Assessment of myocardial injury using 3T MRI and potential attenuation in ST-segment elevation myocardial infarction

Background:

Microvascular obstruction (MVO) is an important predictor of short- and longer-term outcome following primary percutaneous coronary intervention (PPCI) treatment of ST-elevation myocardial infarction (STEMI). The evidence base supporting the role of adenosine and sodium nitroprusside (SNP), as the most evaluated adjunctive therapies aimed at attenuating MVO and infarct size (IS), remains weak as the trials have had variable endpoints, differing drug doses and delivery. As such, the results regarding benefit are conflicting.

Objectives:

To determine whether intracoronary administration of adenosine or SNP following thrombus aspiration reduce IS and MVO measured by cardiac magnetic resonance (CMR) in patients undergoing PPCI within 6h of onset of STEMI.

Design and Setting:

Multi-centre, prospective, randomized, controlled and open-label trial with blinded end-point analysis undertaken at four high-volume PPCI centres in the UK.

Participants:

Patients presenting with STEMI undergoing planned PPCI with Thrombolysis in Myocardial Infarction (TIMI) 0/1 flow in the infarct-related artery (IRA) and no significant bystander coronary artery disease on angiography.

Interventions:

Participants were allocated to three groups: (1) PPCI with adjunctive intracoronary (IC) adenosine, (2) PPCI with adjunctive IC SNP, (3) control (standard PPCI), following Bivalirudin anticoagulation and thrombus aspiration in all patients.

Main outcome measures:

The primary outcome was IS (determined as a percentage of total left ventricular mass, LVM) measured by CMR undertaken at 48-72 hours post-PPCI. Secondary outcome measures included MVO (hypoenhancement within the infarct core) on CMR, electrocardiographic and angiographic markers of microvascular perfusion and MACE during median 6-month follow-up. The study aimed to recruit 240 patients (powered at 80% to detect a 5% absolute reduction in IS).

Results:

In total, 247 patients (79% male with mean age 59.3±12.3 years) were randomized and CMR was undertaken in 207 patients with 197 (80%) completing for the primary outcome. There was no significant difference in IS between groups. However, adjusting for infarct location, there was a borderline significant increase in mean IS in the adenosine group (HR 2.86, 95% CI: +0.01 to +5.72, p=0.05) compared to control.

Furthermore, on per-protocol analysis, IS was increased in adenosine treated patients compared to control (12.0 vs 8.3, p=0.031). Increased LV volumes and reduced EF were also observed in the adenosine arm. There was a significant increase in MACE in patients undergoing adenosine-facilitated PPCI compared to control driven by heart failure HR 5.39 [1.18-24.60], LogRank P=0.04) at 30 days and 6 months (HR 6.53 [1.46-29.2], LogRank P=0.01) post-randomisation.

Conclusions:

The randomised REFLO-STEMI trial tested the potential impact of locally delivered Adenosine and SNP, using a sensitive marker (CMR), on MVO and infarct size. There was no demonstrated efficacy with either drug. However, an increase in MACE rate was observed with adenosine. Adenosine is not routinely used prophylactically and so this is unlikely to lead to any change in current guidelines. The results probably have no bearing on Adenosine used to relieve observed angiographic no-reflow although they must be noted. However, the use of high-dose intra-coronary adenosine may be associated with cardiac toxicity and should not be used routinely in the setting of PPCI to prevent reperfusion injury.