ALPS: No Overall Survival Increase From Amiodarone, Lidocaine After Out-of-Hospital Arrest

Deborah Brauser

April 07, 2016

CHICAGO, IL — The use of either of two antiarrhythmic medications doesn't significantly improve survival to discharge or neurologic outcomes over placebo in patients who have an out-of-hospital cardiac arrest, according to new research[1].

The Amiodarone, Lidocaine, or Placebo Study (ALPS) assessed more than 3000 patients who had an out-of-hospital arrest caused by pulseless ventricular tachycardia or shock-refractory ventricular fibrillation (VF). It showed that those who received a modified formulation of amiodarone that reduces hypotensive effects (Nexterone, Baxter Healthcare) had a statistically nonsignificant 3.2% higher rate of survival than those who received saline placebo (primary outcome, P=0.08); and those receiving lidocaine had a 2.6% higher rate vs placebo (P=0.16). The difference between the amiodarone vs lidocaine groups was only 0.7%.

In addition, rates of favorable neurologic function at discharge were similar between the treatment groups: 19% of those receiving amiodarone, 18% of those receiving lidocaine, and 17% of those receiving placebo.

However, in prespecified subgroup analysis of the participants who had a bystander-witnessed cardiac arrest, survival to discharge was significantly higher in those receiving amiodarone vs placebo (P=0.04) and those receiving lidocaine vs placebo (P=0.03).

There were no between-treatment differences for those with unwitnessed arrests, resulting in "no harm, no foul for them," said Dr Peter J Kudenchuk (University of Washington, Seattle) to attendees here at the American College of Cardiology (ACC) 2016 Scientific Sessions. The results were simultaneously published April 4, 2016 in the New England Journal of Medicine.

Dr Peter Kudenchuk

Kudenchuk told heartwire from Medscape that because unwitnessed arrests often have poor outcomes, "when you combine the groups together, you come up with a value that's diluted. Those who were, frankly, too late to respond made the numbers look worse."

Still, "if you give these drugs to somebody who has shock-refractory VF, you'll do no harm to someone who can't be saved. But to the majority, the witnessed group, you'll improve their survival substantially. And I think that's a big win."

Dr Alfred Bove (Temple University School of Medicine, Philadelphia, PA) told heartwire that although it was a negative trial overall, it was good to see that both drugs appeared to work in at least the witnessed arrests. "And it will help with our decision making."

"The message is: if it's a witnessed event, and the witness will do something, you're going to get a better outcome. Not a lot better outcome, but certainly a bit of an advance," said Bove, who was not involved with this research.

1800 Lives Saved Each Year?

Between May 2012 and October 2015, the investigators enrolled 3026 adult patients (80% men; mean age 63 years) from 10 North American sites who were part of the Resuscitation Outcomes Consortium (ROC). All participants were randomized to receive amiodarone (n=974), lidocaine (n=993), or placebo (n=1059) before arriving at the hospital.

The mean time from initial call to first treatment dose in cardiac arrest not witnessed by emergency medical services (EMS) was 19 minutes for all of the treatment groups. The time to first dose for those whose cardiac arrest was witnessed by EMS was 12 minutes.

Cardiac pacing was the only treatment-related adverse event that was different between the groups, occurring in 4.9% of the amiodarone group vs 2.7% of the placebo group (P=0.02).

At discharge, survival rates were 24.4%, 23.7%, and 21.0% for the amiodarone, lidocaine, and placebo groups, respectively.

In addition, "there was heterogeneity of treatment effect with respect to whether or not the out-of-hospital cardiac arrest was witnessed (P=0.05 for interaction)," write the investigators.

Survival rates for the 1934 study participants with bystander-witnessed cardiac arrest were 27.7% for those receiving amiodarone, 27.8% for those receiving lidocaine, and 22.7% of those receiving placebo. The survival rates were also significantly higher in the amiodarone group who had an EMS-witnessed arrest vs the placebo group (P=0.01). But there were no significant differences between treatments for those who had unwitnessed arrests.

"Overall, there was no statistically significant benefit. But you don't expect an overall benefit when you have such a wide group of patients," said Kudenchuk. "No treatment can save every patient with cardiac arrest, but we can save some of the bystander-witnessed patients."

He noted that a survival rate of 3% to 5% means that up to 1800 lives can be saved each year.

Don’t Dismiss Findings

In an accompanying editorial[2], Dr Jose A Joglar (University of Texas Southwestern Medical Center, Dallas) and Dr Richard L Page (University of Wisconsin School of Medicine and Public Health, Madison) note that both active-treatment groups had, vs placebo, fewer shocks needed after the first dose of the drug was given, less need for rhythm-control meds, and fewer incidents of in-hospital CPR.

The editorialists write that the negative results could be because the trial was underpowered or possibly that "drug delivery was provided too late to overcome the metabolic consequences of prolonged arrest."

"Because the overall study showed no benefit, it would be easy to dismiss it. But looking at the subgroups, it enables us who are practicing in the field to say, 'is there something we can do to help our patients?' And I think in the witnessed ones, we have a chance to do this. This is further evidence that this helps," added Dr C Michael Valentine (Stroobants Cardiovascular Center, Lynchburg, VA), who was the official discussant after Kudenchuk's press conference talk.

The study was funded by the National Heart, Lung, and Blood Institute (NHLBI); US Army Medical Research and Materiel Command; the Canadian Institutes of Health Research Institute of Circulatory and Respiratory Health; Defense Research and Development Canada; the Heart and Stroke Foundation of Canada; and the American Heart Association. Baxter Healthcare provided the trial drugs without cost. Kudenchuk reports receiving grant support from the National Institutes of Health/NHLBI "during the conduct of the study." Disclosures for the coauthors are listed in the article. The editorialists report no relevant financial relationships.

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