Midodrine in Heart Failure With Reduced Ejection Fraction With Hypotension
Trial statusRecruiting
Trial phasePhase 2, Phase 3
Trial typeInterventional
Biological sexAll
Age18+
SponsorOttawa Heart Institute Research Corporation
About this trial
The evidence-based pharmacologic treatments available for patients with heart failure with reduced ejection fraction (HFrEF) has been established over the last few decades of cardiovascular research. These treatments, termed Foundational Guideline-Directed-Medical Therapies (GDMT), prolong patient life, improve patient-reported symptoms, and reduce hospitalizations for heart failure. A direct effect of most medication classes encompassed within GDMT is the reduction in blood pressure due to their mechanisms of action. In addition, as patients with HFrEF become more advanced in their disease, a significant proportion develop hypotension related to pump failure and autonomic dysfunction, amongst other possible mechanisms. As a result, a significant proportion of HFrEF patients are not optimized on GDMT with hypotension as their limiting barrier that would otherwise have served to improve their heart function, heart failure symptoms, and mortality. Currently, there does not exist any evidence-based strategies to address the problem of hypotension in HFrEF patients who are not optimized on GDMT.
Midodrine is an alpha-adrenergic agonist (α1-AR) that exerts its effects on peripheral venous and arteriolar vasculature to increase blood pressure. This medication has been used off-label by some clinicians in the hypotensive HFrEF population to increase blood pressure and has been reported to have beneficial effects in improving GDMT utilization as well as increasing left ventricular ejection fraction (LVEF) in published case reports/case series. There does not exist any randomized prospective data on the use of midodrine in the hypotensive HFrEF population. The investigators' objective is to complete the first open-label, randomized control trial of midodrine in the hypotensive HFrEF population to demonstrate feasibility in performing a trial in this patient population and to show efficacy in increasing blood pressure without associated harm. The results of this trial will be used as the foundation and rationale for future studies assessing the impact of midodrine use on GDMT utilization as well as hard cardiovascular outcomes in the hypotensive HFrEF population, including hospitalizations for heart failure and mortality.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Adults >= 18 years of age.
LVEF <= 40 % within the last 3 months as determined by any one of: Transthoracic echocardiogram, transesophageal echocardiogram, cardiac magnetic resonance imaging, MUGA scan, angiogram with left ventriculogram.
AHA/ACC Stage B or C Heart Failure
Hospitalized patients in the ward setting OR in the cardiac intensive care unit (who are >= 48 hours after their last dose of vasopressor or inotrope).
Disqualifiers
Patient OR substitute decision-maker (SDM) unwilling or unable to provide informed consent
Documented allergy or intolerance to midodrine
Treatment for active infection (either documented infection or empiric treatment) with antimicrobials at the time of recruitment.
Current use OR any use within the last 48 hours of an intravenous inotrope or vasopressor medication OR the need for IV inotrope or vasoproessor use to treat hypotension
Trial design
Design model
Parallel
Treatments tested in this trial
Midodrine Oral Tablet
DrugExposure to up to 5 days of midodrine (or until hospital discharge) in hospital at escalating doses with the following protocol: 2.5 mg po TID x 1 day, 5.0 mg po TID x 1 day, 7.5 mg po TID x 1 day, 10 mg po TID x 2 days.
Treatment groups
56 Participants
are divided into 2 treatment groupsGroup A: Midodrine treatmentExperimental treatment 1 intervention
Group B: ControlNo intervention 0 interventions
Trial outcomes
Primary outcomes
1
Enrollment rate
Number of participants enrolled per week
Time frame
From the date of enrolment of the first study participant, to the date of enrolment of up to 56 patients, assessed up to a maximum of 80 weeks (20 months)2
Percent enrollment
Number of participants enrolled divided by number screened eligible
Time frame
From the date of enrolment of the first study participant, to the date of enrolment of up to 56 patients, assessed up to a maximum of 80 weeks (20 months)3
Randomization proportion
Number of participants randomized divided by number of participants enrolled
Time frame
From the date of enrolment of the first study participant, to the date of enrolment of up to 56 patients, assessed up to a maximum of 80 weeks (20 months)4
Percentage of protocol completion
Number of participants completing the study protocol divided by the number of participants randomized.
Time frame
From the date of enrolment of the first study participant, to the date of enrolment of up to 56 patients, assessed up to a maximum of 80 weeks (20 months)Secondary outcomes
1
SBP at baseline compared to Day 4 or hospital discharge if earlier
Measurement of systolic blood pressure averaged over at least two measurements per day at study enrolment compared to average systolic blood pressure averaged over at least three measures on Day 4, or hospital discharge if earlier. The measurement is numerical difference in systolic blood pressure averages (mmHg). Blood pressure measurements are both supine lying measurements.
Time frame
Measures from time of enrolment (Day -1 or 0) and Day 4, or hospital discharge if earlier2
Proportion of patients achieving sBP > 105 mmHg on Day 4 or hospital discharge if earlier
Measurement of systolic blood pressure averaged over at least three measures on Day 4, or hospital discharge if earlier. The measurement is numerical percentage. Blood pressure measurements are both supine lying measurements.
Time frame
Measurement from Day 4 of study protocol, or hospital discharge if earlier3
DBP at baseline compared to Day 4 or hospital discharge if earlier
Measurement of diastolic blood pressure averaged over at least two measurements per day at study enrolment compared to average diastolic blood pressure averaged over at least three measures on Day 4, or hospital discharge if earlier. The measurement is numerical difference in diastolic blood pressure averages (mmHg). Blood pressure measurements are both supine lying measurements.
Time frame
Measures from time of enrolment (Day -1 or 0) and Day 4, or hospital discharge if earlier4
NT-proBNP at baseline compared to Day 4 or hospital discharge if earlier.
Measurement of NT-proBNP blood test at baseline at time of study enrolment minus the measurement of NT-proBNP at Day 4 of the study protocol, or hospital discharge if earlier.
Time frame
Measures from time of enrolment (Day -1, or earlier if available) and Day 4, or hospital discharge if earlierOther outcomes
1
Number of serious adverse events after initiation of midodrine.
Defined as any untoward medical occurrence that: * Results in death * Is life-threatening * Requires in patient hospitalization or prolongation of existing hospitalization * Results in persistent or significant disability/incapacity (i.e. a substantial disruption in an individual's ability to conduct normal life functions) * Is a congenital anomaly or birth defect * Other medically important condition that, based on medical judgment, may jeopardize the patient, and may require medical or surgical intervention to prevent one of the outcomes listed above
Time frame
At Day 0 (or hospital discharge if earlier) up to 48 hours after last dose of midodrine2
Midodrine intolerance
Intolerance defined as the percentage of patients that needed to stop taking midodrine due to any AE or SAE, or other reasons as indicated by the patient.
Time frame
At Day 0 to Day 4 (or hospital discharge if earlier).3
Adverse Drug Reactions (ADR) reported after initiating midodrine
* Supine hypertension (SBP\>160 mmHg) * New bradycardia (if HR \< 50 bpm) * Genitourinary symptoms (Increased urinary frequency, retention, incomplete emptying, dysuria) * Gastrointestinal symptoms (nausea, vomiting, abdominal pain, diarrhea) * Pilomotor reaction * Paresthesia * Pruritis * Chills * Worsening pain (including headache) * Rash * Other
Time frame
At Day 0 (or hospital discharge if earlier) up to 48 hours after last dose of midodrineSponsors and contacts
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Source ClinicalTrials.gov