Critical Care, Critical Care Alert

Critical Care Alert: Milrinone vs. Dobutamine in the Treatment of Cardiogenic Shock

Critical Care Alert

ARTICLE
Mathew R, Di Santo P, Jung RG, et al. Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock. N Engl J Med. 2021 Aug 5;385(6):516-525.

OBJECTIVE
Determine if there is a meaningful difference between milrinone and dobutamine in the treatment of critically ill patients with cardiogenic shock.

BACKGROUND
Cardiogenic shock is a state of low cardiac output resulting in end-organ hypoperfusion. Although mechanical circulatory support for cardiogenic shock has gathered serious attention, vasopressors and inotropes remain the mainstay of treatment for most patients with this condition. To date, however, there has been no head-to-head comparison of the two more commonly used positive inotropes: dobutamine and milrinone. Dobutamine is a synthetic catecholamine that acts as a β1- and β2-receptor agonist, improving blood pressure and increasing cardiac output. Milrinone is a phosphodiesterase 3 inhibitor that increases cardiac inotropy, lusitropy, and peripheral vasodilation.

Selection of one inotrope over the other is often guided by physician and center preference, often based on the clinical scenario and theoretical benefits weighed against its adverse effects. For instance, milrinone is often preferred in patients with severe pulmonary hypertension because of a purported mechanism of reducing pulmonary-artery pressures and improving right ventricular function. On the other hand, dobutamine’s β-adrenergic activity can have adverse effects on heart rate and myocardial oxygen demand which reduces its risk for patients at risk of tachyarrhythmias or myocardial ischemia.

DESIGN
Randomized, double-blind clinical trial (Dobutamine Compared with Milrinone trial, DOREMI) of consecutive patients admitted to the Coronary Care Unit (CCU) at the Ottawa Heart Institute from 8/2017 to 6/2020. In total, 319 patients were screened with 192 being enrolled (96 in each treatment group). For dosing, dobutamine and milrinone were given 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.

INCLUSION CRITERIA (≥ 18 years old with one or more of the following indications for inotropic therapy)

  • Low cardiac output state, evidenced by sustained hypotension (systolic blood pressure <90 mmHg) and end-organ dysfunction (altered level of consciousness, elevated lactate, renal or hepatic dysfunction)
  • Clinical evidence of systemic and/or pulmonary congestion despite use of vasodilators and/or diuretics
  • ACS complicated by cardiogenic shock (defined as persistent hypotension with systolic blood pressure <90 mmHg with severe reduction in cardiac index [<1.8 L/min/m² without support or <2.2 L/min/m² with support], left ventricular end-diastolic pressure >18 mmHg)
  • A clinically determined need to augment cardiac output in addition to ongoing vasopressor therapy
  • A treating team’s clinical assessment that inotropic therapy is required for developing cardiogenic shock without current evidence of hypoperfusion

EXCLUSION CRITERIA

  • Transfer to the ICU after milrinone or dobutamine had already been initiated prior to randomization
  • Unwillingness or inability to provide informed consent
  • Female participants who are currently pregnant
  • Patients presenting with an out-of-hospital cardiac arrest (OOHCA)
  • Treating physician was of the opinion the patient was not eligible for the study
  • Enrollment in another interventional trial

PRIMARY OUTCOME
Composite of in-hospital death from any cause, resuscitated cardiac arrest, receipt of a cardiac transplant or mechanical circulatory support, nonfatal myocardial ischemia, transient ischemic attack or stroke diagnosed by a neurologist, or initiation of renal replacement therapy

SECONDARY OUTCOMES
The individual components of the primary composite outcome listed above in addition to the following efficacy and safety endpoints:

  • Efficacy endpoints: total time of inotropes, length of stay in CCU ≥ 7 days, need for and total number of days requiring non-invasive or invasive mechanical ventilation, change in cardiac index and/or pulmonary artery pressure, presence of acute kidney injury (AKI), normalization of serum lactate, arrhythmia requiring medical team intervention
  • Safety endpoints: sustained hypotension, atrial arrhythmias, need for IV or oral antiarrhythmic therapy, ventricular arrhythmias, need for up-titration or addition of a new vasopressor

KEY RESULTS
PRIMARY OUTCOME: The composite endpoint occurred in 47 participants (49%) in the milrinone group and in 52 participants (54%) in the dobutamine group (relative risk, 0.90; 95% confidence interval [CI], 0.69 to 1.19; P=0.47), no statistically significant difference between treatment groups.

SECONDARY OUTCOMES: no significant differences between the groups in any category, including: in-hospital death from any cause (37% and 43% of the participants, respectively; relative risk, 0.85; 95% CI, 0.60 to 1.21), resuscitated cardiac arrest (7% and 9%; hazard ratio, 0.78; 95% CI, 0.29 to 2.07), receipt of mechanical circulatory support (12% and 15%; hazard ratio, 0.78; 95% CI, 0.36 to 1.71), or initiation of renal replacement therapy (22% and 17%; hazard ratio, 1.39; 95% CI, 0.73 to 2.67). Median length of stay in the ICU and total hospital length of stay did not differ significantly between treatment groups.

STRENGTHS

  • Addresses knowledge gap with regards to dobutamine vs. milrinone specifically looking at patients with cardiogenic shock. Previous RCT comparing the two drugs only looked at hospitalized patients awaiting cardiac transplantation (including those without cardiogenic shock) and two prior observational studies showed no difference in in-hospital mortality
  • Inclusion criteria were based primarily on clinical assessment in order to maximize generalizability
  • Patients were enrolled based on the Society for Cardiovascular Angiography and Interventions (SCAI) cardiogenic shock classification. Proposed in 2019, this is one of the first studies to use the new classification system that stratifies patients into 5 stages (A-E) based on clinical, biochemical, and hemodynamic variables
  • Study outcomes included both efficacy and safety endpoints, in addition to surrogate markers of resuscitation, providing a more robust comparison of milrinone and dobutamine in this patient population.

LIMITATIONS

  • Performed at a single center, limiting external generalizability
  • Only in-hospital outcomes were evaluated. It’s possible that there could be differences noted beyond the index hospitalization, as was seen in the SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) trial
  • Dose adjustments were based on individual physician assessment rather than guided by a standardized protocol based on hemodynamic or biochemical measures, allowing for potential differences in dose adjustments to arise between treatment groups
  • Power calculation was based on the expectation of a large treatment effect. Based on a prior meta-analysis, the pooled incidence of the composite primary outcome was estimated to be 55% in the dobutamine group. Based on reported reduced incidences of death and arrhythmia with milrinone in observational studies of patients with acute decompensated heart failure, it was hypothesized that milrinone would have a primary outcome event 20 percentage points lower than the dobutamine group. As a result, the trial was underpowered to detect smaller effects, reflected in the wide confidence interval for the primary outcome.
  • Most of the patients included had more advanced cardiogenic shock (SCAI Class C or D). It may be interesting to focus more on patients in Class B (“beginning” cardiogenic shock) to examine if use of inotropic agents earlier in the disease course can alter the progression of cardiogenic shock, rather than after significant hypoperfusion and end-organ dysfunction have already occurred.

EM TAKE-AWAYS
For patients with cardiogenic shock, there was no significant advantage of milrinone over dobutamine in a number of important in-hospital outcomes such as death of any cause, resuscitated cardiac arrest, or receipt of a cardiac transplant or mechanical circulatory support. For the time being, selection of one inotrope over the other should be based on physician or center preference.


References
Clinical trials page for the same study: https://clinicaltrials.gov/ct2/show/NCT03207165 

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