But not ready for prime time as long-term survival still unknown

Treatment with a combination of vasopressin and methylprednisolone in patients experiencing in-hospital cardiac arrest significantly increased return of spontaneous circulation compared with placebo, according to a study published in JAMA. Effects of this combination treatment on long-term survival, however, are as yet unknown.

“In-hospital cardiac arrest occurs in approximately 2,000 patients each year in Denmark and 300,000 patients each year in the United States. Outcomes remain poor, with only approximately 25% surviving to hospital discharge in 2017 in the United States. Despite this low survival, there has been limited research focused on improving outcomes for this patient population,” wrote researchers led by Lars W. Andersen, MD, MPH, PhD, DMSc, of Aarhus University and Aarhus University Hospital, Denmark.

“Most recommendations for treatment of in-hospital cardiac arrest are extrapolated from the out-of-hospital setting. Drugs currently used during in-hospital cardiac arrest, when appropriate, includes epinephrine and amiodarone or lidocaine,” they added.

To further characterize the rationale behind the choice of combining vasopressin and methylprednisolone, Andersen told BreakingMED, “Two previous trials had shown promising results with the combination of vasopressin and steroids during in-hospital cardiac arrest. However, these trials were relatively small and external validation was therefore needed. Both drugs have properties that are theoretically beneficial during a cardiac arrest. Vasopressin is a potent vasoconstrictor and steroids have multiple effect including on the vasculature. It is also possible that they have a synergistic effect.”

Thus, Andersen and colleagues conducted this multicenter, randomized, double-blind, placebo-controlled study at 10 hospitals in Denmark, and included 501 patients (mean age: 71 years; 64% male) who experienced in-hospital cardiac arrest who were followed for 90 days.

They randomized patients to either vasopressin (20 IU) combined with methylprednisolone (40 mg) or placebo, the first doses of which were given after a first dose of epinephrine, with additional doses given after each additional dose of epinephrine (maximum: four doses).

The primary outcome of the study was return of spontaneous circulation, and secondary outcomes included survival and favorable neurologic outcomes at 30 days, defined as a Cerebral Performance Category score of 1 or 2.

With the combo treatment, significant improvements were seen in the return of spontaneous circulation, which occurred in 42% of the vasopressin/methylprednisolone group compared with 33% of the placebo group (risk ratio: 1.30; 95% CI: 1.03-1.63), for a risk difference of −2.0% (95% CI: −7.5% to 3.5%; P=0.48).

At 30 days, favorable neurologic outcomes were demonstrated by 7.6% in both groups (risk ratio: 1.00; 95% CI: 0.55-1.83; risk difference: 0.0%; 95% CI: −4.7% to 4.9%; P>0.99).

Also at 30 days, health-related quality of life was not significantly different between the two groups, and by 90 days, between-group differences in outcomes were not significantly different, including survival (8.4% in the vasopressin/methylprednisolone group compared with 9.1% in the placebo group; difference: −0.7%; 95% CI: —5.7 to 4.5).

Adverse events included hyperglycemia, which occurred in 77% of patients treated with vasopressin/methylprednisolone who experienced spontaneous circulation and in 73% of those treated with placebo; and hypernatremia, in 28% and 31%, respectively.

Andersen noted that while the beneficial effects of this combination treatment on patients was not surprising, results were “disappointing” in that there was “no effect on more long-term survival as seen in the earlier trials.” He added that at this time, these results are not enough to recommend this drug combination during routine cardiac arrest.

“This clinical trial represents the largest and most generalizable study to evaluate the combination of vasopressin and steroids when added to usual care advanced life support for in-hospital cardiac arrest, and was ostensibly performed to validate results of the prior trials by Mentzelopoulos et al,” wrote Jason Haukoos, MD, MSc, of the University of Colorado School of Medicine and the Colorado School of Public Health, Aurora; Ivor S. Douglas, MD, also fo the University of Colorado School of Medicine; and Comilla Sasson, MD, PhD, of the American Heart Association, Dallas, Texas, in their accompanying editorial.

They noted, however, that this study from Andersen et al did not stipulate the use of glucocorticoids after the return of spontaneous circulation, which, with immediate and sustained use, can improve outcomes.

Haukoos, Douglas, and Sasson also wrote: “Among the 124 patients who survived at least 24 hours, 46% (28/61) from the placebo group received some form of glucocorticoid administration versus 24% (15/63) from the vasopressin and methylprednisolone group (P=0.01), and 30% (18/61) from the placebo group underwent venoarterial extracorporeal membrane oxygenation versus 14% (9/63) from the vasopressin and methylprednisolone group (P=0.04). Whether extracorporeal life support was implemented as a cardiopulmonary resuscitation modality or in the context of post-arrest vasopressor-resistant shock was not fully characterized.”

These results, nevertheless, provide important new data on the use of vasopressin and steroids for in-hospital cardiac arrest, the editorialists noted.

“As with all resuscitation research, there are challenges with conducting studies involving patients with cardiac arrest in both out-of-hospital and in-hospital environments, highlighting the need for enhanced global efforts to standardize the design, implementation, and analysis of resuscitation studies to improve external validity and reproducibility. Additional research is needed to further define the effect of vasopressin and steroids, and other interventions, on outcomes for patients with in-hospital cardiac arrest (including continued use of steroids during the highly vulnerable post-resuscitation phase and standardized post-resuscitation modalities), evaluated in clinical trials specifically powered to test a difference in survival with good neurologic function. Until then, the use of vasopressin and steroids for patients with in-hospital cardiac arrest is not ready for usual care but may be considered when patients remain unresponsive to more conventional treatments,” they concluded.

Study limitations include the exclusion of a large number of patients who were potentially eligible, later delivery of drugs in some patients, that the trial was powered only to assess return of spontaneous circulation rather than survival and favorable neurologic outcomes, and the low overall survival that likely reflects the requirement of at least one dose of epinephrine.

  1. Significantly more patients with in-hospital cardiac arrest who were treated with vasopressin plus methylprednisolone achieved return of spontaneous circulation.

  2. The benefits of this combination adjunctive treatment on long-term survival are, as yet, unknown, and researchers urged further studies.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

Funding for the trial was provided by Aarhus University Research Foundation; the Department of Clinical Medicine, Aarhus University; the Central Denmark Region; and the Independent Research Fund Denmark. Empressin and corresponding placebo ampoules were provided free of charge by Amomed Pharma GmbH.

Andersen reported receiving grants from Aarhus University Research Foundation, the Department of Clinical Medicine at Aarhus University, and Independent Research Fund Denmark, and nonfinancial support from Amomed Pharma GmbH, which provided trial drug during the conduct of the study.

Haukoos is supported, in part, by grants from the National Institute on Drug Abuse, the Centers for Disease Control and Prevention (CDC), the National Heart, Lung, and Blood Institute (NHLBI), and the Department of Defense (DoD). Douglas is supported, in part, by grants R01NR016459 from the National Institute of Nursing Research and from the NHLBI. Sasson is an employee of the American Heart Association (AHA) and is supported, in part, by the Veterans’ Affairs Pain Management, Opioid Safety, and PDMP Program and by the Substance Abuse and Mental Health Services Administration (SAMHSA).

Cat ID: 358

Topic ID: 74,358,501,728,791,575,730,358,192,925