It is still unknown whether upstream administration of glycoprotein (Gp) IIb/IIIa inhibitors, aiming at cooling the culprit lesion before angioplasty, is superior to its selective downstream administration in high-risk patients with acute coronary syndromes (ACSs) undergoing coronary angioplasty. Therefore, the aim of the present study was to perform a meta-analysis of randomized trials comparing upstream to downstream administration of Gp IIb/IIIa inhibitors in high-risk patients with ACS undergoing early invasive strategy. We obtained results from all randomized trials on this issue. The literature was scanned by formal searches of electronic databases from January 1990 to March 2010. The following key words were used: “randomized trial,” “myocardial infarction,” “ACS,” “coronary angioplasty,” “upstream,” “downstream,” “Gp IIb/IIIa inhibitors,” “abciximab,” “tirofiban,” and “eptifibatide.” Primary and secondary clinical end points were mortality and myocardial infarction at 30 days, respectively. Major bleeding complications were assessed as a safety end point. Seven randomized trials were included in the meta-analysis, involving 19,929 patients (9,981 or 50.0% in the upstream Gp IIb/IIIa inhibitors group and 9,948 or 50% in the downstream Gp IIb/IIIa inhibitors group). Upstream Gp IIb/IIIa inhibitors did not decrease 30-day mortality (2.0% vs 2.0%, p = 0.84) or recurrence of myocardial infarction (7.0% vs 7.6%, p = 0.11) but were associated with higher risk of major bleeding complications (1.8% vs 1.3%, p = 0.0002). In conclusion, this meta-analysis shows that in high-risk patients with ACS undergoing an early invasive strategy, upstream administration of Gp IIb/IIIa inhibitors does not improve clinical outcome compared to a downstream selective administration, and it is associated with an increased risk of major bleeding complications. Therefore, a strategy of upstream Gp IIb/IIIa inhibitors cannot be recommended.
Platelet activation and aggregation represent the major determinant in the pathophysiology of acute coronary syndromes (ACSs). Glycoprotein (Gp) IIb/IIIa inhibitors are the strongest available antiplatelet therapy and thus represent a very attractive strategy in high-risk patients with ACS to prevent ischemic complications. Several randomized trials and a previous meta-analysis have shown that use of Gp IIb/IIIa inhibitors is associated with improved outcome in high-risk patients with ACSs undergoing coronary angioplasty and therefore has represented for years a main pillar in the treatment of this subset of patients. However, it is still unknown whether a strategy of upstream administration of Gp IIb/IIIa inhibitors, aiming at cooling the culprit coronary plaque before angioplasty, is superior to a strategy of downstream selective administration of such drugs. In fact, an unselective upstream administration of these drugs may increase the risk of bleeding complications, in addition to higher costs. Therefore, the aim of the present study was to perform a meta-analysis of randomized trials comparing upstream to downstream administration of Gp IIb/IIIa inhibitors in high-risk patients with ACS undergoing an early invasive strategy.
Methods
We obtained results from all randomized trials comparing upstream to downstream adjunctive Gp IIb/IIIa inhibitor treatment in patients with ACS undergoing an early invasive strategy. The literature was scanned by formal searches of electronic databases (MEDLINE, CENTRAL, and Google Scholar databases) from January 1990 to March 2010. Furthermore, oral presentations and/or expert slide presentations were included (searched on the transcatheter coronary therapeutics [ http://www.tctmd.com ], European Percutaneous Coronary Revascularization [ http://www.europcr.com ], American College of Cardiology [ http://www.acc.org ], American Heart Association [ http://www.aha.org ], and European Society of Cardiology [ http://www.escardio.org ] Web sites from January 2002 to March 2010). The following key words were used: “randomized trial,” “myocardial infarction,” “acute coronary syndrome,” “coronary angioplasty,” “upstream,” “downstream,” “Gp IIb/IIIa inhibitors,” “abciximab,” “tirofiban,” and “eptifibatide.”
Inclusion criteria were (1) randomized treatment allocation and (2) availability of complete clinical data. Exclusion criteria were (1) follow-up data in <90% of patients and (2) ongoing studies or irretrievable data. No language restrictions were enforced.
Data were independently abstracted by 2 investigators. For incomplete or unclear data, authors, where possible, were contacted. Disagreements were resolved by consensus. Data were managed according to the intention-to-treat principle.
Primary and secondary clinical end points were mortality and myocardial infarction at 30 days, respectively. Major bleeding complications were assessed as a safety end point. No language restriction was applied.
Statistical analysis was performed using Review Manager 4.27 (Cochrane Corporation, Oxford, UK) and SPSS 11.0 (SPSS, Inc., Chicago, Illinois). Odds ratio (ORs) and 95% confidence intervals (CIs) were used as summary statistics. The pooled OR was calculated using a fixed-effect model with the Mantel-Haenszel method. The DerSimonian-Laird random effect model was also applied to calculate the pooled OR for significant heterogeneity across studies. Between-study heterogeneity was analyzed as I 2 = ([Q − df]/Q) × 100%, where Q is the chi-square statistic and df is its degrees of freedom. Potential publication bias was examined by constructing a “funnel plot,” in which the SE of the natural log OR was plotted against the OR of the primary end point (30-day mortality).
The study was performed in compliance with Quality of Reporting of Meta-Analyses (QUOROM) guidelines.
Results
From the 458 potentially relevant articles screened, 10 trials were initially identified ( Figure 1 ). One trial was excluded because there were no available data on clinical outcome ; an additional trial was excluded because Gp IIb/IIIa inhibitors were administrated in the catheterization laboratory not as a downstream strategy before the procedure but only as a bail-out strategy, whereas in the intracoronary stenting and antithrombotic regimen cooling-off all patients received Gp IIb/IIIa as an upstream strategy. Thus, 7 randomized trials were included in the meta-analysis, involving 19,929 patients (9,981 or 50.0% in the upstream Gp IIb/IIIa inhibitors group and 9,948 or 50.0% in the downstream Gp IIb/IIIa inhibitors group). Characteristics of the included trials are presented in Table 1 . In almost all trials, patients received clopidogrel 300-mg loading dose. A high-dose bolus (600 mg) of clopidogrel was administrated in only 1 trial, whereas in the acute catheterization and urgent intervention triage strategy (ACUITY) the dosage (300 or 600 mg) was left at the discretion of the physician. The ACUITY trial primarily compared heparin plus Gp IIb/IIIa inhibitors to bivalirudin plus Gp IIb/IIIa inhibitors to bivalirudin alone. All patients treated with Gp IIb/IIIa inhibitors were subsequently randomized to a deferred selective (downstream) or upstream administration of abciximab or eptifibatide. In all other studies the decision to administrate the drug in the downstream group was left at the discretion of the operator.
Study | Period | Patients | Study Drug | Clopidogrel | Time From Randomization to Angiography (hours) | Duration of Upstream Gp IIb/IIIa (hours) | GP in Late Arm (%) | Primary End Point | Major Bleeding Complications |
---|---|---|---|---|---|---|---|---|---|
ACUITY | 2003–2005 | 9,207 | Eptifibatide or abciximab | 300–600 mg | 10/11 | 4.1 | 55.7% | Death from any cause, MI, or unplanned revascularization for ischemia at 30-day follow-up | Intracranial or intraocular bleeding, access site hemorrhage requiring intervention, >5-cm hematoma, decrease in hemoglobin >4 g/L or ≥3 for overt bleeding source, reoperation for bleedings, blood product transfusion |
EARLY ACS | 2004–2008 | 9,406 | Eptifibatide | 300 mg | 21.4/21.4 | 21.4 | 23.1% | Death from any cause, MI, recurrent ischemia requiring urgent revascularization, or thrombotic bailout at 96 hours | TIMI/GUSTO major criteria |
ELISA Pilot | 2000–2001 | 220 | Tirofiban | 300 mg | 6/50 | 50 | 8% | Enzymatic infarct size | >2-U blood transfusion, decrease in hemoglobin >2 mmol/ml, gastrointestinal, cerebrovascular or retroperitoneal bleedings, groin surgery |
ELISA 2 | 2002–2005 | 328 | Tirofiban | 600 mg | 22.5/22.2 | 22.2 | 22% | Enzymatic infarct size | >2-U blood transfusion, decrease in hemoglobin >2 mmol/ml, gastrointestinal, cerebrovascular or retroperitoneal bleedings, groin surgery |
EARLY Pilot | NR | 311 | Eptifibatide | 300 mg | NR | NR | 100% | NR | TIMI major criteria |
CLOTILDA | 2002–2004 | 300 | Tirofiban (upstream) or abciximab (downstream) | 300 mg | 37/38 | 37.1 | 17.3% | Enzymatic infarct size | TIMI major criteria |
Liu et al | 2006–2007 | 160 | Tirofiban | 300 mg | NR | NR | NR | MACEs at 24 hours and 3, 7, 30, 180 days | TIMI major criteria |
In total 405 patients had died at 30-day follow-up (primary study end point). As shown in Figure 2 , upstream Gp IIb/IIIa inhibitors did not decrease 30-day mortality (2.0% vs 2.0%, OR 1.02, 95% CI 0.84 to 1.24, p = 0.84, p heterogeneity = 0.77). As shown in Figure 3 , no publication bias was observed.