Facilitated angioplasty with combo therapy among patients with ST-segment elevation myocardial infarction:

a meta-analysis of randomized trials

Giuseppe De Luca MD?, Paolo Marino MD

Division of Cardiology, “Maggiore della Carita” Hospital, Eastern Piedmont University “A. Avogadro,” Novara, Italy

Received 24 April 2008; revised 17 May 2008; accepted 21 May 2008

Abstract

Introduction: Time to treatment has been shown to be a major determinant of mortality in primary angioplasty. The aim of the current study was to perform a meta-analysis of randomized trials evaluating the benefits from pharmacologic facilitation with adjunctive glycoprotein (Gp) IIb-IIIa inhibitors + reduced lytic therapy vs adjunctive Gp IIb-IIIa inhibitors among patients with ST-segment elevation myocardial infarction (MI).

Methods: We obtained results from all randomized trials comparing facilitated PCI with adjunctive Gp IIb-IIIa inhibitors and reduced lytic therapy vs adjunctive Gp IIb-IIIa inhibitors among patients with ST- segment elevation MI (STEMI). The literature was scanned by formal searches of electronic databases (MEDLINE and CENTRAL) from January 1990 to December 2007. The following key words were used: randomized trial, MI, reperfusion, primary angioplasty, pharmacologic facilitation, facilitated angioplasty, combo therapy, fibrinolysis, thrombolysis, half-dose lytic therapy, duteplase, reteplase, tenecteplase, alteplase, abciximab, tirofiban, eptifibatide, and Gp IIb-IIIa inhibitors. Angiographic end points were the rate of preprocedural and postprocedural thrombolysis in MI (TIMI) 3 flow. Clinical end points assessed were mortality and reinfarction at 30-day follow-up, whereas major Bleeding complications were assessed as safety end point. No language restriction was applied.

Results: We identified 6 randomized trials, including 2684 patients with STEMI. Even though combo therapy was associated with a significant improvement in preprocedural TIMI 3 flow (44.3% vs 15.2%, P b .0001, P_het b .0001), it did not improve the rate of postprocedural TIMI 3 flow (91.5% vs 91.2%, P = .12). No benefits were observed in terms of 30-day mortality (4.2% vs 4.6%, P = .66, P_het = .22) and/or 30-day reinfarction (1.3% vs 1.3%, P = .84). However, combo therapy was associated with higher risk of major bleeding complications (5.8% vs 3.9%, P = .03).

Conclusions: This meta-analysis shows that among patients with STEMI undergoing primary angioplasty, pharmacologic facilitation with combined reduced-dose thrombolytic therapy and Gp IIbIIIa inhibitors is not superior to Gp IIb-IIIa inhibitors alone and, thus, may not be routinely recommended. However, future randomized trials should investigate whether this strategy may further improve outcome when applied within the first hours from symptoms onset, especially in patients undergoing transferring for primary angioplasty.

(C) 2009

* Corresponding author. Tel.: +39 0321 3733141; fax: +39 0321 3733407.

E-mail address: [email protected] (G. De Luca).

0735-6757/$ – see front matter (C) 2009 doi:10.1016/j.ajem.2008.05.021

Introduction

Despite the benefits in mortality as compared with thrombolysis [1], Primary PCI has not become the preferred treatment for most of patients with STEMI because of logistical issues. In fact, most patients present to non-PCI hospitals with the need of transportation and subsequent delay to treatment [2]. This is a relevant issue because time to treatment has been shown to be a major determinant of survival in primary angioplasty as well [3-4]. Early pharmacologic reperfusion may potentially overcome any delay to mechanical reperfusion. Full-dose fibrinolysis- facilitated PCI has recently been shown to result in worse outcome than primary PCI alone and is potentially explained by the higher rate of thrombotic complications as a consequence of the restricted use of glycoprotein (Gp) IIb- IIIa inhibitors [5]. The adjunctive benefits of a facilitated angioplasty strategy with combination of reduced-dose thrombolytic and Gp IIb-IIIa inhibitors before PCI in patients with myocardial infarction (MI) are still unclear. Recent large randomized trials have been completed [6-7] and not included in previous meta-analyses [8-9]. Thus, the aim of the current study was to perform an updated meta- analysis of randomized trials evaluating the benefits from adjunctive Gp IIb-IIIa inhibitors and reduced lytic therapy vs adjunctive Gp IIb-IIIa inhibitors among patients with STEMI.

Methods

Eligibility and search strategy

We obtained results from all completed randomized trials comparing pharmacologic facilitation with Gp IIb-IIIa inhibitors alone or in combination with half-dose lysis among patients with STEMI undergoing primary angio- plasty. The literature was scanned by formal searches in electronic databases (MEDLINE and CENTRAL) and the scientific session abstracts in Circulation, Journal of the American College of Cardiology, European Heart Journal, and American Journal of Cardiology from January 1990 to December 2007. Furthermore, oral presentations and/or expert slide presentations were included (searched on the TCT [www.tctmd.com], EuroPCR [www.europcr.com], ACC [www.acc.org], AHA [www.aha.org], and ESC [www.escardio.org] Web sites from January 2002 to December 2007). The following key words were used: randomized trial, myocardial infarction (MI), reperfusion, primary angioplasty, pharmacologic facilitation, facilitated angioplasty, combo therapy, fibrinolysis, thrombolysis, half- dose lytic therapy, duteplase, reteplase, tenecteplase, alte- plase, abciximab, tirofiban, eptifibatide, and Gp IIb-IIIa inhibitors. Inclusion criteria were as follows: (1) randomized treatment allocation and (2) availability of complete clinical

data. Exclusion criteria were as follows: (1) follow-up data in less than 90% of patients and (2) ongoing studies or irretrievable data. No language restrictions were enforced.

Data extraction and validity assessment

Data were independently abstracted by 2 investigators. In case of incomplete or unclear data, authors, where possible, were contacted. Disagreements were resolved by consensus. Data were managed according to the intention- to-treat principle.

Outcome

Angiographic end point was preprocedural and post- procedural thrombolysis in MI (TIMI) 3 flow. Clinical end points were mortality and reinfarction. Safety end points were the rates of major bleeding and Intracranial bleeding complications.

Data analysis

Statistical analysis was performed using the Review Manager 4.27 and SPSS 11.0 statistical package (SPSS, Chicago, Ill). Odds ratio (OR) and 95% confidence intervals (CIs) were used as summary statistics. The pooled OR was calculated by using a fixed-effect model with the Mantel- Haenszel method. The DerSimonian and Laird random effect model was additionally applied to calculate pooled OR in case of significant heterogeneity across studies. Between- study heterogeneity was analyzed by means of I² = [(Q – df)/ Q]100%, where Q is the ?2 statistic and df is its degrees of freedom. The potential publication bias was examined by constructing a “funnel plot,” in which the SE of the ln OR was plotted against the OR (for 6-12 months’ mortality). In addition, a linear regression approach to measure funnel plot asymmetry was used [10].

Fig. 1 Flow diagram of the systematic overview process. RCT indicates randomized controlled trials.

Table 1 Characteristics of randomized trials included in the meta-analysis

Combination IIb/IIIa inhibitors Combination IIb/IIIa inhibitors therapy group group therapy group group

ADVANCE STEMI 74

74

–

–

Tenecteplase

TIMI 3 flow grade

30-d death, reinfarction, or

Abciximab dose: 0.25 mg/kg IV bolus followed by 12 hours of infusion at 0.125 mg/kg per minute. Eptifibatide dose: 2 boluses of 180 mg/kg IV 10 minutes apart, then 2.0 mg/kg per minute infusion. Tirofiban: 10 ug/kg bolus and 0.15 ug/kg per minute infusion or 24 hours. NA indicates not applicable.

Facilitated PCI with combo therapy among patients with STEMI

685

Study	Inclusion	No. of patients	Symptom onset to drug		Agents	Angiographic end point	Clinical end point
	criteria		administration (min)

MI	b6 h					(0.25 mg/kg IV bolus) + eptifibatide	new congestive heart failure
SPEED	STEMI	191	63	153	138	Reteplase TIMI 3 flow grade	30-d death, reinfarction, or
	b12 h					(5U + 5U bolus) +	urgent revascularization
						abciximab
BRAVE	STEMI	125	128	160	164	Reteplase TIMI 3 flow grade	Death, reinfarction, major
	b12 h					(5U + 5U bolus) +	bleeding, and hemorrhagic
						abciximab	stroke
APAMIT	STEMI	34	36	205	259	Alteplase TIMI 3 flow grade	Death, reinfarction, TVR,
	b6 h					(15 mg bolus +	stroke, and major bleeding
						35 mg infusion) +
						abciximab
FINESSE	STEMI	828	818	NA	NA	Reteplase TIMI 3 flow grade	90-d all-cause mortality,
	b6 h					(5U + 5U bolus) +	cardiogenic shock,
						abciximab	rehospitalization for heart
							failure, resuscitated
							ventricular fibrillation N48 h
							after randomization
ATAMI	STEMI	151	162	170	212	Alteplase TIMI 2-3 flow grade	Mortality and in-stent
	b6 h					(15 mg bolus + 35 mg infusion	thrombosis at 30 d and major
						for 60 min) + tirofiban	bleeding

The study was performed in compliance with the Quality of Reporting of Meta-Analyses (QUORUM) guidelines [11].

Results

Eligible studies

Of the 1462 potentially relevant articles initially screened, a total of 7 trial were initially identified [6- 7,12-16], and 6 randomized trials [6-7,12-15] were finally included in the meta-analysis (Fig. 1), involving 2684 patients (1403 or 52.3% randomized to combo therapy and 1281 or 47.7% randomized to early Gp IIb-IIIa inhibitors). Characteristics of the included trials are shown in Table 1. The ADVANCE MI trial [12] was designed to enroll 5640 patients but was prematurely stopped after the enrollment of 148 patients because of slow recruitment. Even though the trial design was quite similar in all studies, there were some differences regarding the type and dose of thrombo- lytic and/or Gp IIb-IIIa inhibitors used (Table 1). Even though the Strategies for Patency Enhancement in the Emergency Department (SPEED) study group tested

multiple doses of reteplase, we included only the 5 + 5 U dose regimen because it was confirmed as the better dose in phase B of the trial [13]. The Alteplase and Tirofiban in Acute Myocardial Infarction (APAMIT) trial [14] was included despite being a rescue angioplasty trial because all the patients in both groups had angiography and only those patients with TIMI 3 flow post-reduced-dose alteplase did not have angioplasty.

Angiographic outcome

As shown in Fig. 2, combo therapy was associated with a significant improvement in preprocedural recanalization (TIMI 3) (44.3% vs 15.2%, OR [95% CI] = 4.14 [3.44-

4.99], P b .0001, P_het b .0001). Combo therapy did not improve the rate of postprocedural TIMI 3 flow (91.5% vs 91.2%, OR [95% CI] = 1.09 [0.81-1.46], P = .59, P_het =

0.12) (Fig. 2).

Clinical outcome

As shown in Fig. 3, combo therapy did not improve the rate of 30-day mortality (4.2% vs 4.6%, OR [95% CI] =

Fig. 2 Combo therapy and benefits in preprocedural (upper graph) and postprocedural (lower graph) TIMI 3 flow as compared with early Gp IIb-IIIa inhibitors administration, with ORs and 95% CIs. The size of the data markers (squares) is approximately proportional to the statistical weight of each trial.

Fig. 3 Combo therapy and benefits in mortality (upper graph) and reinfarction (lower graph) at 30-day follow-up as compared with early Gp IIb-IIIa inhibitors administration, with ORs and 95% CIs. The size of the data markers (squares) is approximately proportional to the statistical weight of each trial.

0.92 [0.63-1.34], P = .66, P_het = 0.22) and/or 30-day

reinfarction (1.3% vs 1.3%, OR [95% CI] = 0.90 [0.32- 2.54], P = .84, P_het = 0.81). The potential publication bias was analyzed by the visual analysis of the funnel plot (Fig. 4) and by the mathematical estimate of the asymmetry of this plot provided by a linear regression approach. The intercept of the regression line did not deviate significantly from zero (? = .17, 95% CI., -2.45 to 2.8, P = .86). Finally, as shown in Fig. 5, combo therapy was associated with higher risk of major bleeding complications (5.8% vs 3.9%, OR [95% CI] = 1.50 [1.04-2.18], P = .03, P_het = 0.45).

Discussion

The main finding of this meta-analysis is that facilitation with combination between Gp IIb-IIIa inhibitors and half- lysis improved preprocedural recanalization, as compared with early Gp IIb-IIIa inhibitors alone, without any benefit in terms of postprocedural TIMI 3 flow, short-term mortality, and reinfarction, but with a higher risk of major bleeding complications.

Recent investigations have demonstrated that time to treatment is a relevant issue in primary angioplasty, with a

significant impact on mortality [3-4]. Therefore, early administration of Pharmacologic therapy by improving earlier reperfusion may reduce infarct size and improve survival, particularly when long-distance transportation is required. In fact, Mortality benefit of primary PCI is lost for patients with prolonged Door-to-balloon times [17-19] compared with patients treated with thrombolysis, particu-

Fig. 4 Funnel plot of all studies included in the meta-analysis. The SE of the ln OR was plotted against the OR for mortality. No skewed distribution was observed, suggesting no publication bias.

Fig. 5 Combo therapy and risk of major bleeding complications as compared with early Gp IIb-IIIa inhibitors administration, with ORs and 95% CIs. The size of the data markers (squares) is approximately proportional to the statistical weight of each trial.

larly in high-risk patients. A subanalysis of the Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long-term follow-up (ADMIRAL) trial showed that early abciximab administra- tion (in the emergency department or in the ambulance) did improve clinical outcome as compared with late administra- tion [20]. Several randomized trials have been conducted to investigate the benefits from early administration of Gp IIb- IIIa inhibitors in patients undergoing primary angioplasty [6,21-33], with discordant results. Recent data from the EUROTRANSFER registry [34], conducted in consecutive patients enrolled in high-volume primary PCI centers, did show a significant improvement in preprocedural TIMI flow and survival with early abciximab administration. The benefits in survival from early Gp IIb-IIIa inhibitors have also been confirmed by a retrospective analysis of the large Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-MI) trial [35].

The use of thrombolysis, due to higher rates of preprocedural recanalization, may potentially provide more benefits as compared with Gp IIb-IIIa inhibitors alone. Data from the Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT-4 PCI) trial [5] have clearly demonstrated that facilitation with full-dose lytic therapy is associated with impaired survival, mainly because of thrombotic complica- tions as a consequence of the prothrombotic effects determined by lysis, in the absence of strong Antiplatelet therapy. Data from the large Facilitated INtervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial [6], recently presented at the ESC 2007 annual meeting, did not show any clinical benefit from facilitation with either combo therapy or Gp IIb-IIIa inhibitors alone, with higher risk of major bleeding complications. Some limitations should be taken into account in the interpretation of the results of this trial. First of all, it was prematurely stopped after 4 years because of slow recruitment. Thus, the very low enrollment rate per center per year certainly led to a selection bias. In addition, even though the study was focused on

facilitation, more than 50% of patients were enrolled in primary PCI centers.

It must be recognized that, even though in most trials the time window for enrollment was restricted to the first 6 hours from symptoms onset, a large proportion of patients did receive facilitation after the first 3 hours, when clinical benefits, especially with combo therapy, are certainly low. In this case, in fact, the risk of bleeding complications outweighs the benefits from early pharmacologic reperfusion because of less myocardium that can be saved and reduced drug effectiveness. In a prespecified analyses of the FINESSE trial, some benefits in terms of clinical outcome were observed among patients presenting within the first 3 hours from symptom onset.

In our meta-analysis, including 2684 patients, as compared with early Gp IIb-IIIa inhibitors, facilitation with combo therapy, despite the clear benefits in terms of preprocedural TIMI flow, did not provide benefits in terms of survival, with higher risk of bleeding complications. The absence of benefits in outcome despite improved preproce- dural recanalization may depend on relatively late recanali- zation, with a potential Hemorrhagic transformation of the infarction zone with lytic therapy.

Limitations

The availability of individual patients data would have further improved the results of our meta-analysis. In addition, we analyzed Short-term outcomes, whereas some Gp IIb-IIIa inhibitor studies have often demonstrated increased Survival benefit with longer follow-up [36].

Conclusions

This meta-analysis shows that among the patients with STEMI, undergoing primary angioplasty pharmacologic facilitation with combined reduced-dose thrombolytic therapy and Gp IIb-IIIa inhibitors is not superior to Gp

IIb-IIIa inhibitors alone and, thus, may not be routinely recommended. However, future randomized trials should investigate whether this strategy may further improve outcome when applied within the first hours from symptoms onset, especially in patients undergoing transfer- ring for primary angioplasty.

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