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

• Purpose of the study 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 (primary or secondary) 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 will be assessed. Barriers to acquisition of ivabradine will be explored.
• Background \& significance Heart failure is a major public health issue. More than 5 million Americans have HF and the prevalence is expected to increase as the population ages and survival from coronary, hypertensive, and valvular heart disease improves. Data from randomized clinical trials have established the efficacy of a number of medical and device therapies for patients with chronic Heart failure with reduced ejection fraction (HFrEF), but patient outcomes remain poor, especially after a hospitalization for heart failure. The 1-year mortality rate after a HF hospitalization is 20-30%, and this number has been relatively unchanged over the past decade. These data suggest that there is an unmet need for novel treatment strategies and supports the assessment of new approaches in the post-acute HF setting.

There is also wide variation in the implementation of clinical trial evidence into routine practice. Previous data highlight a multi-year gap between the generation of new evidence through clinical trials and the adoption of the data into routine clinical practice. This gap in care translates into many unnecessary deaths and hospitalizations each year for patients with HFrEF. While there are multiple reasons for this quality gap, clinical inertia has most often been noted as a major barrier. Ivabradine have been approved for use in Europe for several years for patients with symptomatic chronic HFrEF (LVEF <35%) and a heart rate >75 bpm on guideline-directed medical therapy (or intolerance/contra-indication to beta-blocker use). Ivabradine was recently approved for use in the United States. However, no US data exist regarding the potential adoption of ivabradine into routine clinical care.

Since ivabradine is a newly approved drug, this study also serves as a strategy trial to challenge study sites to explore drug acquisition for a drug that has been proven efficacious to the heart failure population and has been added to 2016 ACC/AHA/HFSA guidelines, however, has not been adopted rapidly into clinical practice. Ivabradine is not being provided for this study. Data are being captured to assess the number of subjects who were able to obtain ivabradine pre and post discharge as well as the barriers to acquisition.

Previous data for patients with HFrEF suggest that the hospital setting may provide a unique opportunity for patients to initiate guideline-directed medical therapy. In the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in HF (IMPACT-HF) study, patients with an LVEF<40% hospitalized for HF that were started on carvedilol prior to hospital discharge were more likely to be on a beta-blocker at 60 days post-randomization compared to those receiving usual care. These improvements in care were achieved without increasing side effects or index hospitalization length of stay. Similar to beta-blockers and other medical therapies for HF, ivabradine was initially studied in patients with chronic HF. The initiation of ivabradine specifically in patients following stabilization for acute HF has not been evaluated.

• Design \& procedures The PRIME-HF study is a multi-center, patient-level, randomized, open-label study of approximately 450 patients with reduced LVEF of ≤35% and heart-rate ≥70 bpm who are being discharged from the hospital following stabilization from acute HF 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 (KCCQ and PGA) will be assessed. The attending physician may initiate ivabradine per usual care clinical practice.