Predischarge Initiation of Ivabradine in the Management of Heart Failure (PRIME-HF)
Condition: Heart Failure
MeSH terms: Heart Failure
Intervention: ivabradine; Usual Care
Intervention description: Active Comparator: ivabradine; Placebo Comparator: usual care
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 104.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The PRIME-HF study is a multi-center, patient-level, randomized, open-label study of
      approximately 450 patients with reduced (left ventricular ejection fraction) LVEF of ≤ 35%
      and heart-rate ≥70 beats per minute (bpm) who are being discharged from the hospital
      following stabilization from acute heart failure (HF)(primary or secondary) and will be
      randomized to a treatment strategy of predischarge initiation of ivabradine or usual care.

      All participants should have a follow-up visit within 7-14 days of hospital discharge. Heart
      rate and systolic blood pressure will be assessed at this clinical visit. For participants
      randomized to predischarge initiation of ivabradine and on ivabradine 5mg BID, the heart rate
      may be used to adjust the dose the dose to 2.5mg BID or 7.5mg BID. For participants
      randomized to usual care, ivabradine may be initiated at the provider's discretion. All
      participants will have a second follow-up study visit 6 weeks (42 +/- 14 days)
      post-discharge. Heart rate, systolic blood pressure and quality of life (KCCQ and PGA) will
      be assessed. For participants already taking ivabradine in either treatment group, the heart
      rate may again be used to adjust the dose of ivabradine. For participants not yet receiving
      ivabradine, it may be initiated at the provider's discretion. All participants will receive a
      90 (+/-7) day post-discharge phone call by site to assess for event status and tolerability
      of ivabradine. All participants will have a final study visit at 180 (+/-14) days
      post-discharge. Heart rate, systolic blood pressure and quality of life (Kansas City
      Cardiomyopathy Questionnaire and Patient Global Assessment) will be assessed. The attending
      physician may initiate ivabradine per usual care clinical practice.

      The primary hypothesis of the PRIME-HF study is that, compared with usual care, a treatment
      strategy of initiation of ivabradine prior to discharge for a hospitalization with acute HF
      will be associated with a greater proportion of participants using ivabradine at 180 days.
      Secondary objectives are to assess the impact of predischarge initiation of ivabradine
      on:Heart Rate (Change in heart rate from baseline to 180 days and Median heart rate at 180
      days) and Patient-Centered Outcomes (Kansas City Cardiomyopathy Questionnaire (KCCQ) and
      Patient Global Assessment (PGA)). Tertiary objectives will be to explore the impact of
      predischarge initiation of ivabradine on other assessments of evidence-based implementation
      of ivabradine and beta-blockers at 180 days. Evaluations will incorporate data based on
      whether or not indication status was retained and whether or not an ivabradine prescription
      was provided. Tolerability of ivabradine and adverse events during study follow-up.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Hospitalized with acute HF (primary or secondary diagnosis) based on clinician
             assessment

          2. A prior clinical diagnosis of HF (i.e., not a new diagnosis of heart failure during
             the current hospitalization)

          3. Most recent LVEF ≤ 35% and within 6 months of randomization or LVEF ≤ 25% within 12
             months of randomization

          4. On optimal guideline-directed medical therapy for HFrEF (or previously deemed
             intolerant) as determined by the clinician including ACE-inhibitors or angiotensin
             receptor antagonists or neprilysin inhibition, aldosterone receptor antagonists, and
             maximally-tolerated doses of beta-blockers at the time of current evaluation (which
             may differ from long-term targets)

               -  Maximally-tolerated doses of beta-blockers will be defined by the treating
                  physician when considering aspects such as current dose relative to the target
                  dose used in clinical trials, patient heart rate and blood pressure, and patient
                  symptoms

               -  Patients with intolerance or contraindication to beta-blocker use are eligible
                  for enrollment (details will be documented in the case report form)

          5. Age >18 years

          6. Willingness to provide informed consent from the subject (or their guardian or legally
             authorized representative [LAR])

          7. On the day of planned randomization, all participants:

               -  Must be in sinus rhythm with a resting heart rate >70 bpm as measured on ECG or
                  10-second rhythm strip

               -  Must have a blood pressure of >90/50 mm Hg

        Exclusion Criteria:

          1. Documented plan for uptitration of beta-blocker in the following 4 weeks

          2. Permanent atrial fibrillation or atrial flutter

          3. Patients with recent atrial fibrillation or flutter defined by either precipitating
             the current HF hospitalization or occurring during the current HF hospitalization

          4. History of untreated sick sinus syndrome, sinoatrial block, or second and third degree
             atrio-ventricular block

          5. Pacemaker with atrial or ventricular pacing (except biventricular pacing) >40% of the
             time

          6. Family history or congenital long QT syndrome

          7. Recent myocardial infarction (<2 months prior to screening) [troponin elevation
             secondary to acute HF as determined by the clinician is not an exclusion]

          8. Acute or chronic severe liver disease as evidenced by any of the following:
             encephalopathy, variceal bleeding, INR > 1.7 in the absence of anticoagulation
             treatment

          9. Creatinine clearance <15 mL/min within 48 hours of screening that was not due to acute
             kidney injury that resolved

         10. Planned mechanical circulatory support within 180 days

         11. Pregnant or breastfeeding women. Women with child-bearing potential should use
             effective contraception.

         12. Medical conditions likely to lead to poor non-cardiac survival at 180 days (e.g.,
             cancer)

         13. Inability to comply with planned study procedures

         14. If the following medications are needed at inclusion or during the study:

               -  Non-dihydropyridine calcium channel blockers (e.g., diltiazem and verapamil)

               -  Class I anti-arrhythmics (e.g., quinidine, procainamide, lidocaine, phenytoin)

               -  Strong inhibitors of cytochrome P450 3A4 (CYP3A4), including some macrolide
                  antibiotics (e.g., clarithromycin, erythromycin), cyclosporine, antiretroviral
                  drugs (e.g., ritonavir, nelfinavir), and systemic azole antifungal agents (e.g.,
                  ketoconazole, itraconazole), and nefazodone

               -  Inducers of cytochrome P450 3A4 (CYP3A4) including St. John's wort, rifampicin,
                  barbiturates, and phenytoin.

               -  Treatments known to be associated with significant prolongation of the QT
                  interval, including sotalol