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Milrinone Versus Dobutamine in Critically Ill Patients

Primary Purpose

Low Cardiac Output Syndrome, Cardiogenic Shock, Acute Coronary Syndrome

Status
Completed
Phase
Phase 4
Locations
Canada
Study Type
Interventional
Intervention
Milrinone
Dobutamine
Sponsored by
Ottawa Heart Institute Research Corporation
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Low Cardiac Output Syndrome focused on measuring Cardiogenic shock, Inotropes, Low cardiac output syndrome

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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)

Sites / Locations

  • University of Ottawa Heart Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Left ventricular [LV] +/- Biventricular dysfunction

Right ventricular [RV] dysfunction

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.
All-cause in-hospital death
All-cause in-hospital death
Non-fatal myocardial infarction [MI]
As defined by Thygesen et al., 2012 (Circulation)
Transient ischemic attack [TIA] or cerebrovascular accident [CVA]
Transient ischemic attack or cerebrovascular accident as diagnosed by a Neurologist either clinically and/or radiographically
Stay in CCU greater than or equal to 7 days
Stay in CCU greater than or equal to 7 days
Acute kidney injury requiring renal replacement therapy
Acute kidney injury requiring renal replacement therapy (intermittent hemodialysis or continuous renal replacement therapy)
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

Secondary Outcome Measures

Time on inotropes
Total time on inotropes (in hours)
Non-invasive or invasive mechanical ventilation
Total number of days requiring non-invasive or invasive mechanical ventilation
Change in cardiac index ([CI]
Change in cardiac index measured with PA catheter
Change in pulmonary capillary wedge pressure [PCWP]
Change in pulmonary capillary wedge pressure measured with PA catheter
Change in pulmonary vascular resistance [PVR]
Change in pulmonary vascular resistance measured with PA catheter
Change in systemic vascular resistance [SVR]
Change in systemic vascular resistance measured with PA catheter
Presence of acute kidney injury
Presence of acute kidney injury (defined by KDIGO as creatinine increased by 26.5 umol/L, 1.5 times baseline within prior 7 days, or urine volume <0.5 mL/kg/hour for greater than or equal to 6 hours
Serum lactate
Normalization of serum lactate
Arrhythmia requiring medical team intervention
Arrhythmia requiring medical team intervention, either through electrical or chemical cardioversion or any intravenous anti-arrhythmia medication administration

Full Information

First Posted
June 27, 2017
Last Updated
June 29, 2020
Sponsor
Ottawa Heart Institute Research Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT03207165
Brief Title
Milrinone Versus Dobutamine in Critically Ill Patients
Official Title
Comparison of Milrinone Versus Dobutamine in a Heterogeneous Population of Critically Ill Patients
Study Type
Interventional

2. Study Status

Record Verification Date
June 2020
Overall Recruitment Status
Completed
Study Start Date
August 30, 2017 (Actual)
Primary Completion Date
June 12, 2020 (Actual)
Study Completion Date
June 12, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ottawa Heart Institute Research Corporation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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.
Detailed Description
The use of various inotropes in the care of critically ill cardiac patients has become increasingly widespread: while predominantly used in decompensated heart failure, they have also been used in cardiogenic shock complicating acute coronary syndrome (ACS) and septic shock. Purported mechanisms of efficacy include improved cardiac output, improved end-organ perfusion, and vasodilation of both pulmonary and systemic circulations. Two of the most commonly used agents are Milrinone, a phosphodiesterase 3 inhibitor, and Dobutamine, a synthetic catecholamine with affinity for both beta-1 and 2 receptors. Both the American College of Cardiology (ACC) and the European Society of Cardiology (ESC) support inotropes for acute and chronic heart failure management with low cardiac output states. Furthermore, the ACC recommends consideration of inotropic therapy within the STEMI guidelines when ACS is complicated by cardiogenic shock, heart failure or for hemodynamic support in isolated right ventricle infarctions. Beyond primarily cardiac etiologies, inotropes have been identified as first-line additive therapy for cardiac augmentation to Norepinephrine in patients with septic shock complicated by myocardial dysfunction. Despite the lack of convincing data supporting a morbidity or mortality benefit with the use of inotropes in severe, decompensated heart failure, cardiogenic or septic shock, or in ACS, inotropic therapy is still widely used across various critical care settings. Furthermore, to date, there has been no head to head comparison of the two more commonly used positive inotropes: Dobutamine and Milrinone. Selection of one inotrope over another is often guided by physician and center preference, and consideration of and purported avoidance of possible adverse effects. In this pilot study, the investigators aim to describe that characteristics of patients receiving inotropic support in the CCU setting and identify possible differences in morbidity and mortality between Dobutamine and Milrinone among a heterogeneous population of patients admitted to the CCU at UOHI, which may help to inform a larger clinical trial in the future. The purpose of this pilot study is to: (a) describe the characteristics of patients receiving inotropic support in the coronary care unit (CCU) setting (hemodynamics prior to inotrope initiation, etiology of cardiogenic shock state, use of PA catheter and values if deemed necessary by medical team) and (b) identify possible differences in morbidity [atrial and ventricular arrhythmias, hepatic and renal function, markers of end-organ perfusion (lactate, urine output, mentation status), use of vasopressors, sustained hypotension of systolic blood pressure less than or equal to 90 mmHg for greater than 30 minutes, need for mechanical support, cardiac transplant, total length of CCU stay, length of CCU stay greater than 14 days] and mortality between patients in cardiogenic shock treated with Dobutamine versus Milrinone.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Low Cardiac Output Syndrome, Cardiogenic Shock, Acute Coronary Syndrome, Pulmonary Edema
Keywords
Cardiogenic shock, Inotropes, Low cardiac output syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
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.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
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.
Allocation
Randomized
Enrollment
192 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Left ventricular [LV] +/- Biventricular dysfunction
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Right ventricular [RV] dysfunction
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Milrinone
Other Intervention Name(s)
Mil, Phosphodiesterase-3 inhibitors [PDE3] Inhibitor
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Dobutamine
Other Intervention Name(s)
Dob, Beta 1/2 Agonist
Intervention Description
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.
Primary Outcome Measure Information:
Title
Composite Primary End Point
Description
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.
Time Frame
Through duration of hospitalization, up to 12 weeks following admission
Title
All-cause in-hospital death
Description
All-cause in-hospital death
Time Frame
Through duration of hospitalization, up to 12 weeks following admission
Title
Non-fatal myocardial infarction [MI]
Description
As defined by Thygesen et al., 2012 (Circulation)
Time Frame
Through duration of hospitalization, up to 12 weeks following admission
Title
Transient ischemic attack [TIA] or cerebrovascular accident [CVA]
Description
Transient ischemic attack or cerebrovascular accident as diagnosed by a Neurologist either clinically and/or radiographically
Time Frame
Through duration of hospitalization, up to 12 weeks following admission
Title
Stay in CCU greater than or equal to 7 days
Description
Stay in CCU greater than or equal to 7 days
Time Frame
Through duration of hospitalization, up to 12 weeks following admission
Title
Acute kidney injury requiring renal replacement therapy
Description
Acute kidney injury requiring renal replacement therapy (intermittent hemodialysis or continuous renal replacement therapy)
Time Frame
Through duration of hospitalization, up to 12 weeks following admission
Title
Need for advanced mechanical support [specifically, intra-aortic balloon pump, Impella, ventricular assist device or extra-corporeal membrane oxygenation] or cardiac transplant
Description
Need for new mechanical support or cardiac transplant
Time Frame
Through duration of hospitalization, up to 12 weeks following admission
Secondary Outcome Measure Information:
Title
Time on inotropes
Description
Total time on inotropes (in hours)
Time Frame
Through duration of hospitalization, up to 12 weeks following admission
Title
Non-invasive or invasive mechanical ventilation
Description
Total number of days requiring non-invasive or invasive mechanical ventilation
Time Frame
Through duration of hospitalization, up to 12 weeks following admission
Title
Change in cardiac index ([CI]
Description
Change in cardiac index measured with PA catheter
Time Frame
Through duration of hospitalization, up to 12 weeks following admission
Title
Change in pulmonary capillary wedge pressure [PCWP]
Description
Change in pulmonary capillary wedge pressure measured with PA catheter
Time Frame
Through duration of hospitalization, up to 12 weeks following admission
Title
Change in pulmonary vascular resistance [PVR]
Description
Change in pulmonary vascular resistance measured with PA catheter
Time Frame
Through duration of hospitalization, up to 12 weeks following admission
Title
Change in systemic vascular resistance [SVR]
Description
Change in systemic vascular resistance measured with PA catheter
Time Frame
Through duration of hospitalization, up to 12 weeks following admission
Title
Presence of acute kidney injury
Description
Presence of acute kidney injury (defined by KDIGO as creatinine increased by 26.5 umol/L, 1.5 times baseline within prior 7 days, or urine volume <0.5 mL/kg/hour for greater than or equal to 6 hours
Time Frame
Through duration of hospitalization, up to 12 weeks following admission
Title
Serum lactate
Description
Normalization of serum lactate
Time Frame
Through duration of hospitalization, up to 12 weeks following admission
Title
Arrhythmia requiring medical team intervention
Description
Arrhythmia requiring medical team intervention, either through electrical or chemical cardioversion or any intravenous anti-arrhythmia medication administration
Time Frame
Through duration of hospitalization, up to 12 weeks following admission
Other Pre-specified Outcome Measures:
Title
Sustained hypotension of systolic BP
Description
Sustained systolic blood pressure hypotension of less than or equal to 90 mmHg for greater than or equal to 30 minutes (or requiring medical intervention)
Time Frame
Through duration of hospitalization in CCU, up to 12 weeks following admission
Title
Atrial arrhythmias requiring medical intervention
Description
Atrial flutter, fibrillation or tachycardia requiring medical intervention
Time Frame
Through duration of hospitalization in CCU, up to 12 weeks following admission
Title
Need for intravenous or oral anti-arrhythmic therapy
Description
Initiation of intravenous or oral anti-arrhythmic therapy
Time Frame
Through duration of hospitalization in CCU, up to 12 weeks following admission
Title
Ventricular arrhythmias
Description
Ventricular arrhythmias (monomorphic or polymorphic ventricular tachycardia [VT] greater than 30 seconds or hemodynamically unstable ventricular arrhythmia requiring intervention, or VF)
Time Frame
Through duration of hospitalization in CCU, up to 12 weeks following admission
Title
Need for up-titration or addition of new vasopressor therapy
Description
Need for up-titration or addition of new vasopressor therapy
Time Frame
Through duration of hospitalization in CCU, up to 12 weeks following admission

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 Exclusion Criteria: 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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Benjamin M Hibbert, MD, PhD
Organizational Affiliation
Ottawa Heart Institute Research Corporation
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Ottawa Heart Institute
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1Y 4W7
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
15992636
Citation
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.
Results Reference
background
PubMed Identifier
12595851
Citation
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.
Results Reference
background
PubMed Identifier
8903534
Citation
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.
Results Reference
background
PubMed Identifier
28475215
Citation
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.
Results Reference
background
PubMed Identifier
11717603
Citation
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.
Results Reference
background
PubMed Identifier
35261289
Citation
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.
Results Reference
derived
PubMed Identifier
34713704
Citation
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.
Results Reference
derived
PubMed Identifier
34376218
Citation
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.
Results Reference
derived
PubMed Identifier
34347952
Citation
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.
Results Reference
derived

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Milrinone Versus Dobutamine in Critically Ill Patients

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