No Win for Milrinone Over Dobutamine in Cardiogenic Shock

Patrice Wendling

August 06, 2021

A head-to-head randomized comparison of milrinone and dobutamine — the most used inotropes in cardiogenic shock therapy in North America — failed to find a significant advantage for one agent over the other.

Patients treated with milrinone and dobutamine had similar rates of the primary composite outcome (49% vs 54%; relative risk [RR], 0.90; 95% confidence interval [CI], 0.69  – 1.19), its individual components, and safety outcomes.

"A lot of people believed milrinone was better, so it's a surprising outcome for the field. And I think a lot of people also feel relieved that there's no difference because they can continue to choose whichever drug they feel is best for their patients," senior author Benjamin Hibbert, MD, PhD, told | Medscape Cardiology.

Results of the DOREMI trial were published in the August 5 issue of the New England Journal of Medicine.

"This trial might play an essential role in changing our day-by-day practice but remains to be confirmed," Claudia Gidea, MD, medical director of the cardiogenic shock program at NYU Langone Health, New York City, told | Medscape Cardiology.

Anecdotal data favored milrinone over dobutamine with regard to its effect on atrial arrhythmias, postmyocardial infarction (MI) ischemia, and right ventricular failure, but randomized clinical trials are lacking, she noted in an email. The use of inotropic therapy in chronic heart failure is shown to decrease survival, but, again, there are no data to support this in cardiogenic shock.

The two agents also have unique mechanisms of action. Milrinone is a phosphodiesterase 3 inhibitor that increases cardiac inotropy, lusitropy, and peripheral vasodilation, whereas dobutamine is a synthetic catecholamine that acts as a β1- and β2-receptor agonist and improves blood pressure by increasing cardiac output.

The double-blind DOREMI trial randomly assigned 192 patients to receive milrinone or dobutamine based on a standardized scale that ranged from stage 1 to stage 5, corresponding to 2.5, 5.0, 7.5, 10.0, and >10.0 μg per kilogram of body weight per minute for dopamine and 0.125, 0.250, 0.375, 0.500 and >0.500 μg/kg of body weight/min for milrinone.

Patient enrollment was based on the Society for Cardiovascular Angiography and Interventions (SCAI) cardiogenic shock classification — one of the first studies to use the new classification that provides a common lexicon among cardiogenic shock providers, Gidea pointed out. Eight percent of the patients enrolled satisfied criteria for "classic" cardiogenic shock (stage C).

The mean time from admission to randomization was 23.4 hours in the milrinone group and 17.9 hours in the dobutamine group, and slightly more than a third of patients were women.

No differences were observed between milrinone and dobutamine in the individual components of the primary outcome:

  • In-hospital death: 37% vs 43% (RR, 0.85; 95% CI, 0.60 – 1.21)

  • Resuscitated cardiac arrest: 7% vs 9% (hazard ratio [HR], 0.78; 95% CI, 0.29 – 2.07)

  • Cardiac transplantation or mechanical circulatory support: 12% vs 15% (HR, 0.78; 95% CI, 0.36 – 1.71)

  • Neurologist-diagnosed transient ischemic attack or stroke: 1% vs 2% (HR, 0.50; 95% CI, 0.05 – 5.50)

  • Need for renal replacement therapy: 22% vs 17% (HR, 1.39; 95% CI, 0.73 – 2.67).

Interestingly, nonfatal MI and strokes were also similar between groups and occurred in a small proportion of patients, thus "choosing one agent over the other is not supported by the data," Gidea said.

A pulmonary-artery catheter (PAC) was used in only about 25% of patients, so hemodynamic data were not collected, but there were no differences in heart rate, blood pressure, and lactate levels between the two agents, she noted.

"The cardiology community needs more of these randomized, blinded clinical trials in order to have a better understanding of the inotropic therapy we can offer to patients in classic cardiogenic shock and avoid practice preferences or anecdotal beliefs that one inotrope is better than the other," Gidea said.

Current guidelines advise selective use of a PAC, which was reserved for patients who were sicker and not responding to therapy, Hibbert said. "Because we didn't have universal PACs, we can't confidently report on pulmonary pressures and things like cardiac index and cardiac output between the two cohorts but in terms of hemodynamic parameters that were routinely monitored in the perfusion markers, there was absolutely no difference between the cohorts," he said.

Hibbert agreed that further randomized trials are needed and said the team has a protocol under review for another double-blind trial in 192 patients with cardiogenic shock, but this time it will be a multicenter comparison of milrinone and dobutamine with placebo, at the clinicians' decision.

Hibbert described DOREMI as another "swing-and-a-miss" for a field that has little to offer its patients, having seen no significant improvement in outcomes with other therapies like the intra-aortic balloon pump in IABP-SHOCK II or multivessel percutaneous coronary intervention in CULPRIT SHOCK. Still, the neutral findings will likely inform practice, and cost — which is about 10 times higher for milrinone — may also play a role.

"I believed milrinone was going to be the better agent, that's what I was taught and certainly had a lot more comfort using milrinone," he said. "Now I'm going to preferentially use dobutamine and I know that my patients are going to have the same outcome and I can do that at a lower cost. So, it's going to change my practice in terms of what I do for my patients, but I understand if other operators feel different."

N Engl J Med. 2021;385:516-525. Abstract

Hibbert reports no relevant financial relationships. The study was funded b y the Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario.

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