REVERSE

Principal Investigator:
Liaqat Zaman, MD

Sub Investigators:
Sarosh Anwar, MD
Jeffery W. Carney, MD
Peter G. Fattal, MD
Rehan Mahmud, MD
Asim Yunus, MD

Sponsor:
Medtronic

Study:
(REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction)

Objective:
The purpose of the Reverse study is to determine if pacing both ventricles results in slowing down or stopping the progression of heart failure in patients with no or mild symptoms of heart failure. One of the things that will be measured is the size of the patients’ heart and how it compares to symptoms of heart failure progression. Patients will have a Bi-V Implant with NYHA I/II heart failure; the Bi-V pacing may or may not be turned on for the first twelve months. There is a 2/3 (ON) to 1/3 (OFF) randomization. At the end of twelve months all patients have the Bi-V pacing on. Patients are blinded therapy.

Inclusion/Exclusion Criteria

Inclusion:

Patient has signed and dated study informed consent
Patient is able to receive a pectoral implant
Patient is NYHA Functional Class I or II with current American College of Cardiology/American Heart Association (ACC/AHA) Stage C classification as confirmed by the documented consensus of two qualified individuals with 30 days prior to enrollment or during the baseline assessment. Stage C classification includes patients who have current or prior symptoms of heart failure associated with underlying structural heart disease. Qualified individuals must include at least one cardiologist and another physician or a heart failure clinician/ nurse. A minimum of one classifying individual must be recorded on the Blinding Log. If the two-qualified individuals assessing the NYHA Functional classification do not reach a consensus, the patient is not eligible.
Patient has ventricular dyssynchrony by QRS duration > 120ms (at Baseline or within the 30 days prior to enrollment).
Patient has a history of a left ventricular ejection fraction < 40%, which is confirmed at the baseline echo.
Patient has a history of a LVEDO > 55 mm or the equivalent value via LVEDD Index (i.e., LVEDDi > 2.8 cm/m2), which is confirmed at the baseline echo.
Patient is on a stable optimal medical regimen, which minimally includes:
- ACE Inhibitor or ARB at therapeutic dose for one month prior to enrollment, if tolerated.
- Beta blocker that is approved and indicated for HF within the geography for 3 months prior to enrollment, if tolerated, with a stable dosage for one month prior to enrollment.
If the patient is intolerant of ACE-I or BB, documented evidence must be available. If anti-aldosterone therapy is needed in the NYHA Functional Class II patients, it must be initiated and optimized prior to enrollment. Eplerenone requires dosage stability for one month prior to enrollment. Diuretics may be used as necessary to keep the patient euvolemic. Therapeutic equivalence for ACE-I substitutions is allowed within the enrollment stability timelines.
Patient is expected to remain available for follow-up visits.
Patient is willing and able to comply with the clinical investigation plan.
Patients who will be implanted with a CRT/ICD system will have an indication for an ICD as defined by the associated geography. (In the U>S., patients must have a Class I or II ICD indication.)

Exclusion:

Patient requires permanent cardiac pacing.
Patient has been classified as NYHA functional class III or IV in the 3 months prior to enrollment.
Patient is < 18 years of age, or the patient is under a higher minimum age that is required as defined by local law.
Patient has experienced decompensation of heart failure requiring hospitalization for the treatment of heart failure within the 3 months prior to enrollment.
Patient has experienced unstable angina, acute MI, CABG or PTCA within the 3 months prior to enrollment.
Patient has chronic (permanent) or persistent atrial arrhythmias. Chronic (permanent) atrial arrhythmias are defined as cases of long-standing atrial fibrillation (e.g., greater than 1 year) in which cardioversion has not been indicated or attempted. Persistent atrial arrhythmias are defined as recurrent atrial fibrillation (i.e., 2 episodes or more) that does not self terminate.
Patient has had cardioversion for atrial fibrillation or paroxysmal atrial fibrillation event within the past month.
Patient is enrolled in a concurrent study, with the exception of a study-manager approved study that is strictly observational in nature and does not confound the results of this study (e.g. registries).
Patient has a life expectancy of less than 12 months.
Women who are pregnant or women of childbearing potential who are not on a reliable form of birth control. Women of childbearing potential are required to have a negative pregnancy test within the seven (7) days prior to device implant.
Patients with a CRT, pacemaker, ICD or CRT/ICD device implanted previously or currently, except in cases where previously implanted non-CRT ICD device lifetime counters indicated the device or the patient records cannot provide this data, the patient is not eligible.
Patient has a mechanical right heart valve.
Primary valvular disease and indication for valve repair or replacement.
Patient has had a heart transplant.
Patient is on continuous or intermittent (i.e., more than two infusions per week) intravenous inotropic drug therapy.
Documentation that the following exclusion criteria do not exist: (required within 30 days prior to enrollment or at the baseline visit :)
Patient has significant renal dysfunction, as manifested by serum creatinine level > 3.0 mg.dl.
Patient has significant hepatic dysfunction, as evidenced by a hepatic function panel (serum) > 3 times upper limit of normal.
Chronic or treatment resistant anemia (hemoglobin < 10.0 g/dL).

Study Purpose:
All patients that participate in this research study will receive a CRT implanted system. The purpose is to determine whether biventricular pacing (CRT) will result in a stabilization or improvement in patients’ clinical status over the course of 12 months as compared to optimal medical therapy (OMT) alone in patients with asymptomatic or mild heart failure (NYHA functional class I or II, stage C), ventricular dyssynchrony (QRS > 120 ms), and reduced systolic left ventricular ejection fraction (EF < 40%).
Assignment to one of the two study groups will be randomized. For every three patients randomized, two patients will be assigned to the CRT ON Group and one patient will be assigned to the CRT OFF group. After 12 months, every patient will have the CRT device turned on. Follow up study visits will continue yearly for four more years and will include echocardiograms. It is very important that the implanting doctors and nurses do not reveal the randomization assignment so that it doesn’t influence the information collected for the study.

Outcome:
The outcome of the study is expected to support modification (expansion) of existing U.S. indications for implantable asynchronous biventricular pacing devices and provide further evidence to support the current medical data regarding the use of cardiac resynchronization therapy in patients with asymptomatic to mild heart failure.

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