What did the ALPS trial results really show?
The trial pitted amiodarone against lidocaine with a saline control group for the termination of shock-resistant ventricular tachycardia and ventricular fibrillation
By Jeff Poland
When the results of the amiodarone, lidocaine, or placebo trial, the ALPS trial, were recently published, I was stoked to read the study. With any luck, by the end of this article, you’ll want to read it, too.
If you haven’t taken the time to read the study, I highly suggest that you do. Chances are, though, that you’ve probably read the press release. The study’s lead author, Peter Kudenchuk, MD, describes the research as overwhelmingly positive, and if all you have read was the press release, you would think that there is no question that every patient should get amiodarone for their ventricular fibrillation or ventricular tachycardia.
But is that really what the data showed?
Before we go any further, I first want to acknowledge the extreme difficulty of undertaking any clinical research, much less prehospital research across 55 EMS services. It was truly a monumental task, and nothing here is meant to diminish any of the hard work that went into the ALPS trial, nor is it meant to suggest that any results were intentionally biased by any of the research staff. With all of that out of the way, however, let’s talk details.
The ALPS trial was a double-blind, randomized controlled trial which pitted amiodarone against lidocaine, with a saline control group — commonly called an arm of the trial — for the termination of shock-resistant ventricular tachycardia and ventricular fibrillation. While this has been studied before, this trial was very different in a very important way — the primary outcome. Historically, cardiac arrest research has focused on one, or both, of two outcomes: return of spontaneous circulation or survival to hospital admission.
The ALPS trial, however sought to get away from what the late Dr. John Hinds referred to as BSE — bullsh*t surrogate endpoints — and toward outcomes that are patient-important. In this case, instead of looking at if patients given these medications survived the ambulance ride to go rack up a supremely expensive, three-week ICU stay before finally dying, researchers asked if patients would survive to hospital discharge. And if the patients did survive to hospital discharge, what is their quality of life defined by a Modified Rankin score of 3 or less.
The Resuscitation Outcomes Consortium is a group of EMS agencies and physicians that research prehospital care — usually related to cardiac arrest and trauma resuscitation. In the ROC ALPS trial, 55 agencies in 10 cities followed a protocol which had the medics reaching for a medication kit on every cardiac arrest call. The kit was unlabelled except for a coded tag number which was recorded — the trial blinding, and then the paramedics administered the medications in the kit, regardless of what the syringes actually contained — amiodarone, lidocaine or a saline solution.
The rest of the patient care proceeded as normal, and once the patient entered the hospital, they could be given either drug if the attending clinician felt it was necessary. The patients were treated according to the best clinical judgment of the EMS provider, all of which is in-line with currently accepted practice in clinical trials.
The ALPS trial enrolled 4,667 patients, with 4,653 patients placed into the intention to treat population which means that the drug kit was open and the patients were considered to be a part of the trial.
A further 1,627 patients were removed from the intention to treat group for a variety of reasons, the most common being they had a non-shockable initial rhythm (but converted later to a shockable rhythm, as evidenced by the study drug being administered), meaning that a total of 3,026 patients were enrolled in per protocol population, on which most of the analysis was performed.
Drug formulation used was different than commonly used amiodarone
Although the methodology used adheres to professional standards, the following items should be considered prior to applying the results to clinical practice. The first concerns a change to the amiodarone used in the trial drug kits. The ALPS trial used Nexterone instead of Cordarone (or the generic formulation), which is a very important distinction because although the active ingredient is the same, the amiodarone which is used on most ambulances and in most hospitals is formulated with a chemical that can cause hypotension — clearly not desirable in an arrest scenario, while Nexterone is thought to be more hemodynamically stable.
In addition to the change of formulation, the dosing scheme heavily favors amiodarone. Patients only received a total of 180 milligrams of lidocaine, an initial 120 mg dose, followed by 60 mg 5 minutes later, without repeated boluses or drips, which is non-standard dosing. While the dosing scheme appears to have been done out of convenience, the half-life of lidocaine calls for either repeated bolus dosing or a drip after an initial bolus. While this would have complicated the administration slightly, it is not unfeasible.
Overall, the study found that while there was a difference in survival to hospital discharge between the groups, the differences were not large enough to say that they weren’t caused by chance. It is important to note that the statistics used in this study were not designed to check for harms associated with the study drugs — only for benefits.
Moderately harmful or relatively beneficial, but which?
The p-value is a decimal representing the probability that the outcome of a treatment is due to chance. Typically, a p-value less than 0.05 is considered statistically significant, which means the outcome has a less than 5 percent probability of being due to random chance.
While the p-value is used to test if the results are genuine, researchers also investigated the potential benefit using a test called the confidence interval. This uses a scale where 1 is neither benefit nor harm, the lower the number is, the more harmful, the higher the number is, the more benefit. The investigators are 95 percent sure that the effect of the medication lies somewhere in the ranges given (for example, -0.4 to 7 is saying that they are 95 percent sure that it’s moderately harmful, relatively beneficial, or somewhere in the middle).
The results of the confidence interval testing are found in table 3 of the published study, under the heading "Difference (95% CI)."
It should also be noted that the items above are much more likely to make the results of the trial look better than they actually are.
That information in and of itself is extremely important. If you look at the confidence intervals, they are very wide, with a few of the groups getting close to statistical significance.
This is actually fantastically exciting. The wide confidence intervals tell me that there is a subgroup of patients who will benefit from these drugs, we just don’t know which ones, and we need to study them further (though it is very likely that is is patients with an underlying cause that is amenable to antidysrhythmic therapy).
The results also provide some significant evidence that how we treat cardiac arrest patients now isn’t really doing much good, except for early CPR and defibrillation (to slow progression to the metabolic phase of arrest), and an emphasis on treating the underlying cause of the arrest (remember that only a few underlying causes can be definitely treated with antidysrhythmics).
Also worth noting is that in one of the subgroups — witnessed cardiac arrest, both by laypeople and by EMS — did have an improved outcome, which was statistically significant, with high confidence intervals. However, no mention of neurologic function was made, and the subgroup the results were drawn from was very small compared to the total population (which can increase the chances of a spurious result, despite the low p-value). One key piece of cardiac arrest care this highlights is the importance of early and adequate CPR.
Finally, when the data from all of the patients was included (the intention to treat population), the effects of an antiarrhythmic disappeared almost completely. Survival to discharge decreased to 19 percent overall and 18.4 percent and 17.6 percent for amiodarone, lidocaine, and placebo, respectively, which decreased even further when good neurological outcomes were concerned. Reading through the supplementary index, especially tables S1 and S6, is quite enlightening.
Overall, the ALPS trial, like most research, brings up just as many questions as it answers (but that doesn’t mean that it doesn’t have value). It is also really important to keep in mind that a single study shouldn’t alter your clinical practice. Look up prior studies on this and compare them to the results seen here. The different findings may surprise you.
This is an exciting time to be a part of resuscitation science, and if you, as an EMS clinician, are only getting your updates from press releases, you’re missing out on quite a bit of information that’s relevant to your practice.
About the author:
Jeff Poland, NRP, FP-C is a critical care paramedic in Washington state with a passion for critical care and pharmacology. A self-professed critical care nerd, Jeff avidly follows all of the podcasts that end in "-crit," and strives to ride the bell curve between innovation and early adoption to deliver the absolute best care to his patients. He welcomes any and all correspondence at firstname.lastname@example.org.