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Wednesday, March 28, 2012

The IMMEDIATE trial: Should EMS give Glucose-Insulin-Potassium?

The results of the IMMEDIATE trial have been popping up repeatedly today on Facebook, partly because I "like" a few EMS FB pages, and also because one of the authors (Hi Carin!) is a FB friend (IRL too!).

Here's an example of the way the trial is being described:

"Cut the risk of death in half." Sounds great!

The result they are describing, to be specific, is that 8.7% of the people getting the placebo had a cardiac arrest, or died while they were hospitalized, while only 4.4% of the patients getting the study drug did. That's either an (absolute) difference of 4.3%, or about a (relative) 50% decline.

Such an effect would be stunning.  In the years after thrombolytics and aspirin were introduced, the incremental benefits of new therapies for AMI have been getting smaller and smaller. This result here would blow the others out of the water.

For instance, back in 1988, it was shown that either the use of aspirin or of thrombolytics reduced the risk of death in MI by about 2-3% over placebo. The combination was better of course.

After that, it's been harder to show that the more complicated and expensive therapies save that many more lives. When we send a patient to the cath lab for an AMI (instead of giving a thrombolytic in the ED), for example, there isn't that huge a benefit. One recent analysis suggested that, overall, you could only find a 0.7% difference in mortality (6.6% vs 5.9%) between lysed patients, and those that went for PCI. A lot of money for not much gain.

So, if this combination of glucose, insulin, and potassium (GIK) could cut mortality in AMI from 6.6% to, say, 3.3%, it would be freakin' amazing.

"I bet there's a catch. There's always a catch."
Well, I don't mean to be an Eeyore, but the perhaps we should wait for, yes, "further study." I offer three reasons why:

1. They weren't studying mortality.

The principle outcome they were studying was whether the initial presentation of ACS would progress to an MI, or it would be an "aborted" MI. This is the outcome that they believed had the most biochemical and clinical justification, and they clearly thought that it had a reasonable chance of being demonstrated.

It turns out there was no difference in the percent of people who progressed to completed MI - the GIK infusion did not help, at least not here. So the trial is negative for the real primary outcome.

2. There were 12 secondary outcomes.

Look at the table of the results:

Remember: the outcome they staked the success of the trial on was the one at the top: "Progression to MI," for all participants.  The rest are a bunch of secondary outcomes, and they don't count to the same degree as the primary outcome.

Analogy: A friend is flipping a coin, and you call heads. That's your primary outcome of interest. But if you also say to your friend "Okay, I call heads, but I also call it if you drop the coin, if it flips over 5 times in the air, if your phone rings in the next 30 seconds, or if your nose starts to itch in the next 10 seconds.

Now, you may be wrong about heads, but say your friend's nose does indeed start to itch in the next 10 seconds? Will he concede defeat? What will he say?

"No pick! NO PICK!" 
Most likely your friend will point out that the most relevant and important prediction you made was heads vs tails. Furthermore, you called out such a long list of other items that you were almost certain to come up with a positive result. He will insistent on another coin toss, where the primary outcome is now nose-itching, not heads or tails.

The same holds in statistics and study design, and is also why the authors state in their conclusion (my emphasis):
"The primary end point was not significantly different between groups, and the observed favorable results of GIK were based on prespecified but secondary end points, although biologically plausible and consistent with preclinical studies. The study tested one primary hypothesis, 3 major secondary, and 6 other secondary hypotheses. All were prespecified and no adjustment for multiple comparisons among the secondary end points was made; thus, reported significance levels should be considered approximate. Accordingly, given the lack of complete consistency of the findings, and the modest P values for most of the statistically significant findings, it would be appropriate to describe the observed favorable effects on the secondary outcomes as generating clinically testable hypotheses for evaluation in larger cohorts."

3. 30 day mortality seems pretty important too...

Ok, say you can take the "cardiac arrest or in-hospital mortality" results at face value. What, then, shall we make of the 30-day mortality? It was shown to be basically the same in both groups.

We just saw this discussion take place last month. A study from Japan showed that giving epinephrine in cardiac arrest got people to the hospital with ROSC more often, but the 30-day mortality was no different (We'll leave the neuro results alone for now.).

It would be nice if epi put all the dots on the right side of the graph. But it doesn't.
So, say the results are right - people don't die or arrest in the hospital as often, but they still die in the first 30 days just as often. Now, maybe everyone's hospital stay was over 30 days, but I doubt it.

Still feel excited?

Bottom line:

I believe that EMS has an essential role in managing ACS, of course. But, as it stands, giving this mixture to your ACS patients is not yet ready to be added to your drug box.


  1. I found the primary end-point of "progression to MI" to be an odd choice (it seems only 85% of their STEMI's progressed to an MI; and only half of their STEMI patients received pPCI).

    Although, they did not achieve any significance on any point of note besides surrogate end-points they acknowledge the study was not sufficiently powered to detect any difference. It was neat to see their GIK patients had smaller infarct sizes, but again not well powered.

    I would say the big take-away of the study should have been, "we should do a better study on this." Unfortunately, as you note, that was not what was reported.

    1. Well, at least the hype is about how medics are saving lives. Pretty nice to hear!

    2. Positive press is always good.

      I've been wondering about glycemic control in our STEMI patients and perhaps if EMS could play a role in ensuring this is identified or even treated early.

  2. Just a brief thought regarding the linked study on lysis vs. PCI -- this is yet another example IMO of "mortality tunnel vision." Dead or not dead are not the only options and decreased infarct size, better subsequent EF, and lower long-term risk of death presumably still give PCI an edge. I am, however, curious as to what "new thrombolytic strategies" they're referring to; any knowledge on this?

    1. Mortality is hard to beat as an endpoint, especially when you look at risk and cost versus benefit, and comparing therapies.

      Perhaps they were referring to the half-dose strategies, "drip & ship," not sure!

  3. Well, "interesting secondary data" is how drugs like Viagra came to be marketed for ED. They were originally being developed as more profitable--umm, "better" anti-anginals than good old nitro. It seems that the "salutary side effects" made a better marketing point.

    Sometimes advancement in therapy happens because of a footnote in other studies.

  4. Good analysis also over at EM Literature of Note!