In adults with acute cardiogenic shock (often post‑myocardial infarction), what were the efficacy and safety outcomes of milrinone versus dobutamine in the DOREMI trial, and how should the inotrope be selected?

DOREMI Trial: Milrinone vs Dobutamine in Cardiogenic Shock

Primary Findings

The DOREMI trial found no significant difference between milrinone and dobutamine for the treatment of cardiogenic shock, with similar rates of the primary composite outcome (49% vs 54%, relative risk 0.90,95% CI 0.69-1.19, P=0.47) and in-hospital mortality (37% vs 43%, relative risk 0.85,95% CI 0.60-1.21). 1

Trial Design and Population

• The DOREMI trial was a double-blind randomized controlled trial that enrolled 192 patients with cardiogenic shock (96 in each arm) 1
• The primary composite outcome included in-hospital death, resuscitated cardiac arrest, cardiac transplant or mechanical circulatory support, nonfatal myocardial infarction, stroke/TIA, or initiation of renal replacement therapy 1
• Approximately one-third of patients (n=65) had acute myocardial infarction complicated by cardiogenic shock (AMICS), while two-thirds (n=127) had non-AMICS 2

Key Efficacy Outcomes

Overall Population

• No significant differences were observed in any secondary outcomes between milrinone and dobutamine: 1
  • Resuscitated cardiac arrest: 7% vs 9% (HR 0.78,95% CI 0.29-2.07) 1
  • Mechanical circulatory support: 12% vs 15% (HR 0.78,95% CI 0.36-1.71) 1
  • Renal replacement therapy: 22% vs 17% (HR 1.39,95% CI 0.73-2.67) 1

AMICS Subgroup

• Patients with AMICS had significantly worse outcomes compared to non-AMICS regardless of inotrope choice (HR 2.21,95% CI 1.47-3.30, P=0.0001) 2
• The increased risk in AMICS was driven by higher rates of mortality, mechanical circulatory support, and renal replacement therapy 2
• No interaction was observed between inotrope type and AMICS status, suggesting both agents perform similarly in this high-risk subgroup 2

Critical Safety Considerations

Acute Kidney Injury Interaction

A significant interaction exists between acute kidney injury (AKI) and inotrope selection that fundamentally alters treatment efficacy. 3

• In patients without AKI, milrinone demonstrated lower risk of the primary outcome and death compared to dobutamine 3
• In patients with AKI (present in 65% of cardiogenic shock patients), this potential benefit of milrinone was completely attenuated (P interaction = 0.02 for primary outcome, P interaction = 0.04 for death) 3
• Baseline renal dysfunction (eGFR <60 mL/min/1.73 m²) was present in 45% of patients but did not modulate treatment effect 3

Hypotension Risk

• Milrinone causes more profound systemic hypotension than dobutamine due to its vasodilatory properties as a phosphodiesterase-3 inhibitor 4, 5
• The loading dose should be omitted in patients with systolic blood pressure <100 mmHg 5
• Hypotension can typically be reversed with isotonic crystalloid/colloid boluses or by initiating norepinephrine or vasopressin 5

Arrhythmia Risk

• Milrinone increases atrial automaticity and shortens atrial action potential duration, triggering atrial fibrillation 5
• In mixed cardiogenic shock with sepsis, milrinone was associated with significantly more antiarrhythmic agent use (56.0% vs 44.5%, P<0.001) 6

Inotrope Selection Algorithm

Step 1: Assess for Contraindications and Risk Factors

Choose DOBUTAMINE if:

• Acute kidney injury is present or developing (most critical factor) 3
• Systolic blood pressure <90 mmHg without vasopressor support 5
• High risk for atrial arrhythmias 5
• Mixed shock with concurrent sepsis (associated with shorter inotrope duration and hospital stay) 6

Choose MILRINONE if:

• Patient is on beta-blocker therapy (milrinone maintains full efficacy as its mechanism is distal to beta-adrenergic receptors) 4, 5
• Pulmonary arterial hypertension is present (milrinone has neutral or beneficial effects on pulmonary vascular resistance) 5
• Right ventricular failure with adequate blood pressure (requires careful dosing) 5
• No acute kidney injury and stable renal function 3

Step 2: Dosing Considerations

Milrinone dosing: 5

• Omit loading dose if systolic BP <100 mmHg 5
• Standard loading: 25-75 μg/kg over 10-20 minutes (or divide into five aliquots over 10 minutes each for BP stability) 5
• Maintenance infusion: 0.375-0.75 μg/kg/min 5
• Reduce dose in renal dysfunction (e.g., 0.43 μg/kg/min for CrCl 50 mL/min, down to 0.2 μg/kg/min for CrCl 5 mL/min) 5

Dobutamine dosing: 4

• Initial: 2.5 μg/kg/min 4
• Titrate gradually at 5-10 minute intervals up to 10 μg/kg/min 4

Step 3: Concurrent Vasopressor Support

• Target mean arterial pressure ≥65 mmHg 4, 5
• Norepinephrine is the preferred first-line vasopressor in cardiogenic shock, particularly post-myocardial infarction 4
• Dopamine is associated with increased mortality and more arrhythmic events compared to norepinephrine in cardiogenic shock 4
• Consider starting vasopressor support before or concurrent with milrinone to prevent hypotension-related complications 5

Step 4: Monitoring Requirements

• Continuous ECG telemetry for arrhythmia detection 5
• Close hemodynamic monitoring with attention to blood pressure, cardiac output, and end-organ perfusion 5
• Discontinue immediately if arrhythmia or hypotension from excessive vasodilation occurs 5
• Monitor for at least 48 hours after discontinuation to assess adequacy of oral-based strategies 5

Important Clinical Caveats

Duration and Weaning

• Milrinone was associated with longer inotrope duration (5.1 vs 3.5 days, P<0.001) and longer hospital stay (10.0 vs 9.1 days, P<0.001) in mixed shock patients 6
• Gradual tapering is essential to prevent acute decompensation 5
• Milrinone has a prolonged half-life (1-10 hours depending on organ function) requiring extended observation 5

Long-term Use Warning

• Long-term milrinone use outside of palliative care or bridge therapy may be harmful, particularly in ischemic heart failure 5
• Oral milrinone invariably increases arrhythmias and mortality 5

Revascularization Priority

• In AMICS, early coronary revascularization is the cornerstone of management and the only therapy associated with reduced mortality 4
• Inotropes may be of limited value for initial stabilization in AMICS due to increased risk of worsening myocardial ischemia 4

Mixed Shock Considerations

• In patients with concurrent cardiogenic shock and sepsis, no mortality difference exists between agents, but secondary outcomes favor dobutamine (shorter duration, shorter stay, fewer arrhythmias) 6