Intracoronary injection of adenosine before reperfusion in patients with ST-segment elevation myocardial infarction: A randomized controlled clinical trial

Highlights

• Beneficial effect of intracoronary adenosine on myocardial infarction is discrepant.

• We conducted a placebo controlled randomized clinical trial.

• No benefits were found in the whole population.

• A benefit was observed in patients receiving early PCI.

Abstract

Background

The effect of intracoronary adenosine (ADO) on ST-segment elevation myocardial infarction (STEMI) size and adverse remodeling is not well established.

Methods

In a double-blind trial, 201 patients with STEMI were randomized to receive percutaneous coronary intervention (PCI) within 6 hours of symptom onset, 4.5 mg ADO or saline immediately prior to reperfusion. Primary end-point: percentage of total myocardial necrotic mass by cardiac magnetic resonance (CMR) 2–7 days post-reperfusion. Secondary end-points: changes in left ventricular volumes and ejection fraction (LVEF) at baseline and at 6 months.

Results

Baseline CMR could not be performed in 20 patients. Overall, no significant differences were observed between ADO and placebo regarding infarct size (20.8% vs. 22.5%; p = 0.40). However, infarct size was significantly reduced (19.4% vs. 25.7%; p for interaction = 0.031) in those with ischemia duration below the median (200 min). CMR at 6 months, performed in 138 patients, did not show statistically significant differences between groups in the rate of LVEF increase (3.3 units (SD 9.6) in ADO group vs. 1.5 units (SD 9) in placebo group; p = 0.25). In the subgroup analysis, among patients with ischemia time below 200 min, the increase in LVEF was slightly higher with ADO (3.59% vs. 0.43%; p for interaction = 0.06).

Conclusions

Although our study failed to demonstrate that intracoronary administration of ADO prior to PCI limits infarct size, in patients receiving early PCI ADO might enhance myocardial salvage and has a favorable effect on LVEF evolution, which may help to reconcile apparently contradictory results of previous studies.

Clinical trial registration

http://clinicaltrials.gov (NCT00781404).

Introduction

Although reperfusion therapy has improved survival in patients with acute ST-segment elevation myocardial infarction (STEMI) [1], it does not prevent the occurrence of significant myocardial necrosis and, eventually, adverse left ventricular remodeling and heart failure in the majority of cases [2], [3], [4]. Based on extensive preclinical studies, a number of clinical trials aimed at identifying therapies able to limit infarct size in patients with STEMI have been conducted [5].

The ability of adenosine to protect against myocardial ischemia-reperfusion injury has been extensively studied in laboratory models and also in patients with STEMI, with unclear initial results that were not translated to clinical practice [6]. More recently, adenosine was shown to induce protective signaling in cardiomyocytes, involving both nitric oxide and protein kinase G (PKG) [7], [8], [9]. The ability of intracoronary adenosine infusion immediately before coronary stenting to limit infarct size has been tested in clinical trials with disappointing results [10], [11], [12]. A proof-of-concept study in patients with STEMI receiving primary percutaneous coronary intervention (PCI) within 4 hours of symptom onset suggested a protective effect [10] although a larger, more recent study showed discrepant results [11]. However, both studies differed not only in size, but also in critical aspects of their design, such as ischemia duration and TIMI flow at the time of PCI, which render their results difficult to compare. Patients in the Marzilli study received reperfusion during the first 3 hours of ischemia versus 12 hours in the Desmet trial [10]. Only TIMI flow grade 0–1 was included in the Marzilli study vs. 0–3 in the Desmet trial.

The present trial was designed to determine whether an intracoronary injection of adenosine immediately prior to coronary artery recanalization limits infarct size and prevents adverse remodeling in patients with STEMI receiving PCI within 6 hours of symptom onset and with TIMI flow grade 0–I. In a pre-specified subgroup analysis we additionally hypothesized, that the ability of adenosine to limit infarct size is greater in patients receiving PCI earlier after symptom onset than in those receiving it later.