Trial Assessing the Effectiveness of Ivabradine Started at Discharge From the Observation Unit
Trial Assessing the Effectiveness of Ivabradine Started at Discharge From the Observation Unit
Ivabradine (IVA) has been shown to decrease the risk of hospitalizations for worsening Heart
 Failure and was associated with a trend towards improved mortality in the SHIFT1 trial.
 SHIFT1 excluded patients within 4 weeks of hospital discharge, so the efficacy and safety of
 IVA in this setting is less clear.

 In today's health care environment more and more patients that present to the Emergency
 Department (ED) for mild Acute Heart Failure (AHF) are being placed into observation unit and
 subsequently discharged, or discharged outright from the ED. This is not only a growing
 segment of patients, but also represents an important window of opportunity to intervene with
 a potentially effective therapy.

 Moreover, at this point in a patient's experience (being discharged after getting treated for
 exacerbation of Heart Failure), it's not clear that beta blockers (BB) should yet be
 increased/started due to the recent state of exacerbation.

 Standard treatment of worsened heart failure presenting to the ED or urgent care includes
 diuretics (e. g. furosemide) and vasodilators (e.g. ACE-I, ARB, Hydralazine/Isosorbide or
 ARNi), but according to usual standard of care, titration of beta blockade is often reserved
 for outpatient follow up after a period of demonstrated stability (in the ambulatory
 setting).

 This is in contradistinction to hospitalized patients, where patients have been observed by
 the treating team for days, presumably show stability and improvement, and starting low dose
 BB at the time of hospital discharge has been shown to be safe. As such these ED/Observation
 discharge patients are often not optimal candidates for intensification of BB at the time of
 release, and could be considered to be at maximally tolerated BB dose (for at least for 2-4
 weeks). This may represent a vulnerable period for these patients; its unknown in the setting
 of Observation discharge but evidence from hospitalized patients indicates that the highest
 daily risk of rehospitalization is in the days just after discharge. IVA may be effective
 post observation unit management (where lower risk Heart Failure (HF) patients are typically
 placed), to reduce heart rate (without decreasing contractility, such as a BB would) to help
 reduce the risk of hospitalization or emergency care, but safety and efficacy (in terms of
 heart rate lowering) in this setting has not been previously explored.

 Additionally, the SHIFT1 trial lacked African Americans and this unique patient population
 has not been previously studied with IVA. The investigating sites serve a predominantly
 African American patient population. Therefore the proposed study represents an important
 opportunity to gather data on IVA effect in this understudied group of patients.
Subjects will be enrolled at the time of discharge from the observation unit (visit 1), all
 baseline procedures will be performed at this time, these would include blood draw for
 biomarker assessments, vitals, physical examination, and IP dispensation. At the baseline
 visit, the study team will schedule a follow-up appointment post Day 28 +/- 2 (Visit 3) with
 the subject's primary care physician(PCP)/cardiologist, if the subject does not have their
 own PCP/cardiologist the study team will schedule and facilitate this appointment with the
 Gateway Clinic. A list of current medications and doses will be provided. At Day 14 +/-1
 (visit 2) the subject will return for a follow up visit for IP accountability and titration
 (if needed), BB uptitration (if needed), replacement of the HR monitor (Zio patch),
 assessment of any adverse events, ECG, vital signs, and will undergo a physical examination.
 At Day 28 +/-2 (visit 3), the patient will return for study exit procedures, which include
 blood draw for biomarker assessments, vitals, physical examination, assessment of adverse
 events (if any), and IP return.

 As with any clinical trial, no un-blinding will occur unless there is a concern for patient
 safety, as this could affect the integrity of data. The study team will provide the patient
 and patient's PCP/cardiologist a clinical summary, inclusive of ECGs. On-going management for
 the patient's condition will be at the discretion of their PCP/cardiologist and will not be
 influenced directly by participation in this study.

 At Randomization the initial Ivabradine dose will be 5 mg BID. At Day 14 follow up,
 medication adjustments will be made (if needed). At Day 28 follow up, IP will be permanently
 stopped.

 At the last visit, the study team will contact the patient's primary care physician and/or
 the cardiologist to notify that the patient has completed the study and is off study drug and
 it is now the PCP/cardiologist's discretion to prescribe open label ivabradine (Corlanor) to
 the patient or not, as clinically indicated. If the patient's primary care physician and/or
 cardiologist prescribes open label ivabradine (Corlanor) after the completion of the study,
 the patient or patient's insurance will be responsible for payment as this would then be part
 of routine clinical care.

 The Zio patch will be placed at discharge from the observation unit. At the 14-day follow-up
 the original Zio patch will be collected and a second one will be placed. At the 28-day
 follow-up the second Zio patch will be collected

 Based on the SHIFT1 study, the mean heart rate reduction with IVA is 8 bpm with a standard
 deviation of 13 bpm. A sample size of 57 in each group will have 90% power to detect a
 difference in means of 8.0 assuming that the common standard deviation is 13.0 using a two
 group t-test with a 0.05 two-sided significance level. To account for a projected dropout
 rate of 15%, 66 subjects will be enrolled in each group (132 total for the study over a
 2-year period). Furthermore, the investigators expect that the enrollment centers will
 recruit a cohort that is 75% self-identified African Americans. This number (n=99) will
 provide 80% power to detect the same effect size when analyzed in African Americans only.

 For the safety endpoint (unplanned presentation for medical care), assuming an event rate of
 25% at 1 month (estimated based on local hospital readmission rates), the sample size will
 provide 80% power to detect a doubling of the relative risk. If the Control group event rate
 is higher there will be greater power; for example, with an event rate of 35% we would have
 98% power for risk ratio of 2.0 and 83% power for risk ratio of 1.75.
Inclusion Criteria:

 1. Age >18 and <90.

 2. Established HF with reduced ejection fraction (EF ≤35 %), assessment done within 12
 months of index visit.

 3. Admitted under observation unit for management of AHF.

 4. Heart rate ≥70 beats per minute, with sinus rhythm.

 5. Receiving guideline based medical therapy in the judgement of the treating physician.

 6. Patient currently on a Beta Blocker regimen. Achieved clinically determined
 stabilization during treatment under observation unit such that the treating physician
 is planning to discharge home without hospital admission.

 Exclusion Criteria:

 1. Known intolerance to study drug.

 2. End stage renal disease.

 3. Plan to titrate BB at the time of discharge from the observation unit.

 4. Any condition that in the opinion of the investigators will interfere with the ability
 to complete the study (e.g. history of extreme non-adherence, extreme psychosocial
 instability).

 5. Inability to provide written informed consent.

 6. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
 female after conception and until the termination of gestation, confirmed by a
 positive hCG laboratory test (women of childbearing age will be included only if they
 agree to use adequate contraceptive methods or engage in sexual abstinence).

 7. Systolic Blood pressure less than 100 mmHg.

 8. Sick sinus syndrome, sinoatrial block or 3rd degree AV block, unless a functioning
 demand pacemaker is present.

 9. Severe hepatic impairment.

 10. Pacemaker dependence (i.e. heart rate maintained exclusively by the pacemaker).

 11. Concomitant use of strong CYP3A4 inhibitors. Examples of strong CYP3A4 inhibitors
 include azole antifungals (e.g., itraconazole), macrolide antibiotics (e.g.,
 clarithromycin, telithromycin), HIV protease inhibitors (e.g., nelfinavir), and
 nefazodone.

 12. Concomitant use of diltiazem or verapamil that are not planned for discontinuation.

 13. Severe, left sided valvular abnormalities (severe aortic stenosis, severe mitral
 stenosis, severe aortic insufficiency or severe mitral regurgitation.

 14. Documented, prior to or at the time of randomization, restrictive amyloid
 cardiomyopathy, or acute myocarditis, or hypertrophic obstructive, restrictive, or
 constrictive cardiomyopathy.