Chinese Medical Journal 2014;127(6):1126-1132:10.3760/cma.j.issn.0366-6999.20131795
Safety and efficacy of early administration of tirofiban in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a meta-analysis

Liu Yangchun, Su Qiang and Li Lang

Keywords
tirofiban; glycoprotein IIb/IIIa inhibitors; percutaneous coronary intervention; myocardial infarction; systematic review
Abstract
Background Tirofiban has been widely used as an adjunctive pharmacologic agent for revascularization in patients undergoing percutaneous coronary intervention, and the outcomes appear attractive. However, the potential benefits from early administration of tirofiban in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) remain unclear.
Methods We conducted a search in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials up to September 2012 without language restriction. A total of eight randomized trials (n=1 577 patients) comparing early (emergency department or ambulance) versus late (catheterization laboratory) administration of tirofiban in STEMI patients undergoing PPCI were included in this meta-analysis. Risk ratio (RR) was computed from individual studies and pooled with random- or fixed-effect models.
Results There were no differences in post-procedural Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 and Corrected TIMI Frame Count (RR=1.02, 95% confidence interval (CI): 0.99–1.05, P=0.18; weighted mean difference (WMD)=–0.93, 95% CI: –5.37–3.52, P=0.68, respectively) between the two groups. Similarly, there were no significant differences in the incidence of 30-day mortality (RR=1.69, 95% CI: 0.69–4.13, P=0.25) and re-myocardial infarction (RR=0.71, 95% CI: 0.21–2.35, P=0.57) between early and late administration of tirofiban. As to the safety end points, no significant difference was observed in hospital minor bleeding (RR=1.08, 95% CI: 0.54–2.14, P=0.83) and hospital and 30-day major bleeding between the two groups (RR=0.98, 95% CI: 0.46–2.10, P=0.96; RR=1.32, 95% CI: 0.59–2.97, P=0.49, respectively).
Conclusions Early administration of tirofiban in patients undergoing PPCI for STEMI was safe, but no beneficial effects on post-procedural angiographic or clinical outcomes could be identified as compared with late administration. Besides the negative finding, more high-quality randomized clinical trials are still needed to explore the efficacy of adequate, earlier administration of tirofiban in patients undergoing PPCI.
Primary percutaneous coronary intervention (PPCI) is considered to be the preferred reperfusion strategy for ST-segment elevation myocardial infarction (STEMI).1However, despite optimal evidence-based percutaneous coronary intervention (PCI), myocardial no-reflow phenomenon and distal embolization can still occur and are associated with a worse in-hospital and long-term prognosis.1,2By preventing the binding of fibrinogen and von Willebrand factor to the glycoprotein IIb/IIIa receptor on the surface of the platelet3and with potential roles in improving myocardial perfusion and clinical outcomes,4,5glycoprotein IIb/IIIa inhibitors (GPIs) as an adjunctive pharmacologic agent to revascularization for patients undergoing PCI appear attractive.
Tirofiban is a small molecule, non-peptide tyrosine derivative which belongs to the class of GPIs.6Though similar to abciximab in that it has a high affinity for GPIIb/IIIa receptors, tirofiban has a shorter half-life and dissociates from the GPIIb/IIIa receptors more rapidly than abciximab.3,6Recently, Zhang et al7investigated the merits of transradial access in PPCI for STEMI patients with upstream use of tirofiban and the results showed good prospects, that is, not only beneficial in reducing bleeding complications but also improving 30-day clinical outcomes. So tirofiban is more commonly used in clinical practice due to the reversibility of the inhibition of platelet aggregation and the improved safety profile as well as lower costs. But the potential benefits from early pharmacological reperfusion by tirofiban are still unclear.
So far, several randomized trials8-15have been conducted to compare the effect of early (emergency department or ambulance) and late (catheterization laboratory) administration of tirofiban in patients undergoing PPCI for STEMI, but all of them are underpowered to detect any differences in terms of post-procedural angiographic or hard clinical outcomes, and controversy remains. So the aim of this study was to perform a thorough and updated meta-analysis of randomized trials to evaluate whether early administration of tirofiban at the point of initial contact (emergency department or ambulance) may offer benefits in clinical outcomes such as death and re-myocardial infarction (re-MI) as compared with late administration (catheterization laboratory) in patients undergoing PPCI for STEMI.
METHODS
Search strategy
We performed an electronic search of the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from their inception to September 2012 without language restriction. The key words used included “tirofiban”, “aggrastat”, “percutaneous coronary intervention”, “primary angioplasty”, “myocardial infarction”, “clinical trial”, and “randomizes”. We also searched the references of all pertinent journal articles to identify additional randomized trials. To ensure that no clinical trials were missed, we also conducted an extensive search of a citation database (ISI Web of Science) using cross references from eligible articles.
Inclusion criteria were (1) randomized treatment allocation, (2) comparison of early (emergency department or ambulance) versus late (catheterization laboratory) administration of tirofiban in patients undergoing PPCI for STEMI, and (3) availability of complete clinical data. Exclusion criteria were (1) follow-up data in less than 90% of patients, (2) duplicate reports failing to report additional or extended clinical outcomes, and (3) non-random treatment allocation.
Data extraction and validity assessment
Two authors (Liu YC and Su Q) independently abstracted the data. Information regarding study and patient characteristics and the prespecified clinical outcomes were systematically extracted. In case of incomplete or unclear data, authors were contacted where possible. Disagreements were resolved by consensus. The primary end point was 30-day death. Secondary end points were re-MI at 30 days, post-procedural Thrombolysis In Myocardial Infarction (TIMI) flow grade 3, and corrected TIMI frame count (CTFC). Death was defined as mortality from any cause, such as death caused by stroke, major bleeding, severe heart failure, as well as re-MI. Here, re-MI was defined as a new increase in creatinine kinase-MB or cTnI fraction of more than three times the upper limit of normal. We also analysed major and minor bleeding (according to the criteria of the TIMI trial16) as the safety end point.
The bias riskof trials was assessed with the components recommended by the Cochrane Collaboration,17including means for generating the randomization sequence, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other sources of bias.
Statistical analysis
Risk ratio (RR) with 95% confidence interval (CI) was used to express the pooled effect on discontinuous variables. The summary estimates of continuous variables were presented as weighted mean differences with 95%CI. Heterogeneity was quantified usingI2statistic, whereI2>50% represented between-study inconsistency. Fixed-effects meta-analyses were conducted to pool these outcomes across the included trials when there was no between-study inconsistency, whereas the random-effects model was used if heterogeneity existed. Publication bias was evaluated using a funnel plot. Results were considered statistically significant atP<0.05. Pooled analyses were performed with ReviewManager 5.0 software (Cochrane Collaboration, Denmark).
RESULTS
Selected studies and baseline characteristics
Of the 328 potentially relevant articles initially screened, a total of eight randomized controlled trials (RCTs)8-15comparing early (emergency department or ambulance) versus late (catheterization laboratory) administration of tirofiban in patients undergoing PPCI for STEMI were finally identified. Figure 1 shows the flow of the process for identifying potential eligible trials and reasons for exclusion. These studies enrolled 1 577 participants (723 randomized to early administration group and 854 randomized to late administration group). Characteristics of the eligible trials are summarized in Table 1.
Patients in five included studies9,10,12,14,15were preprocedurally treated with aspirin and clopidogrel; among them, patients in two studies9,15were given a loading dose of 600 mg of clopidogrel, while the use of clopidogrel in the other three studies8,11,13was unclear. Postintervention antiplatelet therapy consisted of aspirin and thienopyridines. Five studies8,9,12,13,15assessed the pre-treatment time between early group and late group, but the method used for appraising was inconsistent, so comprehensive assessment about the pre-treatment time between the two groups was not available.
The design characteristics of the included studies are shown in Table 2. Among the eight studies, four RCTs8,9,11,13reported the specific random methods that were used. In one study8a block random approach was used, and in the other three studies,9,11,13a random number table was used. Two of the studies8,13described the allocation concealments in detail. In three studies,8,11,14blinded methods were used, with two studies8,11using a double-blind approach and one study14using a single-blind approach. Two studies8,13had a loss of follow-up, but intent-to-treat analysis was done only in one study.13
Angiographic end points
The data of post-procedural TIMI flow grade 3 were available in all eight trials.8-15No significant heterogeneity was found between the two groups (I2=0,P=0.50), so the fixed-effect model was used, and the pooledRRwas 1.02 (95%CI: 0.99–1.05,P=0.18, Figure 2), suggesting no difference was observed between early and late administration of tirofiban in final TIMI flow grade. Of the eight trials, three trials11-13reported data on post-procedural CTFC; there was a statistical heterogeneity between the two groups (I2=51%,P=0.13), so the random-effect model was used. No difference was found in final CTFC between the two groups (WMS=–0.93, 95%CI: –5.37 to 3.52,P=0.68, Figure 3).
Clinical end points
The data of 30-day death and re-MI were available in five trials.8,11-14No significant heterogeneity was found between the two groups (I2=20%,P=0.29;I2=0,P=0.73, respectively), so the fixed-effect model was used. There was no significant difference in the incidence of 30-day death (RR=1.69, 95%CI: 0.69–4.13,P=0.25) and 30-day re-MI (RR=0.71, 95%CI: 0.21–2.35,P=0.57) in patients treated with early administration of tirofiban as compared with those treated with late administration (Figure 4).
Safety end points
The data of major bleeding in hospital and 30-day follow-up were available in five9-11,14,15and three8,12,13studies, respectively. No significant heterogeneity was found between the two groups (I2=7%,P=0.37;I2=0,P=0.81, respectively), so the fixed-effect model was used. There were no differences in the incidence of hospital and 30-day major bleeding between the two groups (RR=0.98, 95%CI: 0.46–2.10,P=0.96;RR=1.32, 95%CI: 0.59–2.97,P=0.49, respectively, Figure 5). Data on hospital minor bleeding were available in three studies.11,14,15No significant heterogeneity was found between the two groups (I2=0,P=0.41), so the fixed-effect model was used. The pooledRRwas 1.08 (95%CI: 0.54–2.14,P=0.83), revealing there was no difference between the two groups in the incidence of hospital minor bleeding (Figure 6).
Publication bias
Based on a visual inspection of the funnel plots, there was no evidence of publication bias among the included studies (Figure 7).
DISCUSSION
The main finding of this meta-analysis is that early (emergency department or ambulance) administration of tirofiban does not provide significant benefits in post-procedural TIMI flow grade 3, post-procedural CTFC, and 30-day mortality and re-MI as compared with late (catheterization laboratory) administration. Regarding safety end points, there were no differences between the two groups in the rates of major bleeding and minor bleeding, which showed that early administration of tirofiban was safe.
PPCI has been shown to be an effective reperfusion modality in patients with acute myocardial infarction (AMI) both at short- and long-term follow-up.18,19Although additional transportation delay exists while transporting patients to PCI center, transportation of AMI patients is safe and the clinical outcomes are superior in patients who undergo angioplasty as compared to thrombolysis.20,21However, although PPCI is able to restore TIMI flow grade 3 in the vast majority of patients, a relatively large proportion of patients experience poor reperfusion because of the distal embolization and no-reflow phenomenon.1,2GPIs are the most powerful class of antiplatelet therapies and can improve angiographic and clinical outcome in patients undergoing PPCI.4,5
Based on the results of several randomized controlled studies and meta-analyses, the adjunctive use of abciximab in patients undergoing PPCI for STEMI is recommended as a class IIa indication by current guidelines.5,22Previous meta-analysis of randomized trials23has demonstrated that early administration of abciximab in patients undergoing primary angioplasty for STEMI is associated with a significant benefit in angiographic and clinical outcomes. Former meta-analyses24,25revealing the potential benefits from early pharmacological reperfusion by GPIIb/IIIa showed that post-procedural TIMI flow grade 3 and myocardial blush grade (MBG) were higher with early GPIs but did not reach statistical significance except for abciximab; as to mortality, no difference was found between early and late groups, although abciximab demonstrated improved survival compared with late administration. Moreover, recent guideline for management of STEMI given by ACCF/AHA also showed that it might be reasonable to administer intervenous GPIIb/IIIa receptor antagonist in the precatheterization laboratory setting (e.g., ambulance or emergency department) to patients with STEMI for whom primary PCI is intended (recommended level IIb; level of evidence B).26Therefore, the benefit from early administration of abciximab is not in doubt, but whether early initiation of tirofiban can deserve the same benefits as abciximab remains unclear.
Tirofiban, which belongs to the same class of antiplatelet agents as abciximab, namely GPIs, differs from monoclonal antibody abciximab in terms of binding characteristics and specificity for the IIb/IIIa integerin.27Compared toabciximab, which binds near irreversibly to the receptor, resulting in a considerably longer effect, the anti-aggregatory effects of tirofiban reverse within hours after the completion of the infusion.3,28Moreover, tirofiban does not inhibit other β3 integrins, which have been traditionally regarded as crucial targets to explain abciximab effect on microcirculation.29In addition, unlike eptifibatide, tirofiban shares the property of high-affinity IIb/IIIa receptor binding with abiciximab.3Because of the reversibility of the inhibition of platelet aggregation, proper affinity to IIb/IIIa receptor, and lower costs, tirofiban represents a very attractive strategy and is more commonly used in clinical practice.
Although similar analyses24,25had been done, they failed to demonstrate the effect of early administration of tirofiban in patients undergoing PPCI, as those were small-size analyses in which both tirofiban and abciximab were taken into consideration. And no meta-analysis has been done to explore the effect of early administration of tirofiban in patients treated by PPCI for STEMI. Recently, more studies comparing early versus late administration of tirofiban have come out, but all of them are underpowered to detect any differences in terms of post-procedural angiographic or hard clinical outcomes, and controversy remains. So we carried a thorough and updated systematic review of randomized clinical trials evaluating the safety and efficacy of early (emergency department or ambulance) versus late (catheterization laboratory) administration of tirofiban in PPCI for STEMI.
We found conflicting results with the former analysis,23which showed that early administration of abciximab had clinical benefits in terms of death and re-MI. Our results showed that no differences were found in final TIMI flow grade 3 and CTFC as well as the rates of death and re-MI in early administration of tirofiban as compared with late administration. The possible explanations for the lack of efficacy of early administration of tirofiban in improving final TIMI flow grade 3, CTFC, and clinical outcomes could be as follows: first, the dose given in most of the included studies (10 μg/kg bolus, 0.15 μg·kg-1·min-1) was inadequate.Kimmelstielet al30found that circulating tirofiban levels demonstrated a trough, which paralleled a reduction in platelet inhibition, and the trough occurred at 30 minutes after intravenous injection, meaning 30 minutes after administration, the anti-aggregatory effects of tirofiban reached low value. So the currently utilized dosage (10 microg/kg bolus, 0.15 microg·kg-1·min-1infusion) is suboptimal and high-dose bolus (25 microg·kg-1·3 min-1,
and infusion of 0.15 microg·kg-1·min-1for 24-48 hours) tirofiban is recommended and is safe and significantly reduces the incidence of ischemic/thrombotic complications of high-risk PCI. Second, inadequate inhibition of platelets presents particularly shortly after administration; it took at least 2 hours before platelet inhibition reached the desired level of 90%–95%.31Because of the inconsistency in assessing the pre-treatment time between the two groups, it was hard for us to list this characteristic in Table 1. So maybe the insufficiency of pre-time treatment in early administration group was another reason; Third, the capacity to inhibit platelet aggregation while using routine dose of tirofiban was weak as compared with abciximab.28Fourth, most of the patients in the included studies received clopidogrel pre-treatment strategy before PCI. So maybe the benefits from PCI and clopidogrel were enough, and the effect from early administration was limited. Finally, the relevant data on the long-term follow-up period were not available from each study. A better outcome may be observed in long-term follow-up.
This meta-analysis has several limitations worth noting. First, our analysis failed to show the pre-treatment time between early and late groups. Second, two of our included studies had a loss of follow-up, but intent-to-treat analysis was done in only one study, and this might impact the quality of the study. Another limitation for the meta-analysis is the potential heterogeneity among studies in terms of protocols, patients, and sample sizes, and the unavailability of patient-level data that might lead to inaccurate conclusions.
In conclusion, this meta-analysis shows that early administration of tirofiban was safe in patients with STEMI undergoing PPCI. In terms of angiographic and clinical outcomes, there were no differences between early and late administration of tirofiban. Due to the limitation in methodology, larger-scale prospective randomized trials with a longer follow-up duration are required to further assess the efficacy of early administration of tirofiban in patients with STEMI treated by PPCI.
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(Received July 10, 2013)
Edited by Cui Yi
DOI: 10.3760/cma.j.issn.0366-6999.20131795
Department of Cardiology, First Affiliated Hospital of Guangxi Medical University, Guangxi Cardiovascular Institute, Nanning, Guangxi 530021, China (Liu Y, Su Q and Li L)
Correspondence to: Dr. Li Lang, Department of Cardiology, the First Affiliated Hospital of Guangxi Medical University, Guangxi Cardiovascular Institute, Nanning, Guangxi 530021, China (Tel: 86-771-5331171. Email: drlilang@163.com)

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Figure 1.Flow diagram of the systematic overview process. RCTs: randomized controlled trials.
Table 1.Characteristics of randomized controlled trials included in the meta-analysis
Study
Year
Age (year)
Participants
Male
(n(%))
Door to balloon
(minutes)
Dosage
Outcomes
Early
group
Late
group
Early
group
Late
group
Early
group
Late group Earlygroup Late
group
Cutlip DE13 2003 59±11 59±13 28 30 24 (86) 15 (83)     A bolus of 10 μg/kg followed by
an infusion of 0.15 μg·kg-1·min-1for 24 hours
Final TIMI flow grade 3
final CTFC
death and re-MI
major bleeding
Lee DP11 2003 63.5±12.6 66.4±14.3 50 50 30 (60) 32 (64) 88.9±20.7 82.7±20.0 A bolus of 10 μg/kg followed by
an infusion of 0.15 μg·kg-1·min-1for 24 hours
Final TIMI flow grade 3
final CTFC
death and re-MI
major and minor bleeding
van’t Hof AW8 2004 63±10 61±11 251 256 199 (79) 205 (80) 41 39 A bolus of 10 μg/kg followed by
an infusion of 0.15 μg·kg-1·min-1for 24 hours
Final TIMI flow grade 3
final CTFC
death and re-MI
major bleeding
Emre A12 2006 58±10 59±12 32 34 26 (81) 82 (34) 43±12 53±9 A bolus of 10 μg/kg followed by
an infusion of 0.15 μg·kg-1·min-1for 24 hours
Final TIMI flow grade 3
final CTFC
death and re-MI
major bleeding
Xu L15 2006 58.8±25.2   78 80 117 (74)       A bolus of 10 μg/kg followed by
an infusion of 0.15 μg·kg-1·min-1for 36 hours
Final TIMI flow grade 3
death
major and minor bleeding
Shen J14 2008 68.0±14.3 65.3±11.6 57 57 43 (75) 47 (83) 79.7±26.7 68.9±24.3 A bolus of 10 μg/kg followed by
an infusion of 0.15 μg·kg-1·min-1for 36 hours
Final TIMI flow grade 3
death and re-MI
major and minor bleeding
El Khoury C9 2010     163 156 123 (75) 124 (80)     A bolus of 25 μg/kg followed by
an infusion of 0.15 μg·kg-1·min-1for 18–24 hours
Final TIMI 3 flow
death
major bleeding
Hsin HT10 2011 57.1±10.9 56.6±12.0 64 191 54 (84) 173 (91) 126±126 168±78 0.4 mcg·kg-1·min-1used before angiography followed by an infusion of 0.1 mcg·kg-1·min-1for 36 hours Final TIMI 3 flow
death major bleeding
Table 2.Assessment of methodological quality of included studies
Study Randomized method Allocation concealment Blinded Withdrawals and lost to follow-up Intent-to-treat analysis
Cutlip DE 200313 Randomized number table Yes Unclear Yes Yes
Lee DP 200311 Randomized number table Unclear Double blind No No
van’t Hof AW 20048 Randomized block design Yes Double blind Yes No
Emre A 200612 Randomized Unclear Unclear Unclear No No
Xu L 200615 Randomized Unclear Unclear Unclear No No
Shen J 200814 Randomized Unclear Unclear Single blind No No
El Khoury C 20109 Randomized number table Unclear Unclear No No
Hsin HT 201110 Randomized Unclear Unclear Unclear No No

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Figure 2.Pooled risk ratio of early versus late administration of tirofiban for final TIMI flow grade 3 after percutaneous coronary intervention. CI: confidence interval; M-H: Mantel–Haenszel; TIMI: Thrombolysis In Myocardial Infarction.
Figure 3.Pooled mean difference of early versus late administration of tirofiban for final CTFC after percutaneous coronary intervention. CI: confidence interval; IV: inverse variance; SD: standard deviation; CTFC: Corrected TIMI Frame Count.
Figure 4.Pooled risk ratio of early versus late administration of tirofiban for 30-day death and re-MI after percutaneous coronary intervention. CI: confidence interval; M-H: Mantel–Haenszel; Re-MI: re-myocardial infarction.

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Figure 5.Pooled risk ratio of early versus late administration of tirofiban for hospital and 30-day major bleeding after percutaneous coronary intervention. CI: confidence interval; M-H: Mantel–Haenszel.
Figure 6.Pooled risk ratio of early versus late administration of tirofiban for hospital minor bleeding after percutaneous coronary intervention. CI: confidence interval; M-H: Mantel–Haenszel.

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Figure 7.Funnel plot assessing publication bias of the included studies. RR: risk ratio; SE: standard error.