DOBERMANN: Dobutamine and Tocilizumab Show Promise in Pre-Shock Patients

WASHINGTON, DC—Two trials evaluating ways to intervene in the narrow therapeutic window after PCI but before signs surface of cardiogenic shock missed their primary endpoints but hinted at the possible effects of inotropic therapy and a monoclonal antibody in high-risk acute MI patients.

While low-dose dobutamine infusion over 24 hours was safe, it did not significantly lower N-terminal pro–B-type natriuretic peptide (NT-proBNP) plasma concentration within 48 hours—a surrogate for hemodynamic instability—or left ventricular infarct size compared with placebo, according to results of the DOBERMANN-D trial. The dobutamine-infused patients did have lower systolic blood pressure by hour 15 that persisted to 48 hours, which the investigators say suggests persistent LV afterload reduction.

In a sister trial, DOBERMANN-T, inhibition of interleukin-6 via a 1-hour infusion of tocilizumab (Actemra; Genentech) showed a nonsignificant trend toward lower NT-proBNP concentrations, with no difference in LV infarct size compared with placebo. However, systemic inflammation, as measured by peak C-reactive protein (CRP), was 78% lower in the tocilizumab group at all time points (P < 0.001), suggesting a possible cardioprotective effect of the intervention.

Sarah Louise Duus Holle, MD, and Joakim Bo Kunkel, MD (both from Copenhagen University Hospital–Rigshospitalet, Denmark), who led DOBERMANN-D and DOBERMANN-T, respectively, said they have built a biobank of patients that will allow them to dig deeper into some of these data.

“The reason for also looking into those secondary endpoints was in fact to try and see where is the signal,” Kunkel said. “Is it in the vasculature? Is it around the infarct itself? If you look at mechanistic studies, you find [interleukin-6] on a local as well as a systemic level.” He added that given the degree of safety seen in the study, the investigators feel that drug therapy therefore may be a way to safely reduce neurohormonal activation, systemic inflammation, and LV infarct size while trying to understand the signals.

The results of DOBERMANN-T and DOBERMANN-D were presented in a late-breaking clinical trials session at CRT 2026 and simultaneously published in JACC.

Speaking with TCTMD, George Dangas, MD, PhD (Icahn School of Medicine at Mount Sinai, New York, NY), a moderator of the session, said given that the identification of patients at risk for cardiogenic shock is challenging and there isn’t a lot of time to potentially stop the cascade of events, both studies raise good questions about how and when to intervene and which marker of progression provides the best information.

“It’s a fast window, so you need something that’s going to fluctuate measurably within that short-term window,” he said. Whether that “something” is NT-proBNP as the DOBERMANN investigators believe, or some other hemodynamic metric more indicative of a trajectory toward cardiogenic shock, is still unclear.

In an accompanying editorial, Shashank S. Sinha, MD, MSc (Inova Schar Heart and Vascular, Falls Church, VA), and colleagues say NT-proBNP reflects myocardial wall stress and neurohormonal activation but is not a validated surrogate for cardiogenic shock prevention and, therefore, more proxy surrogates may be needed.

“Hemodynamic indices such as cardiac power output more directly reflect shock physiology. Biomarkers with more rapid pharmacokinetic profiles may better capture early therapeutic effects,” they write. “A multidimensional, trajectory-based endpoint integrating hemodynamics, biomarkers, and clinical deterioration may ultimately prove more informative than reliance on any single biomarker alone.”

Overall, Dangas said the studies raise important questions about next steps in understanding what may or may not work at this point.

They also illustrate the reality of how difficult it is to do randomized clinical trials in acute cardiac patients, said Helle Søholm, MD, PhD (Copenhagen University Hospital–Rigshospitalet), a co-investigator of both DOBERMANN trials.

“But it’s really important to get us further on with these patients that have a high mortality rate,” she told TCTMD. “As we saw in DanGer Shock, it took 10 years to complete the trial and this took 3 years just to include 100 patients.”

Good Safety Overall

The DOBERMANN trials enrolled acute MI patients (median age 68 years; 23% women) with an ORBI risk score ≥ 10 after PCI, indicating an intermediate-to-high risk of in-hospital cardiogenic shock. More than half of patients were classified as SCAI shock category B, 40% A, and 3% C. Fifty-one patients were allocated to the DOBERMANN-D trial and randomized to a 24-hour intravenous infusion of dobutamine 5 µg/kg/min or placebo. The other 49 patients were allocated to the DOBERMANN-T trial and randomized to a 1-hour intravenous infusion of tocilizumab 280 mg or placebo.

In DOBERMANN-D, at 48 hours, there was a nonsignificant 2% reduction in NT-proBNP plasma concentration, the study’s primary endpoint, with the dobutamine strategy compared with placebo. There was also no difference in LV infarct size, one of the secondary endpoints. No differences were seen in the composite safety endpoint between the dobutamine group and the placebo group during the index admission and initial 7 days (12% vs 11%; P = 1.0) or at 3-month follow-up (16% vs 13%; P = 0.8). There also were no differences in rates of tachyarrhythmia requiring intervention or in mortality.

In DOBERMANN-T, at 48 hours, there was a nonsignificant 18% difference in peak NT-proBNP, the primary endpoint, that favored the tocilizumab group compared with placebo. The difference emerged at 12 hours and persisted through the 48-hour period. No between-group differences were seen in peak plasma troponin T levels, acute infarct size, or final infarct size. There also were no differences in the composite safety endpoint of death, infection requiring intravenous antibiotic therapy and hospital admission, drug-induced neutropenia, drug-induced liver injury, gastrointestinal perforation, or acute kidney injury requiring dialysis.

What’s Next?

During the discussion, Dangas said it might be interesting in future studies to see if more benefit is gained by giving the interventions before or during the PCI.

While the DOBERMANN investigators had to wait to randomize patients until after their PCI to obtain informed consent, Søholm noted to TCTMD that perhaps being able to obtain it after revascularization could improve sample sizes and flexibility in timing for this type of research.

“It’s an interesting concept and obviously this is a challenging issue and [being able] to prevent cardiogenic shock would be great, but I worry a little bit that the sample size is too small to get appropriate insights into what the next step should be,” said panelist Timothy D. Henry, MD (The Christ Hospital, Cincinnati, OH). He added that the population overall was on the lower end of the risk spectrum for cardiogenic shock according to the ORBI risk score, raising the question of whether it might be better to target a slightly sicker population for this type of therapy.

I worry a little bit that the sample size is too small to get appropriate insights into what the next step should be. Timothy D. Henry

Michael Cowley, MD (Virginia Commonwealth University Medical Center, Richmond), wondered whether failure to meet the primary endpoint in these modestly sized studies was the result of “a sample size problem or a dosing problem.”

Kunkel said the sample size is a limitation, but he doubted dosing was an issue since CRP was almost completely suppressed. However, he said some studies have evaluated weight-dependent dosing of tocilizumab, which could be a future consideration.

Panelist Patrick W. Serruys, MD, PhD (University of Galway, Ireland), suggested that having Stroke Volume Index values in these patients might be a good complement to predicting poor prognosis.

Duus Holle said while the DOBERMANN investigators don’t have that information, they do have cardiac MRI data that they plan to study. She added that the ongoing CAPITAL DOREMI2 trial may shed more light on these issues.