Tuesday, December 29, 2009

How much Epi should we give, if we give Epi at all?

Last month JAMA published another article that underscores the need for circumspection when, as by routine, habit, or tradition, we apply the results of laboratory experiments and pathophysiological reasoning to the treatment of intact persons. Olasveengen et al (http://jama.ama-assn.org/cgi/content/abstract/302/20/2222 ) report the results of a Norwegian trial in which people with Out of Hospital (OOH) cardiac arrest were randomized to receive or not receive intravenous medication during resuscitation attempts.

It's not as heretical as it sounds. In 2000, the NEJM reported the results of a Seattle study by Hallstrom et al (http://content.nejm.org/cgi/content/abstract/342/21/1546 ) showing that CPR appears to be as effective (and indeed perhaps more effective) when mouth-to-mouth ventilation is NOT performed along with chest compressions by bystanders. Other evidence with a similar message has since accumulated. With resuscitation, more effort, more intervention does not necessarily lead to better results. The normalization heuristic fails us again.

Several things can be learnt from the recent Norwegian trial. First, recall that RCTs are treasure troves of epidemiological data. The data from this trial reinforce what we practitioners already know, but which is not well-known among uninitiated laypersons: the survival of OOH cardiac arrest is dismal, on the order of 10% or so.

Next, looking at Table 2 of the outcomes data, we note that while survival to hospital discharge, the primary outcome, seems to be no different between the drug and no-drug groups, there are what appear to be important trends in favor of drug - there is more Return of Spontaneous Circulation (ROSC), there are more admissions to the ICU, there are more folks discharged with good neurological function. This is reminescent of a series of studies in the 1990s (e.g., http://content.nejm.org/cgi/content/abstract/339/22/1595 ) showing that high dose epinephrine, while improving ROSC, did not lead to improved survival. Ultimately, the usefulness of any of these interventions hinges on what your goals are. If your goal is survival with good neurological function, epinephrine in any dose may not be that useful. But if your goal is ROSC, you might prefer to give a bunch of it. I'll leave it to you to determine what your goals are, and whether, on balance, you think they're worthy goals.

There are two other good lessons from this article. In this study, the survival rate in the drug group was 10.5% and that in the no-drug group was 9.2%, for a difference of 1.3% and this small difference was not statistically significant. Does that mean there's no difference? No, it does not, not necessarily. There might be a difference that this study failed to detect because of a Type II error. (The study was designed with 91% power, so there's a 9% chance that a true difference will be missed, and the chances are even greater since the a priori sample size was not achieved.) If you follow this blog, you know that if the study is negative, we need to look at the 95% confidence interval (CI) around the difference to see if it might include clinically meaningful values. The 95% CI for this difference (not reported by the authors, but calculated by me using Stata) was -5.2% to +2.8%. That is, no drug might be up to about 5% worse or up to about 3% better than drug. Would you stop giving Epi for resuscitation on the basis of this study? Is the CI narrow enough for you? Is a 5% decrease in survival with no drug negligible? I'll leave that for you to decide.

(I should not gloss over the alternative possibility which is that the results are also compatible with no-drug being 2.8% better than drug. But if you're playing the odds, methinks you are best off betting the other way, given table 2.)

Now, as an extension of the last blog post, let's look at the relative numbers. The 95% CI for the relative risk (RR) is 0.59 - 1.33. That means that survival might be reduced by as much as 41% with no drug! That sounds like a LOT doesn't it? This is why I consistently argue that relative numbers be avoided in appraising the evidence. RRs give unfair advantages to therapies targeting diseases with survivals closer to 0%. There is no rational reason for such an advantage. A 1% chance of dying is a 1% chance of dying no matter where it falls along the continuum from zilch to unity.

Lessons from this article: beware of pathophysiological reasoning, and translation from the hampster and molecule labs; determine the goals of your therapy and whether they are worthy goals; absence of evidence is not evidence of absence; look at CIs for the difference between therapies in "negative" trials and see if they include clinically meaningful values; and finally, beware of inflation of perceived benefit caused by presentation of relative risks rather than absolute risks.

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