprotein IIb/IIIa therapy could be observed, the treatment arms from EXCITE and OPUS TIMI-16 and the low-dose arm of the 2nd SYMPHONY study, which included concurrent aspirin therapy, were pooled and compared with aspirin alone. Conversely, both low- and high-dose treatment arms of the SYMPHONY study and the high-dose arm of the 2nd SYMPHONY study did not include concurrent aspirin and therefore were pooled and compared with aspirin alone.
Clinical End Points
The clinical end-point definitions were similar among
the trials, enabling the use of protocol-defined death, MI, urgent
revascularization, and major bleeding within this meta-analysis. The
number of patients experiencing events in the treatment and control
arms were compiled at this "30 day or greater" end point. The event
rates for each treatment arm reflect the number of events observed
divided by the number of patients enrolled, according to intention to
treat.
Statistical Analysis
Based on the treatment group sample sizes and event
rates for each trial, pooled ORs adjusting for the trial sample sizes
and the corresponding 95% CIs were calculated for death, MI, urgent
revascularization, and major bleeding. The Cochran-Mantel-Haenszel
statistic (SAS 6.12, SAS Institute Inc) was used to evaluate the
association between treatment and outcome, adjusting for trial. The
homogeneity of the ORs across the trials was assessed by Breslow-Day
testing. A value of P<0.05 was
considered statistically
significant.
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Results |
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Mortality
In total, 33 340 patients were enrolled in the 4 randomized trials, of which 33 326 patients have available follow-up. Overall, each trial reported an increased risk of mortality during the follow-up period. This increased mortality risk was statistically significant in the EXCITE trial (OR, 2.1; 95% CI, 0.99 to 4.46; P=0.048), OPUS TIMI-16 trial (OR, 1.4; 95% CI, 1.00 to 1.95; P=0.047), and 2nd SYPMHONY trial (OR, 1.54; 95% CI, 1.02 to 2.34; P=0.038). Pooled results confirm an increase in mortality with the use of any oral glycoprotein IIb/IIIa antagonist regimen, with an OR of 1.37 (95% CI, 1.13 to 1.67; P=0.001; Figure 1A
).
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Myocardial Infarction
Compared with placebo, randomization of any oral
glycoprotein IIb/IIIa antagonists favored an increased risk of MI in
both SYMPHONY trials but was not observed in EXCITE or OPUS TIMI-16. No
trial demonstrated a statistically significant effect on MI, and this
lack of effect was confirmed on pooled analysis of the all the trials
(OR, 1.04; 95% CI, 0.93 to 1.16;
P=0.481;
Figure 1B
).
Urgent Revascularization
Conversely, the need for urgent revascularization was
reduced in each study except the EXCITE trial (OR, 1.06; 95% CI, 0.80
to 1.41; P=0.688). A
statistically significant reduction in urgent revascularization was
observed in both the OPUS TIMI-16 (OR, 0.60; 95% CI, 0.48 to 0.75;
P<0.001) and 2nd SYPMHONY (OR,
0.74; 95% CI, 0.56 to 0.99;
P=0.039) trials. Pooled results
of all the oral glycoprotein IIb/IIIa treatment arms indicated a
statistically significant reduction in urgent revascularization, with
an OR of 0.77 (95% CI, 0.66 to 0.87;
P<0.001;
Figure 1C).
Major Bleeding
A statistically significant increase in bleeding was
observed in each trial individually, with the most substantial increase
observed in the EXCITE trial, which investigated the role of oral
glycoprotein IIb/IIIa antagonism in the setting of PCI. Pooled analysis
of the 4 trials reiterates this increased bleeding risk, with an OR of
1.74 (95% CI, 1.52 to 2.00;
P<0.001;
Figure 1D).
Low-Dose Versus High-Dose Therapy
A total of 15 431 patients were treated with either
low-dose glycoprotein IIb/IIIa inhibition (with or without aspirin) or
aspirin alone. Compared with aspirin, pooled analysis of the low-dose
arms indicates a significant increase in mortality, with an OR of 1.32
(95% CI, 1.01 to 1.73;
P=0.046). As with the overall
analysis, with low-dose therapy the risk of MI was increased while the
need for urgent revascularization was reduced, although both analyses
did not demonstrate statistical significance. Analysis of patients
randomized to high-dose therapy (with or without aspirin) compared with
aspirin alone involves 25 614 patients and indicates an even greater
effect on mortality than observed with low-dose therapy. Mortality was
increased by an OR of 1.40 (95% CI, 1.14 to 1.73;
P=0.002) with high-dose oral
glycoprotein IIb/IIIa therapy. On pooled analysis, a significant effect
on MI was not evident; a more prominent benefit with respect to urgent
revascularization was observed with high-dose therapy (OR, 0.71; 95%
CI, 0.62 to 0.82; P<0.001;
Figure 2).
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Aspirin Versus No Aspirin
A total of 13 574 patients were included in the
analysis of oral glycoprotein IIb/IIIa antagonist without aspirin
compared with aspirin alone. In the absence of concurrent aspirin
therapy, the risks of death and MI are significantly increased with
oral glycoprotein IIb/IIIa inhibitor therapy, with ORs of 1.34 (95%
CI, 1.04 to 1.74; P=0.026) and
1.18 (95% CI, 1.16 to 1.37;
P=0.030), respectively. Oral
glycoprotein IIb/IIIa inhibition without concurrent aspirin therapy
provided a reduction in urgent revascularization (OR, 0.80; 95% CI,
0.65 to 0.98; P=0.031). Pooled
comparison of oral glycoprotein IIb/IIIa therapy and concurrent aspirin
arms with those receiving aspirin alone includes 21 983 patients.
Increased mortality was observed in the patients receiving combined
antiplatelet therapy (OR, 1.44; 95% CI, 1.11 to 1.86;
P=0.005), but a significant
increase in MI (OR, 0.95; 95% CI, 0.83 to 1.09;
P=0.483) was no longer evident.
As with the previous analyses, urgent revascularization was reduced
with the combined regimens of aspirin and oral glycoprotein IIb/IIIa
inhibition (OR, 0.75; 95% CI, 0.64 to 0.87;
P<0.001;
Figure 3).
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Heterogeneity
The Breslow-Day statistic revealed no significant
heterogeneity within the analyses of death, MI, or urgent
revascularization except for the overall and concurrent aspirin
analyses of urgent revascularization
(P=0.016 and
P=0.008, respectively). A
nonstatistically significant increase in the urgent revascularization
rate within the EXCITE trial is responsible for this effect and was no
longer observed when the analysis of urgent revascularization was
stratified by dose. Heterogeneity was also evident in the analysis of
major bleeding (Breslow-Day statistic,
P=0.027), again because of the
greater OR of bleeding risk observed in the EXCITE
trial.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Contrasting the unquestionable benefits of intravenous glycoprotein IIb/IIIa antagonists, the randomized, placebo-controlled trials with oral glycoprotein IIb/IIIa inhibitors demonstrate a 31% increase in mortality (P=0.001) when the entire 33 326-patient clinical experience is combined. In contradistinction, when glycoprotein IIb/IIIa inhibitors are administered with concurrent aspirin, an overall impact on recurrent MI after coronary interventions or in patients presenting with acute coronary syndromes is not observed. Considering the increased bleeding events, which underscores the antiplatelet effect of these agents, these results not only indicate a paradoxical dissociation between inhibition of platelet aggregation and provocation of late adverse events but also demonstrate an isolated increase in mortality, implying the presence of clinically relevant "toxic" mechanisms.
After the initial disappointing results from these trials, several putative explanations have been suggested, including inadequate plasma levels between oral doses, diversity in patient-specific factors, and the lack of concurrent aspirin in some study arms.9 14 Compared with intravenous administration, fluctuation in plasma levels with oral dosing may provide subtherapeutic platelet inhibition for a large proportion of the treatment period.11 12 Experience with the intravenous glycoprotein IIb/IIIa antagonists clearly supports the association between a high level of platelet inhibition at the time of thromboembolic risk and efficacy with this class of agents.15 16 In contrast, compared with the low-dose arms in this analysis, high-dose oral glycoprotein IIb/IIIa inhibition is associated with an even greater fatality risk. Therefore, increased dosing cannot necessarily be expected to deliver superior clinical efficacy.
Individual variation in dose-response may also confound the appropriate therapeutic dosing of these agents.11 12 Although the factors contributing to interindividual and intraindividual diversity of dose-response are not well characterized, variation in patient acuity, intrinsic platelet competence, antecedent medications,17 and renal function12 are likely sources of this diversity. Of particular note, although an increased rate of bleeding may be expected and is reported in patients with reduced renal function, an association with mortality has also been observed with orbofiban therapy.7 Nevertheless, attempts to dose according to weight and renal function with sibrafiban have failed to provide superior efficacy and safety over aspirin therapy alone.9 Likewise, although patients at increased risk of recurrent coronary events (defined by troponin elevation) derive a greater benefit from intravenous glycoprotein IIb/IIIa inhibition,18 19 the oral antagonist trials have not consistently replicated this experience. Subgroup analysis of the Fibrinogen Receptor Occupancy Study Trial (FROST)20 showed a greater reduction in cardiac events associated with lefradafiban therapy in patients presenting with troponin elevation. Contrasting this are the large-scale trials in which no incremental benefit was evident in high-risk patients, such as those with unstable angina undergoing PCI in the EXCITE trial8 and post-MI patients in the SYMPHONY trial.9 Unfortunately, outcomes stratified by troponin elevation at enrollment are currently unavailable in these studies.
Similarly, the increase in mortality was also evident regardless of aspirin coadministration. The increase in MI observed in the treatment arms without concurrent aspirin therapy compared with those receiving concurrent aspirin attests to the importance of aspirin in the treatment of coronary artery disease. Furthermore, without concurrent aspirin, the greater rate of MI may be interpreted by some as evidence for the suggested prothrombotic effects associated with glycoprotein IIb/IIIa inhibitors, corroborating the observation of mortality associated with an increase in thrombotic events reported from OPUS TIMI-16.7 Recently, several intravenous and oral glycoprotein IIb/IIIa inhibition–induced prothrombotic mechanisms have been proposed. Although platelet glycoprotein IIb/IIIa blockade effectively prevents platelet aggregation, other platelet functions, such as secretion, procoagulant activity, and platelet-leukocyte interactions, are not necessarily equally impaired and may be potentiated.21 22 As with endogenous ligands, binding by these agents induces "outside-to-inside" signals within the receptor-cell membrane complex that influence receptor conformational status and competency, membrane fluidity, and calcium metabolism.23 Contrasting the endogenous ligands, these synthetic agents are able to bind both quiescent and competent receptors, thereby possibly contributing to glycoprotein IIb/IIIa receptor activation, continued procoagulant activity, and P-selectin expression.24 25 Continued or augmented prothrombotic activity may therefore explain the synergistic benefit of heparin when combined with orbofiban therapy observed in OPUS TIMI-16.7 Adding to this complexity is the finding that the site of binding within the receptor determines, at least in part, the specific secondary signals induced by specific antagonists.23 Therefore, these outside-to-inside signals are subclass specific and may even be agent specific, raising the possibility that the negative results observed in the current trials are confined to antagonists of the RGD binding site.
However, contrary to the clinical experience with
intravenous glycoprotein IIb/IIIa blockade in which reductions in
ischemic end points (death, MI, and urgent revascularization) have
paralleled each other,1 the
impact of oral glycoprotein IIb/IIIa inhibition on these end points is
incongruous, both in the trials individually and in the collective
analysis. Therefore, these results are not necessarily consistent with
prothrombosis and ischemia as the primary basis for this increased
mortality risk. The 16% increase in MI observed with oral glycoprotein
IIb/IIIa blockade without concurrent aspirin therapy compared with
those receiving aspirin alone is commensurate with the expected 25%
to 30%4 5 increase
in these events in the absence of any effective antiplatelet therapy.
If clinically relevant prothrombotic mechanisms were to account for the
31% mortality risk, an even greater increase in MI would be expected.
Therefore, combined with the reduction in the need for urgent
revascularization, unanticipated toxic effects unrelated to platelet
activation may provide a more adequate explanation and are supported by
evolving evidence. Binding sites for the RGD sequence have been defined
in many proteins, including procaspase-3, the precursor to caspase-3, a
central signal for cellular apoptosis. Animal
studies26 27 have
documented time- and dose-dependent increases in caspase-3 expression
and cardiomyocyte apoptosis when incubated with the RGD peptides,
xemilofiban, or orbofiban; this effect is augmented by hypoxic
conditions. These effects were not observed with eptifibatide or
abciximab, suggesting that these nonplatelet toxic effects are specific
to the RGD peptide subclass. The role of apoptosis in the fatality risk
associated with these agents warrants further
investigation.
Study Limitations
As inherent in all meta-analyses, heterogeneity among
protocols, therapeutic agents studied, and patient populations may be
of sufficient diversity to make the results of a comparison among
trials inaccurate. However, the Breslow-Day test, which examines the
statistical heterogeneity among ORs and therefore assesses the validity
of pooling the results from these trials, fails to demonstrate
significant diversity among the analyses apart from the pooled urgent
revascularization and bleeding analyses. For both of these analyses,
the source of heterogeneity appears to be the EXCITE trial, with the
neutral effect on urgent revascularization and increased bleeding
potentially reflecting the fact that all patients in this study
received percutaneous revascularization.
Follow-up duration reported by each study also varies. Nevertheless, the event rates among the studies are similar and consistent with the relatively small accumulation of events between the 30- and 90-day follow-up observed in recent intravenous glycoprotein IIb/IIIa trials.28 29 In addition, the ORs for mortality reported by each trial at the differing durations of follow-up are remarkably consistent, and mechanisms contributing to the increased hazard observed with these agents are unlikely to be preferentially operative in the early or late follow-up period.
Conclusions
The disparity between the oral and intravenous
glycoprotein IIb/IIIa inhibitor trials is perplexing and requires
reconciliation. This analysis indicates a worrisome increase in
mortality with the oral agents, which is in stark contrast to the
unquestionable benefits provided by short-term intravenous glycoprotein
IIb/IIIa therapy. This isolated fatality risk points toward toxic
effects rather than prothrombotic mechanisms that have been
unanticipated and remain largely unexplained. It is, however, important
to consider that each of the current oral glycoprotein IIb/IIIa
antagonists studied mediates inhibition via the RGD binding site, and
the detrimental effects observed with these agents may not extend to
the antagonists binding to alternative sites within the glycoprotein
IIb/IIIa receptor. Nevertheless, further understanding of the
biological consequences of oral glycoprotein IIb/IIIa blockade should
be sought before continued clinical testing is
undertaken.
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Acknowledgments |
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We thank Donna Bressan for her editorial assistance.
Received June 6, 2000; revision received August 16, 2000; accepted August 16, 2000.
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V. L. Serebruany Aggressive antiplatelet strategies: time to reconsider? Eur. Heart J., September 2, 2007; 28(18): 2183 - 2184. [Full Text] [PDF]
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J. E. Freedman Molecular Regulation of Platelet-Dependent Thrombosis Circulation, October 25, 2005; 112(17): 2725 - 2734. [Abstract] [Full Text] [PDF]
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P. W. Armstrong, L. K. Newby, C. B. Granger, K. L. Lee, R. J. Simes, F. Van de Werf, H. D. White, R. M. Califf, and for the Virtual Coordinating Centre for Global Col Lessons Learned From a Clinical Trial Circulation, December 7, 2004; 110(23): 3610 - 3614. [Full Text] [PDF]
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J. F Viles-Gonzalez, V. Fuster, and J. J Badimon Atherothrombosis: A widespread disease with unpredictable and life-threatening consequences Eur. Heart J., July 2, 2004; 25(14): 1197 - 1207. [Abstract] [Full Text] [PDF]
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N. S. Kleiman Platelets, the cardiologist, and coronary artery disease: moving beyond aggregation J. Am. Coll. Cardiol., June 2, 2004; 43(11): 1989 - 1991. [Full Text] [PDF]
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M. Dalby, G. Montalescot, C. B. d. Sollier, E. Vicaut, T. Soulat, J.-P. Collet, R. Choussat, V. Gallois, G. Drobinski, L. Drouet, et al. Eptifibatide provides additional platelet inhibition in Non-ST-Elevation myocardial infarction patients already treated with aspirin and clopidogrel: Results of the platelet activity extinction in Non-Q-Wave myocardial infarction with aspirin, clopidogrel, and eptifibatide (PEACE) study J. Am. Coll. Cardiol., January 21, 2004; 43(2): 162 - 168. [Abstract] [Full Text] [PDF]
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C. Patrono, F. Bachmann, C. Baigent, C. Bode, R. De Caterina, B. Charbonnier, D. Fitzgerald, J. Hirsh, S. Husted, J. Kvasnicka, et al. Expert Consensus Document on the Use of Antiplatelet Agents: The Task Force on the Use of Antiplatelet Agents in Patients with Atherosclerotic Cardiovascular Disease of the European Society of Cardiology Eur. Heart J., January 2, 2004; 25(2): 166 - 181. [Full Text] [PDF]
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E. J. Topol, D. Easton, R. A. Harrington, P. Amarenco, R. M. Califf, C. Graffagnino, S. Davis, H.-C. Diener, J. Ferguson, D. Fitzgerald, et al. Randomized, Double-Blind, Placebo-Controlled, International Trial of the Oral IIb/IIIa Antagonist Lotrafiban in Coronary and Cerebrovascular Disease Circulation, July 29, 2003; 108(4): 399 - 406. [Abstract] [Full Text] [PDF]
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M. J. Quinn, T. V. Byzova, J. Qin, E. J. Topol, and E. F. Plow Integrin {alpha}IIb{beta}3 and Its Antagonism Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 945 - 952. [Abstract] [Full Text] [PDF]
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J. E. Freedman CD40-CD40L and Platelet Function: Beyond Hemostasis Circ. Res., May 16, 2003; 92(9): 944 - 946. [Full Text] [PDF]
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S. Yusuf, S. R. Mehta, F. Zhao, B. J. Gersh, P. J. Commerford, M. Blumenthal, A. Budaj, T. Wittlinger, K. A.A. Fox, and on Behalf of the CURE (Clopidogrel in Unstable ang Early and Late Effects of Clopidogrel in Patients With Acute Coronary Syndromes Circulation, February 25, 2003; 107(7): 966 - 972. [Abstract] [Full Text] [PDF]
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S. R. Mehta and S. Yusuf Short- and long-term oral antiplatelet therapy in acute coronary syndromes and percutaneous coronary intervention J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 79S - 88S. [Abstract] [Full Text] [PDF]
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P J Sheridan and D C Crossman Critical review of unstable angina and non-ST elevation myocardial infarction Postgrad. Med. J., December 1, 2002; 78(926): 717 - 726. [Abstract] [Full Text] [PDF]
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M. J. Quinn, E. F. Plow, and E. J. Topol Platelet Glycoprotein IIb/IIIa Inhibitors: Recognition of a Two-Edged Sword? Circulation, July 16, 2002; 106(3): 379 - 385. [Full Text] [PDF]
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J. E. Freedman and J. Loscalzo Platelet-Monocyte Aggregates: Bridging Thrombosis and Inflammation Circulation, May 7, 2002; 105(18): 2130 - 2132. [Full Text] [PDF]
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J. Vermylen, M. Hoylaerts, J. Arnout, D. P. Chew, D. L. Bhatt, E. J. Topol, and S. Sapp Increased Mortality With Long-Term Platelet Glycoprotein IIb/IIIa Antagonists: An Explanation? Response Circulation, November 13, 2001; 104 (20): e109 - e109. [Full Text] [PDF]
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A. L. Frelinger III, M. I. Furman, L. A. Krueger, M. R. Barnard, and A. D. Michelson Dissociation of Glycoprotein IIb/IIIa Antagonists From Platelets Does Not Result in Fibrinogen Binding or Platelet Aggregation Circulation, September 18, 2001; 104(12): 1374 - 1379. [Abstract] [Full Text] [PDF]
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A. W. Chan, D. L. Bhatt, D. P. Chew, M. J. Quinn, D. J. Moliterno, E. J. Topol, and S. G. Ellis Early and Sustained Survival Benefit Associated With Statin Therapy at the Time of Percutaneous Coronary Intervention Circulation, February 12, 2002; 105(6): 691 - 696. [Abstract] [Full Text] [PDF]
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