Abstract & Commentary
Commentary by Theodore Chan, MD, FACEP, Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.
Source: Mehta SR, et al. Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction. The CREATE-ECLA randomized controlled trial. JAMA 2005;293:437-446.
Glucose-insulin-potassium (GIK) infusion long has been touted as a simple, inexpensive, and effective treatment for patients presenting with acute myocardial infarction (AMI).1 However, the evidence in support of GIK infusion largely has been based on small, nonrandomized clinical reports. In this study, investigators conducted a large, international, randomized controlled clinical trial (as a part of the CREATE trial) to determine the effect of GIK infusion on mortality in patients presenting with acute ST-segment elevation MI (STEMI).
More than 20,000 patients presenting to 470 centers worldwide within 12 hours of symptom onset with STEMI were randomized to receive either GIK infusion in addition to usual care or usual care alone. Contraindications included diabetes mellitus type 1, renal impairment, or known hyperkalemia. Patients were randomized from the original CREATE study in India and China (see original article abstract), as well as from a separate GIK infusion trial ongoing in Latin America (ECLA). Patients assigned to the GIK infusion group received a 24-hour infusion at a rate of 1.5 mL/kg/hour for 24 hours that included a 25% glucose solution with 50 u/L of regular insulin and 80 mEq/L of potassium.
Overall, 10,091 patients were included in the GIK infusion group and 10,110 in the control group, indicating that this study had 95% power to detect a 15% relative risk reduction with the GIK infusion group. There was no difference between the two groups in the administration of aspirin (97.4 vs 97.1%), fibrinolytic therapy (73% vs 74.2%), or direct percutaneous coronary intervention (9.2% vs 9.0%) for GIK infusion vs control, respectively. At 30 days, there was no difference in the primary outcome measure of death (10.0% vs 9.7%, respectively, P = 0.45). Similarly, there were no significant differences in the composite endpoints of death and nonfatal cardiac arrest, death and cardiogenic shock, or death and reinfarction. There was also no difference in the rates of ventricular tachycardia and fibrillation (21.0% vs 21.4%), second- or third-degree atrioventricular block (19.9% vs 19.8%), or pulseless electrical activity (0.4% vs 0.5%), respectively.
Furthermore, there was no difference in onset of new congestive heart failure episodes at 30 days (17.4 vs 17.4%). However, there was an increase in both hypoglycemic (0.4% vs 0.1%) and hyperkalemic (>5.5 mEq/L) (4.3% vs 1.6%) episodes in the GIK infusion group compared with the control group. In addition, on subgroup analysis, the investigators could not detect any benefit of GIK infusion over usual care alone for those who were treated early (< 4 hours), nor was there any difference with GIK infusion in patients who received fibrinolysis or direct percutaneous coronary intervention (PCI) reperfusion therapies.
Based upon their results, the CREATE-ECLA group concluded that high-dose GIK infusion for patients with acute STEMI has a neutral effect on mortality, cardiac arrest, and cardiogenic shock.
Commentary
The idea of GIK infusion for AMI patients has been reported in the medical literature since the 1960s. The theory of metabolic modulation to reduce AMI mortality rests on several different mechanisms. Exogenous insulin may suppress the circulation and myocardial uptake of toxic free fatty acids; high-dose glucose may provide an important energy substrate for ischemic myocardium; and potassium infusion would raise the dysrhythmia threshold in ischemic mycytes. However, investigations into the benefits of GIK infusion are limited to small clinical studies and reports that likely were skewed toward a positive outcome as a result of publication bias.
With this large, randomized, international clinical trial, the idea of GIK infusion for AMI largely has been laid to rest.
References
1. Fath-Ordoubadi F, et al. Glucose-insulin-potassium therapy for treatment of acute myocardial infarction: An overview of randomized placebo-controlled trials. Circulation 1997;96:1152-1156.
In this study, investigators conducted a large, international, randomized controlled clinical trial (as a part of the CREATE trial) to determine the effect of glucose-insulin-potassium infusion on mortality in patients presenting with acute ST-segment elevation MI.
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