The purpose of this trial is to better understand how the beta-blocker metoprolol works in people with Heart Failure with Reduced Ejection Fraction (HFrEF) according to participants genetics. Participants will have the beta-blocker (BB) polygenic score calculated from genotype data. The score will be used to stratify the patients in the low and high polygenic score groups in the study.
The hypotheses for this trial are:
* HFrEF patients with high polygenic score will have weaker cardiovascular responses to metoprolol succinate than HFrEF patients with low polygenic score. * HFrEF patients with high polygenic score have lower steady-state plasma concentrations of metoprolol succinate than HFrEF patients with low polygenic score. * HFrEF patients with high polygenic score require higher metoprolol succinate plasma concentrations to achieve similar cardiovascular effects as those with low polygenic score.
Heart Failure with Reduced Ejection Fraction (HFrEF)
Has not taken a beta-blocker within the past 6 months (preferred), or if needed to meet enrollment target, patients that have not taken a beta-blocker in the past 3 months, or only taken a low dose of beta-blocker within the past 6 months (i.e., < 50% of the guideline-recommended HFrEF target dose, or for beta-blockers that are not approved for HFrEF, <50% of the maximum dose)
Genetic data already available to calculate the polygenic score (e.g., through participation in the Michigan Genomics Initiative (MGI) or other genetic tests) or willingness to provide a deoxyribonucleic acid (DNA) sample for genetic analysis
White race
Prior heart transplant or left ventricular assist device (LVAD) or planned within treatment period
Planned implantation of a pacemaker or Cardiac Resynchronization Therapy (CRT) during treatment period
Patients with a pacemaker that does not allow their heart rate to change in response to exercise per protocol
Pregnant
Single group
Metoprolol Succinate
DrugParticipants will be given daily metoprolol and the dose will be titrated up to 200 milligrams daily (over 6-12 weeks) or the maximum tolerated dose. Once this dose is reached treatment will continue for approximately 5-8 months. In addition, participants, will have various visits that include laboratory and cardiac testing at certain time points.
Beta-Blocker Polygenic Score
DeviceThe purpose of the beta-blocker polygenic score is to predict which HFrEF patients will respond better to beta-blocker therapy. It will be used to stratify the patients in the low and high polygenic score groups in the study. There are no post-manufacturing modifications to the score.
Illumina Infinium Global Diversity Array with Enhanced Pharmacogenomics (PGx)
DeviceIf the participant does not already have genotype data available through Michigan Genomics Initiative (MGI), then this device will be used to genotype DNA sample, which will be used to calculate the polygenic score. There are no post-manufacturing modifications to the device.
Half Maximal Effective Concentration of Change in Exercise-Induced Heart Rate (EC50 of ΔEIHR)
The plasma concentration of s-metoprolol succinate that causes 50% of the change in exercise-induced heart rate.
Change in left ventricular ejection fraction (LVEF)
Area Under the Curve from 0 to 24 hours s-metoprolol plasma concentration-time curve "at steady state"
Maximum tolerated dose of metoprolol succinate (total daily dose in milligram)
Click on the lead sponsor to view all of their trials.
University of Michigan
Lead sponsor
National Heart, Lung, and Blood Institute (NHLBI)
Collaborator
