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Effectiveness of Drug Combination Measured for Acute Coronary Syndrome Patients

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Review of: Selker H, Beshansky J, Sheehan P, et al. Out-of-hospital administration of intravenous glucose-insulin-potassium in patients with suspected acute coronary syndromes. The IMMEDIATE randomized controlled trial. JAMA. 2012;307(18):1925–1933.

The Science
This is a large double-blind, randomized controlled trial conducted in the prehospital environment, from Tufts University in Boston. The study looked to evaluate the effectiveness of a drug combination of glucose, insulin and potassium (also known as GIK) vs. placebo in patients with acute coronary syndromes, specifically examining the progression of an acute coronary syndrome into an acute myocardial infarction (MI). Several secondary points were incorporated into the trial, but they showed no real statistical differences. One secondary measurement did reach statistical difference: “cardiac arrest or in-hospital mortality was 6.1% with GIK vs. 14.4% with placebo (OR, 0.39; 95% CI, 0.18-0.82; P=.01).” The investigators concluded GIK didn’t reduce the progression of acute coronary syndromes, but it was associated with lower in-hospital mortalities.

Dr. Wesley: I must first state that my service, HealthEast Medical Transportation, in St. Paul, Minn., participated in this study. This was our first national, multi-center research project, and it was eye opening. I had never fully appreciated the complexity of conducting this type of study, and my hat is off to the study authors and research associates.

With that said, the question is what did we learn from this 36 million dollar study?

GIK, an inexpensive solution of glucose, insulin and potassium is easy to administer to patients with possible acute coronary syndromes, and it appears to have some clinical effect on certain patients. Although it doesn’t prevent MIs, it does reduce the size of heart attacks. Additionally, and possibly more importantly, it reduces the incidence of post-MI cardiac arrest during the first 30 days after administration.

However, the IMMEDIATE trial provides additional information that is best illustrated by the following figure that was published with the study.

Context Laboratory studies suggest that in the setting of cardiac ischemia, immediate intravenous glucose-insulin-potassium (GIK) reduces ischemia-related arrhythmias and myocardial injury. Clinical trials haven’t consistently shown these benefits, possibly due to delayed administration.

More than 54,000 patients were screened for eligibility in the study and had a 12-lead ECG performed. One thousand four hundred and eighty-three were considered for the study, and EMS obtained consent in more than 90%. This is an incredible accomplishment and was crucial to having sufficient numbers of patients to make the study reach statistical significance.

However, once patients reached the hospital, the emergency department (ED) physician and others caring for the study patients failed to continue the study for various reasons. Of the 911 patients randomized into the study, 25% were excluded by the ED physician who believed the patient wasn’t suffering from an acute coronary syndrome. Of the remaining 663 patients, 448 weren’t even asked to participate in collection of the biomarkers of MI, which was the cornerstone of determining presence and size of MI.

So at the end of the day, only 141 patients were studied for biological markers.

Could the results been affected by this poor continuation of the study population by the hospitals? We may never know. It’s unfortunate that after spending all this money, we don’t fully understand the potential value of GIK administration to patients with acute coronary syndromes.

Medic Marshall: Because Dr. Wesley and I work for the same organization, I’m going to defer my disclosure to what he said, but with a slightly different twist. Having been the site coordinator for the study, it gave me a very unique perspective into a study of this magnitude and caliber.

I had the unique opportunity to help manage this study for our site. It was fascinating and jaw dropping to understand and see the monstrous undertaking this actually was. The amount of personnel, coordination, materials, training, and resources required to successfully conduct this study wasn’t short of impressive. Hats off to everyone who participated in the IMMEDIATE Trial.

The Doc touched on this a little bit, but I would also like to discuss a little bit of how impressive it is that EMS was able to enroll so many patients into the study. First, I think it shows that we (and by ‘we’ I mean EMS) is highly capable of performing randomized control trials.

Secondly, in general, these were not exactly ‘stable’ patients—these were sick patients. With that, on top of the fact that medics had to still provide standard cardiac care (IVs, aspirin, nitro, etc.) they actually had to go through an abbreviated consent process, establish a second line if possible, and place the medication on a pump and manage the infusion. This is a huge undertaking when you have transport times of 10 to 15 minutes. So I really believe the success of the IMMEDIATE Trial lies with all the medics that made it possible.

So, like the Doc said, what did we really learn from a 36 million dollar study? Well, we learned that GIK doesn’t really seem to make a difference in the short term. However, this is only one paper of several more we can anticipate. Patients enrolled in the study will be followed up to 12 months, and it also includes a six-month follow up. Will numbers change significantly? I doubt it. But we also learned GIK doesn’t hurt you either and may actually be somewhat beneficial. Don’t anticipate seeing this on the truck any time soon, though.

Abstract
Objective: To test out-of hospital emergency medical service (EMS) administration of GIK in the first hours of suspected acute coronary syndromes (ACS).

Design, Setting, and Participants Randomized, placebo-controlled, doubleblind effectiveness trial in 13 U.S. cities (36 EMS agencies), from December 2006 through July 31, 2011, in which paramedics, aided by electrocardiograph (ECG)-based decision support, randomized 911 (871 enrolled) patients (mean age, 63.6 years; 71.0% men) with high probability of ACS.

Intervention Intravenous GIK solution (n=411) or identical-appearing 5% glucose placebo (n=460) administered by paramedics in the out-of-hospital setting and continued for 12 hours.

Main Outcome Measures: The prespecified primary end point was progression of ACS to myocardial infarction (MI) within 24 hours, as assessed by biomarkers and ECG evidence. Prespecified secondary end points included survival at 30 days and a composite of prehospital or in-hospital cardiac arrest or in-hospital mortality, analyzed by intent-to-treat and by presentation with ST-segment elevation.

Results: There was no significant difference in the rate of progression to MI among patients who received GIK (n=200; 48.7%) vs those who received placebo (n=242; 52.6%) (odds ratio [OR], 0.88; 95% CI, 0.66-1.13; P=.28). Thirty-day mortality was 4.4% with GIK vs 6.1% with placebo (hazard ratio [HR], 0.72;95%CI, 0.40-1.29; P=.27). The composite of cardiac arrest or in-hospital mortality occurred in 4.4% with GIK vs 8.7% with placebo (OR, 0.48; 95% CI, 0.27-0.85; P=.01). Among patients with ST-segment elevation (163 with GIK and 194 with placebo), progression to MI was 85.3% with GIK vs 88.7% with placebo (OR, 0.74; 95% CI, 0.40-1.38; P=.34); 30-day mortality was 4.9% with GIK vs 7.7% with placebo (HR, 0.63; 95% CI, 0.27-1.49; P=.29). The composite outcome of cardiac arrest or in-hospital mortality was 6.1% with GIK vs 14.4% with placebo (OR, 0.39; 95% CI, 0.18-0.82; P=.01). Serious adverse events occurred in 6.8% (n=28) with GIK vs 8.9% (n=41) with placebo (P=.26).

Conclusions: Among patients with suspected ACS, out-of-hospital administration of intravenous GIK, compared with glucose placebo, did not reduce progression to MI. Compared with placebo, GIK administration was not associated with improvement in 30-day survival but was associated with lower rates of the composite outcome of cardiac arrest or in-hospital mortality.

 

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