Myocardial protection during acute myocardial infarction: the need for a simple large randomized trial with GIK.

Abstract

Acute myocardial infarction (AMI) is the leading cause of death in western countries and, although an impressive improvement in its care has been obtained, the morbidity is still high. Mortality rates although falling, continue to be a major challenge towards the incorporation of strategies to favorably impact its current natural course. During the last 20 years an outstanding achievement in terms of morbidity and mortality reduction was established by means of the incorporation of evidencebased therapies with proven beneficial effects. Thrombolytics, primary PTCA, aspirin, beta-blockers, and ACE inhibitors are first-line treatments for AMI with ST elevation [1]. Little has been done to protect myocardial tissue. The main purpose of this editorial is to review and establish the basis for the necessity of a large-scale trial of metabolic myocardial protection with glucose-insulin-potassium (GIK) in AMI. Limitation of infarct size was one of the first attempts made in the treatment of AMI. Almost 40 years have elapsed since the publication on the favorable effects of GIK in ST resolution and on incidence of ventricular arrhythmias during the acute phase of AMI [2] GIK infusion gained empirical consensus approval, supported by experimental evidence, as the rationale underlying its benefits. The conflicting results of small clinical trials published during the 1960s and 1970s produced a negative impact and GIK was later abandoned. Evidence-based therapy has achieved great acceptance but GIK treatment has never been tested correctly by the modern methodological standards of clinical research that appeared during the 1980s. Renewed interest in GIK has emerged during the last few years, the consequence of the publication of one meta-analysis and three small clinical trials. The meta-analysis used adequate methodology to collect the most appropriate trials done in the prethrombolytic era. The authors included nine controlled trials involving 1932 patients and showed a 21%(16.1% vs. 21.0%; RR,0.79;95% Cl,0.57–0.90, P = 0.004) significant reduction in mortality [3]. The Digami Trial used an Insulin-glucose infusion followed by intensive subcutaneous insulin in diabetic patients with AMI and reported a 1-year statistically significant mortality reduction of 29% (P= 0.027) [4]. Importantly, the effect seen at 1 year continues for at least 3.5 years (RR, 0.72; 95% Cl, 0.55–0.92; P= 0.01). The ECLA GIK Pilot trial included 407 patients with AMI within 24 hours from symptom onset [5] and was the first step in designing a large trial to test the clinical impact of a 24-hour GIK infusion for AMI with ST elevation. It was successfully concluded and reported the following results: The infusion was well tolerated; phlebitis, the most common side effect, did not produce excess morbidity; fluid overload (due to the large amount of volume infused for the high-dose GIK regime) did not produce an increased incidence of heart failure; and a trend towards a benefit in major clinical outcomes was observed. The GIK group (high-or low–dose) showed a nonstatistically significant reduction in overall mortality (6.7% vs. 11.5%; RR, 0.58; 95% Cl, 0.30–1.10). In 252 patients submitted to a reperfusion strategy, an analyses prespecified in the protocol, there was a significant reduction in mortality of 66% (RR, 0.34; 95% Cl, 0.15–0.77; 2P = 0.008). Even though the magnitude of the effect was impressive, more importantly, the direction of the effect, was consistently towards a benefit in all outcomes influenced by GIK infusion (i.e., mortality, heart failure and severe arrhythmias). By contrast, in the Polish GIK trial of 954 patients included within 24 hours from symptoms onset [6], a significantly higher total mortality rate was observed with low-dose GIK (8.9% vs. 4.8%; RR, 1.95; 95% Cl, 1.12–3.47; P= 0.01). Cardiac mortality did not differ in both groups (RR, 1.45, 95% Cl, 0.79–2.68; P= 0.20). The trial was stopped prematurely and deserves some comments. The Polish trial excluded by protocol severely ill patients (Killip class >2) and used a low-dose GIK infusion (about half the low-dose 24-hour GIK regime infused in the ECLA pilot study). Blinded adjudication of causes of death found a high rate of deaths that could not have been due to GIK, including mesenteric embolism, Gl bleeding, stroke, neoplastic disease, aortic aneurysm, and pneumonia. The difference in total