Inotrope Therapy for Cardiogenic Shock

(DOREMI-2 Trial)

Recruiting at 2 trial locations

Overseen By Baylie Morgan, RN

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Ottawa Heart Institute Research Corporation

Must be taking: Inotropes

Must not be taking: Milrinone, Dobutamine

Disqualifiers: Pregnancy, Breast-feeding, OHCA, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 hours

346 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether two heart medications, Milrinone (Primacor) and Dobutamine (Dobutrex), can aid individuals with severe heart problems, known as cardiogenic shock. These medications aim to enhance the heart's ability to pump blood. Participants will receive either one of these medications or a placebo (a harmless substance with no active ingredients) to determine any real benefit. The trial seeks adults in intensive care with specific heart issues affecting daily life. As a Phase 4 trial, these medications have already received FDA approval and proven effective, and this research aims to understand how they benefit more patients.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What is the safety track record for Dobutamine and Milrinone?

Previous studies have used both dobutamine and milrinone to help the heart pump more effectively in patients with cardiogenic shock, a condition where the heart suddenly can't pump enough blood. Research has shown that patients can tolerate these medications, but they carry risks.

Dobutamine is known to improve heart function, but it hasn't always led to better patient outcomes. Some studies have reported a high rate of serious side effects, including in-hospital deaths, when using this drug. Despite this, it remains widely used and has been part of standard care for a long time.

Milrinone, on the other hand, has shown promise in studies where it appeared to lower the risk of death compared to dobutamine. However, some controlled studies have produced mixed results, showing no clear difference in safety between milrinone and dobutamine.

Overall, both drugs are standard treatments with established safety records in very sick patients, though they are not without risks. Healthcare teams closely monitor these treatments to manage any side effects. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about dobutamine and milrinone for treating cardiogenic shock because these inotropes work by enhancing the heart's ability to pump blood more effectively, which is crucial in this condition. Unlike some standard treatments that might take longer to stabilize the patient's condition, dobutamine and milrinone can quickly improve cardiac output and organ perfusion. They also offer flexibility in dosing, allowing doctors to tailor the treatment based on the patient's hemodynamics and clinical response, potentially leading to quicker and more precise adjustments for optimal care.

What evidence suggests that this trial's treatments could be effective for cardiogenic shock?

In this trial, participants will be randomized to receive either Dobutamine or Milrinone as part of the inotrope treatment arm. Research has shown that both Dobutamine and Milrinone are commonly used to treat cardiogenic shock, a condition where the heart suddenly can't pump enough blood. Studies have found no major difference in the effectiveness of these two drugs at improving patient outcomes in this condition. For example, both medications have similar effects on the length of ICU stays and key outcomes like survival rates. However, some observational data suggest that Milrinone might slightly reduce death rates, though this isn't certain. Both treatments are well-regarded in clinical practice for helping the heart pump better in these critical situations. ^{2 3 5 6 7}

Who Is on the Research Team?

Rebecca Mathew, MD

Principal Investigator

Ottawa Heart Institute Research Corporation

Are You a Good Fit for This Trial?

This trial is for adults over 18 in intensive care with a severe form of heart failure called cardiogenic shock. It's not for pregnant or breastfeeding individuals, those who can't consent, had an out-of-hospital cardiac arrest, took certain heart medications recently, or have specific severe heart valve problems.

Inclusion Criteria

I have severe heart failure.

I am 18 or older and currently in intensive care.

Exclusion Criteria

Patients who are currently pregnant or breast-feeding

Unwilling or unable to obtain informed consent by the participant or substitute decision maker

I have been given milrinone or dobutamine in the last 24 hours.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive inotrope or placebo therapy for cardiogenic shock, with doses adjusted based on clinical status

12 hours

Continuous monitoring in CICU

Open-label Treatment

Participants move to open-label treatment where continued use of inotropes is at the discretion of the treating physician

Duration of hospitalization

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 12 weeks following admission

What Are the Treatments Tested in This Trial?

Interventions

• Dobutamine
• Milrinone
• Normal Saline

Trial Overview

The study tests if drugs that boost the heart's pumping ability (inotropes) help critically ill patients. Participants will randomly receive either Milrinone, Dobutamine, or a placebo without knowing which one. After 12 hours they may continue treatment based on their doctor’s decision.

How Is the Trial Designed?

Group I: Inotrope Active Control 2 Interventions

Participants randomized to receive the inotrope will be initiated on inotrope therapy at starting doses and titrated according to standard clinical care. During reassessment, the treating physicians will make a decision about adjustment of the inotrope dose (increase, maintain or decrease) based on hemodynamics, end-organ perfusion, vasopressor support and clinical exam. Dobutamine doses will be 2.5, 5.0, 7.5, 10 and \>10 ug/kg/min and milrinone doses will be 0.125, 0.250, 0.375, 0.5 and \>0.5 ug/kg/min. These dose stages are identical to those used in Capital Do-Re-Mi and reflect current standard of care.

Group II: Placebo Placebo Group 1 Intervention

Participants in the placebo arm will have an intravenous solution of 0.9% NaCl running at a standardized rate, comparable to the infusion rate of the inotrope arm.

Dobutamine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Dobutrex for:

• Cardiogenic shock
• Heart failure

Approved in European Union as Dobutamine for:

• Cardiogenic shock
• Acute heart failure

Approved in Canada as Dobutamine for:

• Cardiogenic shock
• Heart failure

Who Is Running the Clinical Trial?

Ottawa Heart Institute Research Corporation

Lead Sponsor

Trials

200

Recruited

95,800+

Published Research Related to This Trial

In a meta-analysis of 11 studies involving 21,084 patients with low cardiac output states or cardiogenic shock, milrinone showed a potential benefit in reducing all-cause mortality compared to dobutamine, although this was only evident in observational studies.

Dobutamine was associated with a shorter length of hospital stay, suggesting it may be more effective for quicker recovery, but it also raised concerns about a potential increase in mortality, highlighting the need for larger randomized trials to clarify these outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Milrinone and Dobutamine in Cardiogenic Shock: An Updated Systematic Review and Meta-Analysis. Abdel-Razek, O., Di Santo, P., Jung, RG., et al.[2023]

In a study of 100 adult patients with cardiogenic shock, both milrinone and dobutamine were found to be similarly effective in resolving shock, with resolution rates of 76% and 70% respectively, and a median time to resolution of 24 hours for both groups.

While both inotropes had comparable overall safety profiles, dobutamine was associated with a higher incidence of arrhythmias (62.9% vs 32.8% for milrinone), suggesting that the choice between the two may depend on the patient's tolerance for specific side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Effectiveness and Safety Between Milrinone or Dobutamine as Initial Inotrope Therapy in Cardiogenic Shock. Lewis, TC., Aberle, C., Altshuler, D., et al.[2020]

In a study of 79 patients with stable congestive heart failure, both milrinone and dobutamine significantly improved heart function without major differences in their hemodynamic effects over 48 hours.

Both medications were associated with a low incidence of adverse effects, although there were some cases of ventricular tachycardia and one case of ventricular fibrillation in the milrinone group, indicating that while both drugs are effective, careful monitoring is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of intravenous milrinone and dobutamine for congestive heart failure secondary to either ischemic or dilated cardiomyopathy. Biddle, TL., Benotti, JR., Creager, MA., et al.[2019]

Inotropes and inopressors, such as dobutamine and norepinephrine, are critical first-line treatments for patients experiencing cardiogenic shock, helping to improve heart function and blood pressure.

The article reviews the pharmacology and clinical use of these medications, highlighting their indications and contraindications in managing acute decompensated heart failure and cardiogenic shock.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Review of Inotropes and Inopressors for Effective Utilization in Patients With Acute Decompensated Heart Failure. Nandkeolyar, S., Ryu, R., Mohammad, A., et al.[2023]

In a study of 573 patients with acute decompensated heart failure and cardiogenic shock, milrinone was associated with a significantly lower risk of 30-day mortality compared to dobutamine, with a hazard ratio of 0.52, indicating a 48% reduction in risk.

Patients receiving milrinone also showed improved hemodynamic parameters, such as better pulmonary artery compliance and stroke volume, suggesting that milrinone may be more effective in managing this condition than dobutamine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved mortality and haemodynamics with milrinone in cardiogenic shock due to acute decompensated heart failure. Rodenas-Alesina, E., Luis Scolari, F., Wang, VN., et al.[2023]

In a systematic review of 11 studies involving 23,056 patients, dobutamine was associated with a shorter length of stay in the ICU compared to milrinone, suggesting it may be more effective in managing low cardiac output states and cardiogenic shock.

While milrinone trended towards lower all-cause mortality, the difference was not statistically significant, indicating a potential risk that requires further investigation through randomized trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of milrinone and dobutamine in low cardiac output states: Systematic review and meta-analysis. Mathew, R., Visintini, SM., Ramirez, FD., et al.[2021]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10465094/

Efficacy of Milrinone and Dobutamine in Cardiogenic Shock

There was no difference in length of ICU stay with milrinone, compared with dobutamine in either observational data (mean difference –0.71 d; 95 ...

2.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa2026845

Milrinone as Compared with Dobutamine in the Treatment ...

In patients with cardiogenic shock, no significant difference between milrinone and dobutamine was found with respect to the primary composite ...

3.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/37649849/

Efficacy of Milrinone and Dobutamine in Cardiogenic Shock

The primary outcome, all-cause mortality, favored milrinone in observational studies only (odds ratio [OR] 1.19 (95% CI, 1.02-1.39; p = 0.02).

4.

ahajournals.org

ahajournals.org/doi/10.1161/JAHA.121.021570

Implications of Myocardial Infarction on Management and ...

In patients with cardiogenic shock treated with dobutamine or milrinone, those presenting with acute myocardial infarction had increased 30‐day ...

5.

jacc.org

jacc.org/doi/10.1016/j.jacadv.2023.100393

Milrinone vs Dobutamine for the Management of ...

This study sought to examine the treatment effect of milrinone compared to dobutamine in relation to renal function.

6.

ncbi.nlm.nih.gov

ncbi.nlm.nih.gov/books/NBK470431/

Dobutamine - StatPearls - NCBI Bookshelf - NIH

Despite its ability to improve hemodynamics, dobutamine has not shown positive outcomes for heart failure patients in either the hospital or ...

7.

ahajournals.org

ahajournals.org/doi/10.1161/JAHA.123.029787

State of Shock: Contemporary Vasopressor and Inotrope ...

Cardiogenic shock is characterized by tissue hypoxia caused by circulatory failure arising from inadequate cardiac output.