Milrinone Versus Dobutamine in Critically Ill Patients

NCT03207165 | Completed Phase 4 DMC

• 1 other identifier: 20160975-01H
• Study Type: interventional
• Target: 192
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators are interested in determining if there is a meaningful difference between two of the most commonly used medications used to improve the pumping function of the heart among critically ill patients admitted to the Coronary Care Unit (CCU) at the University of Ottawa Heart Institute (UOHI). To do this, the investigators will randomly assign patients who are felt to require use of these medications by their treating physicians to one of the two most commonly used agents in Canada: Milrinone or Dobutamine. Each patient will be closely monitored by their healthcare team, and their medication will be adjusted based on each patient's clinical status. Information from blood work (e.g. kidney and liver function, complete blood counts, and other markers of how effectively blood is circulating in the body), assessment of end-organ function (e.g. urine output, mentation), abnormal heart rhythms noted on monitoring and results of imaging studies (e.g. angiogram, echocardiograms.) will be collected for analysis. All patients will be followed for the duration of their hospital stay at UOHI.

Conditions

Low Cardiac Output Syndrome; Cardiogenic Shock; Acute Coronary Syndrome; Pulmonary Edema

Keywords

Cardiogenic shock; Inotropes; Low cardiac output syndrome

Outcome Measures

Primary Outcomes (7)

• Composite Primary End Point

  Composite of all-cause in-hospital death, non-fatal MI, TIA or CVA diagnosed by a Neurologist, renal failure requiring renal replacement therapy, need for cardiac transplant or new mechanical support, any atrial or ventricular arrhythmia leading to cardiac arrest and resuscitation.

  Through duration of hospitalization, up to 12 weeks following admission

• All-cause in-hospital death

  All-cause in-hospital death

  Through duration of hospitalization, up to 12 weeks following admission

• Non-fatal myocardial infarction [MI]

  As defined by Thygesen et al., 2012 (Circulation)

  Through duration of hospitalization, up to 12 weeks following admission

• Transient ischemic attack [TIA] or cerebrovascular accident [CVA]

  Transient ischemic attack or cerebrovascular accident as diagnosed by a Neurologist either clinically and/or radiographically

  Through duration of hospitalization, up to 12 weeks following admission

• Stay in CCU greater than or equal to 7 days

  Stay in CCU greater than or equal to 7 days

  Through duration of hospitalization, up to 12 weeks following admission

• Acute kidney injury requiring renal replacement therapy

  Acute kidney injury requiring renal replacement therapy (intermittent hemodialysis or continuous renal replacement therapy)

  Through duration of hospitalization, up to 12 weeks following admission

• Need for advanced mechanical support [specifically, intra-aortic balloon pump, Impella, ventricular assist device or extra-corporeal membrane oxygenation] or cardiac transplant

  Need for new mechanical support or cardiac transplant

  Through duration of hospitalization, up to 12 weeks following admission

Secondary Outcomes (9)

• Time on inotropes

  Through duration of hospitalization, up to 12 weeks following admission

• Non-invasive or invasive mechanical ventilation

  Through duration of hospitalization, up to 12 weeks following admission

• Change in cardiac index ([CI]

  Through duration of hospitalization, up to 12 weeks following admission

• Change in pulmonary capillary wedge pressure [PCWP]

  Through duration of hospitalization, up to 12 weeks following admission

• Change in pulmonary vascular resistance [PVR]

  Through duration of hospitalization, up to 12 weeks following admission

Other Outcomes (5)

• Sustained hypotension of systolic BP

  Through duration of hospitalization in CCU, up to 12 weeks following admission

• Atrial arrhythmias requiring medical intervention

  Through duration of hospitalization in CCU, up to 12 weeks following admission

• Need for intravenous or oral anti-arrhythmic therapy

  Through duration of hospitalization in CCU, up to 12 weeks following admission

Study Arms (2)

Left ventricular [LV] +/- Biventricular dysfunction

ACTIVE COMPARATOR

Assessment of left ventricular \[LV\] or biventricular dysfunction will be based on clinical assessment, available imaging (echocardiogram, left ventriculogram, MUGA/RNA scan, cardiac MRI, etc.) and known past medical history (if available and contributory). Patients identified as having biventricular dysfunction will be randomized within the LV dysfunction arm of the trial. Patients in this arm will be randomized in a 1:1 fashion to Milrinone or Dobutamine.

Drug: Milrinone; Drug: Dobutamine

Right ventricular [RV] dysfunction

ACTIVE COMPARATOR

Assessment of right ventricular \[RV\] dysfunction will be based on clinical assessment, available imaging (echocardiogram, left ventriculogram, MUGA/RNA scan, cardiac MRI, etc.) and known past medical history (if available and contributory). Patients in this arm will be randomized in a 1:1 fashion to Milrinone or Dobutamine.

Drug: Milrinone; Drug: Dobutamine

Interventions

Milrinone DRUG

Patients will be initiated on Milrinone at 0.125 mcg/kg/min \[stage 1\] and will be titrated according to a blinded protocol from stages 2 to 5 \[0.250, 0.375, 0.5 and \>0.5 ug/kg/min\]. All orders to initiate and titrate the dose of the allocated inotrope will be written in the chart as follows: 'Study inotrope dose to be \[increased/decreased/maintained\] at stage \[1-5\]' so as to ensure that treating physicians remain blinded to the allocated drug.

Also known as: Mil, Phosphodiesterase-3 inhibitors [PDE3] Inhibitor

Left ventricular [LV] +/- Biventricular dysfunction; Right ventricular [RV] dysfunction

Dobutamine DRUG

Patients will be initiated on Dobutamine at 2.5 mcg/kg/min \[stage 1\] and will be titrated according to a blinded protocol from stages 2 to 5 \[5.0, 7.5, 10 and \>10 ug/kg/min\]. All orders to initiate and titrate the dose of the allocated inotrope will be written in the chart as follows: 'Study inotrope dose to be \[increased/decreased/maintained\] at stage \[1-5\]' so as to ensure that treating physicians remain blinded to the allocated drug.

Also known as: Dob, Beta 1/2 Agonist

Left ventricular [LV] +/- Biventricular dysfunction; Right ventricular [RV] dysfunction

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have one or more of the following:
• 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)
• Augmentation of cardiac output when patient already on maximal vasopressor therapy
• Or medical team's decision that patient needs inotropic therapy

You may not qualify if:

• Unwillingness or inability to provide informed consent by the patient or substitute decision maker for healthcare decisions
• Female participants who are currently pregnant
• Patients presenting with an out-of-hospital cardiac arrest (OOHCA)
• Healthcare team preference for use of specific inotrope (Milrinone or Dobutamine)

Sponsors & Collaborators

• Ottawa Heart Institute Research Corporation: lead

Study Sites (1)

University of Ottawa Heart Institute

Ottawa, Ontario, K1Y 4W7, Canada

Location

Related Publications (9)

• Abraham WT, Adams KF, Fonarow GC, Costanzo MR, Berkowitz RL, LeJemtel TH, Cheng ML, Wynne J; ADHERE Scientific Advisory Committee and Investigators; ADHERE Study Group. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol. 2005 Jul 5;46(1):57-64. doi: 10.1016/j.jacc.2005.03.051.

  PMID: 15992636 BACKGROUND

• Aranda JM Jr, Schofield RS, Pauly DF, Cleeton TS, Walker TC, Monroe VS Jr, Leach D, Lopez LM, Hill JA. Comparison of dobutamine versus milrinone therapy in hospitalized patients awaiting cardiac transplantation: a prospective, randomized trial. Am Heart J. 2003 Feb;145(2):324-9. doi: 10.1067/mhj.2003.50.

  PMID: 12595851 BACKGROUND

• Karlsberg RP, DeWood MA, DeMaria AN, Berk MR, Lasher KP. Comparative efficacy of short-term intravenous infusions of milrinone and dobutamine in acute congestive heart failure following acute myocardial infarction. Milrinone-Dobutamine Study Group. Clin Cardiol. 1996 Jan;19(1):21-30. doi: 10.1002/clc.4960190106.

  PMID: 8903534 BACKGROUND

• King JB, Shah RU, Sainski-Nguyen A, Biskupiak J, Munger MA, Bress AP. Effect of Inpatient Dobutamine versus Milrinone on Out-of-Hospital Mortality in Patients with Acute Decompensated Heart Failure. Pharmacotherapy. 2017 Jun;37(6):662-672. doi: 10.1002/phar.1939.

  PMID: 28475215 BACKGROUND

• Yamani MH, Haji SA, Starling RC, Kelly L, Albert N, Knack DL, Young JB. Comparison of dobutamine-based and milrinone-based therapy for advanced decompensated congestive heart failure: Hemodynamic efficacy, clinical outcome, and economic impact. Am Heart J. 2001 Dec;142(6):998-1002. doi: 10.1067/mhj.2001.119610.

  PMID: 11717603 BACKGROUND

• Marbach JA, Di Santo P, Kapur NK, Thayer KL, Simard T, Jung RG, Parlow S, Abdel-Razek O, Fernando SM, Labinaz M, Froeschl M, Mathew R, Hibbert B. Lactate Clearance as a Surrogate for Mortality in Cardiogenic Shock: Insights From the DOREMI Trial. J Am Heart Assoc. 2022 Mar 15;11(6):e023322. doi: 10.1161/JAHA.121.023322. Epub 2022 Mar 9.

  PMID: 35261289 DERIVED

• Jung RG, Di Santo P, Mathew R, Abdel-Razek O, Parlow S, Simard T, Marbach JA, Gillmore T, Mao B, Bernick J, Theriault-Lauzier P, Fu A, Lau L, Motazedian P, Russo JJ, Labinaz M, Hibbert B. Implications of Myocardial Infarction on Management and Outcome in Cardiogenic Shock. J Am Heart Assoc. 2021 Nov 2;10(21):e021570. doi: 10.1161/JAHA.121.021570. Epub 2021 Oct 29.

  PMID: 34713704 DERIVED

• Di Santo P, Mathew R, Jung RG, Simard T, Skanes S, Mao B, Ramirez FD, Marbach JA, Abdel-Razek O, Motazedian P, Parlow S, Boczar KE, D'Egidio G, Hawken S, Bernick J, Wells GA, Dick A, So DY, Glover C, Russo JJ, McGuinty C, Hibbert B; CAPITAL DOREMI investigators. Impact of baseline beta-blocker use on inotrope response and clinical outcomes in cardiogenic shock: a subgroup analysis of the DOREMI trial. Crit Care. 2021 Aug 10;25(1):289. doi: 10.1186/s13054-021-03706-2.

  PMID: 34376218 DERIVED

• Mathew R, Di Santo P, Jung RG, Marbach JA, Hutson J, Simard T, Ramirez FD, Harnett DT, Merdad A, Almufleh A, Weng W, Abdel-Razek O, Fernando SM, Kyeremanteng K, Bernick J, Wells GA, Chan V, Froeschl M, Labinaz M, Le May MR, Russo JJ, Hibbert B. Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock. N Engl J Med. 2021 Aug 5;385(6):516-525. doi: 10.1056/NEJMoa2026845.

  PMID: 34347952 DERIVED

MeSH Terms

Conditions

Cardiac Output, Low; Shock, Cardiogenic; Acute Coronary Syndrome; Pulmonary Edema

Interventions

Milrinone; N(1)-methyl-2-lysergic acid diethylamide; Dobutamine

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Myocardial Infarction; Myocardial Ischemia; Vascular Diseases; Infarction; Ischemia; Pathologic Processes; Necrosis; Shock; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Amrinone; Aminopyridines; Amines; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Catecholamines; Phenethylamines; Ethylamines; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Study Officials

• Benjamin M Hibbert, MD, PhD

  Ottawa Heart Institute Research Corporation

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The study participants, treating medical team and research team will be blinded to randomization; the pharmacy staff, CCU nurses and allied healthcare team members will not be blinded to the randomization.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Consecutive patients admitted to the Coronary Care Unit (CCU) at the Ottawa Heart Institute from start of study (tentatively set for August 2017 with anticipated end date of June 2020) and identified by the treating medical team as requiring initiation of inotrope therapy will be screened and randomized based on the healthcare team's clinical assessment of predominantly LV or RV systolic dysfunction (biventricular dysfunction will be assigned to predominantly LV dysfunction). All decisions to initiate inotrope therapy will be made by the primary care team with no involvement from the research team.

Study Record Dates

• First Submitted: June 27, 2017
• First Posted: July 2, 2017
• Study Start: August 30, 2017
• Primary Completion: June 12, 2020
• Study Completion: June 12, 2020
• Last Updated: June 30, 2020

Record last verified: 2020-06

Locations

CA (1)