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. 2011 Oct 25;35(2):93–100. doi: 10.1002/clc.20974

Efficacy and Safety of Unfractionated Heparin Plus Glycoprotein IIb/IIIa Inhibitors During Revascularization for an Acute Coronary Syndrome: A Meta‐Analysis of Randomized Trials Performed With Stents and Thienopyridines

David E Winchester 1, William D Brearley 1, Xuerong Wen 2, Ki E Park 1, Anthony A Bavry 1,✉
PMCID: PMC6652480  PMID: 22028212

Abstract

Background:

Early studies of glycoprotein IIb/IIIa inhibitors (GPIs) demonstrated benefit during percutaneous coronary intervention for acute coronary syndromes (ACS). Since their introduction, the magnitude of benefit of GPIs has become unclear.

Hypothesis:

We hypothesized that adding a GPI to unfractionated heparin in ACS patients treated with stents and thienopyridines is beneficial.

Methods:

We searched the MEDLINE, Cochrane, and clinicaltrials.gov databases for randomized clinical trials that studied the use of GPIs during ACS. We required that patients be randomly assigned to unfractionated heparin plus a GPI versus unfractionated heparin plus placebo (or control). Additional inclusion criteria included the use of coronary stents and periprocedural thienopyridines. Outcomes were assessed at 30 days. Random effects DerSimonian‐Laird summary risk ratios (RR) and 95% confidence intervals (CIs) were constructed.

Results:

Sixteen studies with 7611 patients were included. Myocardial infarction was 3.1% with GPI versus 4.4% with control (RR = 0.74; 95% CI, 0.59–0.94, P = 0.014); revascularization, 1.7% versus 2.7% (RR = 0.64; 95% CI, 0.46–0.89, P = 0.008); major bleeding, 2.5% versus 2.1% (RR = 1.21; 95% CI, 0.89–1.63, P = 0.22); minor bleeding, 5.5% versus 4.1% (RR = 1.37; 95% CI, 1.06–1.78, P = 0.016); and mortality, 2.2% versus 2.9% (RR = 0.79; 95% CI, 0.59–1.06, P = 0.12), respectively.

Conclusions:

Among ACS patients treated with stents and thienopyridines, GPIs were associated with reduced myocardial infarction and revascularization. Minor, but not major bleeding was increased with GPIs. Mortality was similar between the groups. © 2011 Wiley Periodicals, Inc.

Supporting information may be found in the online version of this article

This work was supported by an unrestricted grant from the Florida Heart Research Institute, which had no role in the study design, data collection, analysis, or interpretation, manuscript writing, or decision to proceed with publication.

Anthony A Bavry has received research support from Novartis Pharmaceuticals and serves as a contractor for American College of Cardiology Cardiosource. The other authors have no funding, financial relationships, or conflicts of interest to disclose.

Introduction

Percutaneous coronary intervention (PCI) is commonly performed in patients with an acute coronary syndrome (ACS). The goal of PCI is to reduce mortality and major adverse cardiac events.1, 2 Glycoprotein IIb/IIIa inhibitors (GPIs) are potent antiplatelet medications that have been widely used during PCI to reduce ischemic events. These agents have been the subject of many randomized trials, including early studies that did not use coronary stents and thienopyridines.3, 4 Recent meta‐analysis and a randomized trial of GPIs during PCI for ACS have drawn divergent conclusions from an earlier report about the clinical utility of these agents.5, 6, 7 Our aim, therefore, is to reappraise the benefits and risks of GPIs in ACS patients, specifically those treated with stents and thienopyridines. We hypothesized that the use of GPIs in this setting will reduce the risk of myocardial infarction.

Methods

Selection Criteria

Randomized clinical trials were selected that examined the use of GPIs during PCI for ACS (ST and non‐ST‐elevation myocardial infarction). We required that patients were randomly assigned to unfractionated heparin plus a GPI versus unfractionated heparin plus placebo (or control). To address the efficacy and safety of GPIs in contemporary PCI, we restricted analysis to studies that used coronary stents and periprocedural thienopyridines.

Literature Search

We conducted a systematic search of the MEDLINE database without language restriction using the search terms listed in Figure 1. The search included all studies from inception through July 2010. The search term “NOT medline [sb]” was used to identify trials with incomplete MEDLINE entries.8 We also searched the Cochrane clinical trials database (http://www.clinicaltrials.gov) and the reference lists of other systematic reviews.

Figure 1.

Figure 1

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Search strategy. Flow diagram of the search terms used and the overall search strategy for this analysis. Abbreviations: GPI, glycoprotein IIb/IIIa inhibitor; MeSH, medical subject heading.

Outcomes

The primary efficacy outcome was myocardial infarction and the primary safety outcome was major bleeding. All‐cause mortality provided a net estimate of efficacy and safety. Myocardial infarction was defined as a typical rise in cardiac enzymes with or without ischemic symptoms or electrocardiographic changes. Bleeding outcomes were assessed according to the Thrombolysis In Myocardial Infarction (TIMI) criteria where available.9 TIMI major bleeding was defined as intracranial hemorrhage or clinically overt bleeding with drop in hemoglobin of >5 g/dL, whereas TIMI minor bleeding was defined as clinically overt bleeding with a drop in hemoglobin of 3 to ≤5 g/dL. Revascularization was defined as a coronary artery bypass grafting or PCI beyond the index procedure due to ischemic symptoms. Other outcomes included thrombocytopenia, which was defined as platelet count <100,000/ mm3, and total stroke. All outcomes were assessed at 30 days, except all‐cause mortality, which was also assessed at 6 to 12 months.

Data Extraction

Two authors (W.D.B. and K.E.P.) independently extracted and recorded trial data on case report forms. A research assistant who was unaware of the study hypothesis entered these data into a centralized database where discrepancies were identified and resolved by the consensus of 2 authors (D.E.W. and A.A.B.). When necessary for clarification, personal communication with study authors was undertaken. Non‐English manuscripts were translated using native‐speaking research associates.

Statistical Analysis

We used a DerSimonian‐Laird model to construct random effects summary risk ratios (RRs). We reported outcomes for all trials in aggregate and grouped according to the type of GPI used, abciximab and small molecule GPIs (eptifibatide and tirofiban). We followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement for constructing a high‐quality meta‐analysis.10 Adequate description of randomization strategy, completeness of follow‐up, and blinded assessment of outcomes were used to assess trial quality.11 Begg's method and Egger's funnel plot were used to assess for publication bias.12, 13 We evaluated for study heterogeneity with inconsistency index (I2) (low heterogeneity defined as approximately 25%, moderate as 50%, and high as 75%) and Cochran's Q statistics.14 Sensitivity analysis was performed by limiting the primary analysis to placebo‐controlled trials or by exclusion of the largest study. Two‐tailed P values with α = 0.05, and confidence intervals (CIs) calculated at the 95% level were used to define significance of all statistical tests. All analyses were performed on STATA software, version 11 (STATA Corporation, College Station, TX).

Results

Baseline Characteristics

Our search identified 16 randomized clinical trials in 7611 patients (Figure 1, Table 1).6, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 ST‐elevation myocardial infarction was the presenting diagnosis in 69% of participants (n = 5255). All patients received a thienopyridine that was given prior to PCI 91% of the time (n = 6387). The median age was 62 years, median proportion of diabetes mellitus was 19%, and median proportion of women was 24%. Details about the administration of GPIs and other medications are listed in Supporting Information Table 1. In the largest trial,21 abciximab was used at standard dose and duration during non‐ST‐elevation myocardial infarction, and a 600‐mg loading dose of clopidogrel was given at least 2 hours prior to PCI. Elements of trial quality were extracted for each study and minimal patient dropout was observed (Supporting Information Table 2). Some trials did not report all clinical outcomes; therefore, the summary estimate for a particular outcome may consist of fewer studies than the total number of available studies. One study was written in Chinese and was translated by a research associate.20 We contacted several study authors to clarify data. One study author provided additional mortality data,27 whereas another author responded, but was unable to provide additional mortality data.26

Table 1.

Patient Characteristics

Study Name Year Patient Population Patients (n) Age (y) Female (%) DM (%) Prior MI (%) Symptoms to PCI (h) Stented (%)
ON‐TIME 215, 16 2010 STEMI 1398 62/62 23/25 12/11 9/9 2.8a 90/90
ASSIST6 2009 STEMI 400 60/61 19/28 14/18 11/14 3.3/3.2 93/92
BRAVE‐317 2009 STEMI 800 62/62 24/27 19/16 10/11 5/5.3 92/94
Ivandic et al18 2008 NSTEMI 100 64/65 28/36 30/28 18/22 17.1/16.0 66/74
Fu et al19 2008 STEMI 150 54/52 10/10 18/21 NR 6.7/7.1 93/100
Shen et al20 2007 STEMI 160 64/64 15/11 24/30 NR 6.4/7.1 98/95
ISAR‐REACT 221 2006 NSTEMI 2022 66/67 23/26 25/28 24/24 NR 97/97
Petronio et al22 2005 STEMI 60 60/61 20/13 17/23 NR 3.0/3.2 100/100
Ernst et al (abciximab)23 2004 STEMI 60b 63/60 33/20 20/13 7/3 4.6/4.2 79c
Ernst et al (tirofiban)23 2004 STEMI 60b 62/60 28/20 7/13 3/3 4.8/4.2 79c
Ernst et al (low‐dose tirofiban)23 2004 STEMI 60b 60/60 17/20 7/13 13/3 4.0/4.2 79c
ADVANCE24 2004 NSTEMId 202 69/68 31/34 53/45 52/45 NR 98/98
ACE25 2003 STEMI 400 64/63e 24/21 17/19 10/12 3.7/4.2 99/99
Petronio et al26 2003 STEMI 31 57/58 18/7 12/14 0/0 3.5/4.0 100/100
Wong et al27 2003 NSTEMI 32 61/65 23/27 12/20 NR NR 100/100
CADILLAC28 2002 STEMI 1036 59/60e 26/28 19/16 13/12 3.8/3.9 98/98
ADMIRAL29 2001 STEMI 300 60/62 15/22 15/20 14/7 NR 92/92
ISAR‐230 2000 STEMI 401 61/60 26/23 17/13 NR NR 100/100
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Abbreviations: ADMIRAL, Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long‐Term Follow‐up; BRAVE‐3, Bavarian Reperfusion Alternatives Evaluation‐3; CADILLAC, Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications; DM, diabetes mellitus type 2; ISAR‐2, Intracoronary Stenting and Antithrombotic Regimen 2; ISAR‐REACT 2, Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2; MI, myocardial infarction; NR, not reported; NSTEMI, non‐ST‐elevation MI; ON‐TIME 2, Ongoing Tirofiban In Myocardial Infarction Evaluation 2; STEMI, ST‐elevation MI. All data are formatted as glycoprotein IIb/IIIa inhibitor/control and reported as means unless noted otherwise.

a

Reported for all patients in aggregate.

b

This study had 3 intervention arms, each of which was compared to the same placebo group. The total number of patients in the study was 120.

c

Average over all groups.

d

Included some elective cases.

e

Median age.

Efficacy

The definition of myocardial infarction varied between the studies (Supporting Information Table 3). The incidence of myocardial infarction at 30 days was 3.1% with GPIs versus 4.4% with control (RR = 0.74; 95% CI, 0.59–0.94; P = 0.014) (Figure 2). No publication bias was detected (Begg's test P = 0.37, Egger's test P = 0.36) (Supporting Information Figure 1) and there was no heterogeneity (I2 = 0%). When the analysis was grouped according to the type of GPI used, there was a reduction in myocardial infarction with abciximab (RR = 0.74; 95% CI, 0.58–0.96; P = 0.023); however, not with small molecule GPIs (RR = 0.66; 95% CI, 0.26–1.68; P = 0.38). When the analysis was restricted to placebo‐controlled trials, there was a nonsignificant reduction in the risk of myocardial infarction (RR = 0.78; 95% CI, 0.61–1.002; P = 0.051). The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 (ISAR‐REACT 2) trial contributed 74% of the study weight for myocardial infarction; therefore, excluding this trial as a sensitivity analysis also resulted in a nonsignificant reduction in the risk of myocardial infarction (RR = 0.65; 95% CI, 0.40–1.06; P = 0.086). Myocardial infarction was not significantly reduced when ST‐elevation myocardial infarction studies were grouped together (RR = 0.65; 95% CI, 0.37–1.13; P = 0.13); however, it was marginally reduced when non‐ST‐elevation myocardial infarction studies were grouped together (RR = 0.76; 95% CI, 0.58–1.002; P = 0.051).

Figure 2.

Figure 2

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Risk ratios for myocardial infarction. Trials that did not report an outcome were excluded from analysis. The size of the data markers indicates the relative weight of each study. Abbreviations: CI, confidence interval; GPI, glycoprotein IIb/IIIa inhibitor; RR, risk ratio.

All but 5 trials reported revascularization19, 22, 23, 24, 27 and the incidence of this outcome at 30 days was 1.7% with GPIs versus 2.7% with control (RR = 0.64; 95% CI, 0.46–0.89; P = 0.008). When analyzed separately, abciximab reduced revascularization (RR = 0.55; 95% CI, 0.36–0.86; P = 0.009), but small‐molecule GPIs did not (RR = 0.91; 95% CI, 0.39–2.10; P = 0.82).

Safety

Based on data from all but 2 trials,19, 27 the incidence of major bleeding at 30 days was 2.5% with GPIs versus 2.1% with control (RR = 1.21; 95% CI, 0.89–1.63; P = 0.22) (Figure 3). No publication bias was detected (Begg's test P = 0.44, Egger's test P = 0.39) (Supporting Information Figure 2) and there was no heterogeneity (I2 = 0%). Neither abciximab (RR = 0.96; 95% CI, 0.62–1.50; P = 0.86) nor small‐molecule GPIs (RR = 1.47; 95% CI, 0.97–2.21; P = 0.067) were associated with increased risk of major bleeding. The risk of major bleeding was similar when analysis was restricted to trials that strictly reported the TIMI definition (RR = 1.23; 95% CI, 0.86–1.77; P = 0.26). When the analysis was restricted to placebo‐controlled trials, the risk of major bleeding remained similar between treatment arms (RR = 1.17; 95% CI, 0.75–1.82; P = 0.50).

Figure 3.

Figure 3

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Risk ratios for major bleeding. Abbreviations: CI, confidence interval; GPI, glycoprotein IIb/IIIa inhibitor; RR, risk ratio.

Minor bleeding was reported in 11 trials.6, 15, 17, 18, 20, 21, 23, 26, 28, 29 The incidence of minor bleeding at 30 days was 5.5% with GPIs versus 4.1% with control (RR = 1.37; 95% CI, 1.06–1.78; P = 0.016) (Supporting Information Figure 3). No publication bias was detected (Begg's test P = 0.53, Egger's test P = 0.41) and heterogeneity was low (I2 = 13.5%). Minor bleeding was not significantly increased with abciximab (RR = 1.46; 95% CI, 0.82–2.60; P = 0.20), but was with small molecule GPIs (RR = 1.42; 95% CI, 1.03–1.94; P = 0.031).

Thrombocytopenia was reported at 30 days in 9 trials, with an incidence of 1.4% with GPIs versus 0.8% with control (RR = 1.49; 95% CI, 0.89–2.48; P = 0.13).6, 17, 20, 21, 23, 24, 28, 29 Neither abciximab (RR = 1.99; 95% CI, 0.70–5.68; P = 0.20), nor the small molecule GPIs (RR = 0.98; 95% CI, 0.35–2.74; P = 0.98) were independently associated with thrombocytopenia. Stroke data were available for 5 studies and was not significantly different between GPIs and control (RR = 0.37; 95% CI, 0.13–1.08; P = 0.068).6, 15, 17, 25, 28, 30

All‐Cause Mortality

The incidence of mortality at 30 days was 2.2% with GPIs versus 2.9% with control (RR = 0.79; 95% CI, 0.59–1.06; P = 0.12) (Figure 4). Publication bias was not detected (Begg's test P = 0.72, Egger's test P = 0.97) and heterogeneity was not observed (I2 = 0%). Mortality at 6 to 12 months was reported in 10 trials with an incidence of 3.8% for GPIs versus 5.4% for control (RR = 0.79; 95% CI, 0.57–1.09; P = 0.15).6, 15, 18, 19, 20, 21, 22, 24, 25, 28, 29 Publication bias was not detected (Begg's test P > 0.99, Egger's test P = 0.76) and heterogeneity was moderate (I2 = 28.5%).

Figure 4.

Figure 4

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Risk ratios for mortality. Abbreviations: CI, confidence interval; GPI, glycoprotein IIb/IIIa inhibitor; RR, risk ratio.

Discussion

We analyzed 16 studies with 7611 ACS patients and demonstrated that during PCI, the addition of a GPI to unfractionated heparin was beneficial. GPIs were associated with a significant reduction in myocardial infarction and revascularization with no significant increase in major bleeding. Minor bleeding was increased with GPIs; however, mortality was the same between treatment groups.

Efficacy and Safety of GPIs

Our observation of reduced myocardial infarction with GPIs was marginally significant when the analysis was restricted to placebo controlled trials (P = 0.051) and was no longer significant when the largest trial, ISAR‐REACT 2, was excluded (P = 0.086). Although most of our studies were on ST‐elevation myocardial infarction, benefit was more evident with non‐ST‐elevation myocardial infarction. This is consistent with a recent meta‐analysis of GPIs in ST‐elevation myocardial infarction did not demonstrate a reduction in myocardial infarction.7 By including studies of both non‐ST‐elevation myocardial infarction and ST‐elevation myocardial infarction, which are both processes of plaque rupture, our analysis had more than twice as many patients to analyze. Our results largely apply to patients pretreated with a thienopyridine. Evidence suggests that stent thrombosis may be reduced by 50% with GPIs, even with thienopyridine pretreatment. Stent thrombosis was not specifically reported in most of our included studies, but this could be 1 mechanism for the benefit of GPIs in reducing myocardial infarction, as well as revascularization.31, 32

The reduction in myocardial infarction with abciximab, but not the small molecule GPIs, is likely related to disproportionate study power for this outcome, rather than a biological difference since abciximab contributed 86% of the study weight for this outcome (Figure 2). Recent trials33, 34 and meta‐analyses35, 36 have not detected a difference in mortality, bleeding, or myocardial infarction between these agents. Regardless of the agent selected, rapid and potent platelet inhibition (≥95%) appears to an important characteristic that determines clinical efficacy.37

Small‐molecule GPIs were associated with an increase in minor bleeding. While the tendency might be to discount this outcome, both minor and major bleeds have been associated with poor prognosis.38, 39 The increased frequency of minor bleeding that was observed with small molecule GPIs could be related to the longer infusion duration of these agents, in contrast to abciximab. For elective PCI, an abbreviated infusion of GPIs has been shown to be noninferior at preventing periprocedural myonecrosis while significantly reducing the risk of major bleeding.40 An abbreviated infusion of GPIs (<12 hours) may be beneficial in the ACS setting. Intracoronary GPIs might also maximize efficacy,41 but these approaches would need to be prospectively tested in ACS patients.

All‐cause mortality was similar, although nonsignificantly reduced with the use of GPIs. This suggests that reduction in myocardial infarction is an accurate reflection of the true effect of GPIs and that this benefit outweighs any harmful effects from an increase in minor bleeding. De Luca et al previously concluded that abciximab improved short and long‐term survival during primary PCI for ST‐elevation myocardial infarction5; however, that analysis included many studies which did not routinely use stents or thienopyridines. Our analysis of more current studies documented continued benefit of GPIs in ACS; however, a survival advantage from this agent is now less apparent.

Strengths

An important strength of our analysis is the comprehensive search strategy and our focus on current trials. Because both ST‐elevation myocardial infarction and non‐ST‐elevation myocardial infarction are processes of plaque rupture and activated platelets, we felt it reasonable to include both patient populations in this analysis of GPIs. We employed a strategy of independently extracting and verifying outcome data to optimize the accuracy of our analysis.

Limitations

A major limitation was the variable definition of myocardial infarction across the studies. In fact, three studies reported this outcome, but did not provide a definition. We also acknowledge the difficulty in diagnosing re‐infarction in acute coronary syndromes, especially in ST‐elevation myocardial infarction. Despite this limitation, no statistical heterogeneity was detected for myocardial infarction or major bleeding. Moreover, most of the placebo‐controlled studies shared a more common definition of myocardial infarction (creatinine kinase‐myocardial band >3× upper limit of normal). We included all available studies, including small studies, as this was felt to be necessary to avoid introduction of bias. The ACUITY and HORIZONS AMI trials were excluded because these open label trials included a bivalirudin‐based strategy.42, 43 Lastly, several trials used a higher dose of unfractionated heparin in the control arm than the GPI arm. This difference might have diminished the relative efficacy of GPIs and masked any increased tendency toward bleeding.

Conclusion

In ACS patients undergoing PCI with stents and thienopyridines, GPIs significantly reduce myocardial infarction and revascularization, without increasing the risk of major bleeding. Minor bleeding is increased by GPIs and mortality is similar between treatment groups.

Supporting information

Supporting Information Figure 1. Risk ratios for minor bleeding. Trials that did not report an outcome were excluded from analysis. The size of the data markers indicates

Click here for additional data file. (1.1MB, pdf)

Supporting Information Figure 2. Funnel plot of studies that reported myocardial infarction. Trials that did not report an outcome were excluded from analysis.

Click here for additional data file. (142.1KB, pdf)

Supporting Information Figure 3. Funnel plot of studies that reported major bleeding. Trials that did not report an outcome were excluded from analysis.

Click here for additional data file. (135KB, pdf)

Study Medications

Click here for additional data file. (53.5KB, doc)

Elements of Study Quality

Click here for additional data file. (39.5KB, doc)

Definitions of trial outcomes

Click here for additional data file. (39.5KB, doc)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting Information Figure 1. Risk ratios for minor bleeding. Trials that did not report an outcome were excluded from analysis. The size of the data markers indicates

Click here for additional data file. (1.1MB, pdf)

Supporting Information Figure 2. Funnel plot of studies that reported myocardial infarction. Trials that did not report an outcome were excluded from analysis.

Click here for additional data file. (142.1KB, pdf)

Supporting Information Figure 3. Funnel plot of studies that reported major bleeding. Trials that did not report an outcome were excluded from analysis.

Click here for additional data file. (135KB, pdf)

Study Medications

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Elements of Study Quality

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Definitions of trial outcomes

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