CHICAGO – Glucose, insulin, and potassium given in the field to patients with suspected acute coronary syndrome cut in half the odds of pre- or in-hospital cardiac arrest or death in the prospective, double-blind, randomized IMMEDIATE trial.
The benefits of glucose, insulin, and potassium (GIK) were even more pronounced in patients with ST-elevation myocardial infarction (STEMI), reducing this outcome by a statistically significant 60%, compared with placebo (6% vs. 14%; risk ratio, 0.39).
The study’s primary end point of progression to myocardial infarction at 30 days was reported in 49% of GIK and 53% of placebo patients, a nonsignificant difference.
Although GIK did not prevent infarcts, it significantly reduced their size, coprincipal investigator Dr. Harry P. Selker said at the annual meeting of the American College of Cardiology.
"Risks and side effects rates from GIK are very low and GIK is inexpensive, potentially available in all communities, and deserves further evaluation in trials for widespread," he said.
Despite missing its primary end point, the panel of invited discussants was enthusiastic about the potential for IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care) to revive the 50-year-old therapy, long advocated by the late Tufts researcher Dr. Carl Apstein.
Panelist Dr. Bernard Gersh, from the Mayo Clinic in Rochester, Minn., asked whether the investigators were surprised at the magnitude of the treatment effect, given that GIK has failed in prior trials involving more than 20,000 patients.
"No, first of all, we know that most of the mortality is in that first hour since cardiac arrest and a lot of its effect is [against] cardiac arrest," replied Dr. Selker, professor of medicine and director of the Center for Cardiovascular Health Services Research at Tufts Medical Center in Boston. Experimental animal studies have also shown a 50% reduction in cardiac arrest. GIK decreases plasma and cellular free fatty acid levels, which are known to damage cell membranes and cause arrhythmias, supports the myocardium when there is less blood flow, and preserves myocardial potassium, an antiarrhythmic.
Notably, a subgroup analysis confirmed a significant benefit for GIK on cardiac arrest or hospital mortality only in those patients who received the therapy within 1 hour of symptom onset (odds ratio, 0.28), compared with those receiving GIK at least 1-6 hours (OR, 0.39) or more than 6 hours after symptom onset (OR, 1.18).
Dr. Elliott Antman, professor of medicine at Harvard University and senior faculty member in the cardiovascular division at Brigham and Women’s Hospital in Boston, asked why IMMEDIATE succeeded where so many other earlier GIK trials failed.
GIK was used for 12 hours, not 24-48 hours as previously done in other trials, said Dr. Selker, who also remarked that larger trials are needed to validate the findings since there are opposing data.
IMMEDIATE randomized 911 patients with suspected acute coronary syndrome to usual care or 30% glucose plus 50 IU insulin and 80 mEq potassium chloride/L at 1.5 mL/kg per hour administered en route by paramedics. All patients had a 12-lead ambulance ECG with Acute Ca Ischemia–Time-Insensitive Predictive Instrument (ACI-TIPI) and Thrombolytic Predictive Instrument (TPI) decision support.
Patients had at least one of the following: at least 75% predicted probability of ACS on ACI-TIPI, TPI detection of STEMI, or STEMI identified by local EMS protocol. Their mean age was 63 years and one-third had a history of myocardial infarction. Paramedics were from 36 EMS systems in 13 states across the country.
Pre- or in-hospital cardiac arrest or mortality was reported in 4% of GIK vs. 9% of placebo patients, a significant difference. The individual components of the composite outcome trended in the right direction, but did not achieve significance, Dr. Selker said.
At 30 days, 4% of the 432 GIK patients and 6% of the 479 placebo patients had died, a nonsignificant difference.
Mortality or hospitalization for heart failure was also similar between groups, occurring in 6% of GIK and 8% of placebo patients at 30 days.
Among STEMI patients, only the composite of cardiac arrest or pre- or in-hospital mortality significantly favored the GIK arm.
The percentage of patients with any glucose greater than 300 mg/dL was significantly higher in the GIK arm at 21% vs. 10% in the placebo arm. GIK also raised glucose levels in patients with diabetes (44% vs. 29%), but this did not lead to any serious adverse events, Dr. Selker said.
Dr. Antman asked whether the investigators evaluated the location of the STEMI because of the potential for an imbalance in anterior versus inferior locations that might have favored the GIK group. Dr. Selker said they had not performed that subanalysis.