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.

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