Predischarge Initiation of Ivabradine in the Management of Heart Failure (PRIME-HF)

• Status: Completed
• Trial end date: 2018-10-15
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Duke University
• Collaborator: Amgen

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