Harefield Recovery Protocol Study for Patients With Refractory Chronic Heart Failure

The hypothesis of this study is that patients with dilated nonischemic cardiomyopathy who
require support with an implanted left ventricular assist device (LVAD) for chronic
refractory heart failure can, with a specific two-staged medical regimen designed to enhance
maximal reverse remodeling (an angiotensin converting enzyme inhibitor, beta blocker,
angiotensin receptor blocker, aldosterone antagonist and digoxin [stage 1]) and
prevent/reverse myocardial atrophy (the β2 agonist clenbuterol [stage 2]), recover adequate
left ventricular systolic function to allow LVAD explantation and subsequent
intermediate-term survival without need for mechanical circulatory support or heart
transplantation.

Within one year of this study's start, a new LVAD became the standard of care for
implantation, so the study device became an inferior standard of care shortly thereafter. By
2012 the trial was stopped for futility in enrollment. Thus, certain original outcomes have
been deleted, specifically because there was only a single subject explanted, multivariate
analysis for sustainability of reverse remodeling following LVAD explantation and predictors
of recovery of left ventricular function/remodeling and of LVAD removal could not be done.

Similarly, and for lack of funding, biobank components were not collected; therefore no data
exists to present biochemical, structural, cellular and molecular changes in the myocardium
resulting from the HARPS protocol interventions, changes in systemic inflammation,
circulating progenitor cells and growth factors, or DEXA scan based data: changes in body
mass, lean muscle mass, muscle strength and maximal and submaximal exercise capacity. All
remaining outcome measures have been edited to more precisely show the outcome measures
intended.

Inclusion Criteria:

Patients with refractory symptomatic heart failure (NYHA Class IV, or Stage D) due to
dilated, non-ischemic cardiomyopathy who meet the following criteria:

- Severe clinical heart failure with associated haemodynamic compromise resistant to
intensive medical therapy and requiring LVAD implantation

- Duration of heart failure symptoms to be ≥ 12 months prior to LVAD implant

- Documentation of LVEF ≤ 40% at least 1 year prior to LVAD implantation

- LVEF ≤ 30% and cardiomegaly at the time of LVAD implantation as documented by
radionuclide or contrast ventriculography or by echocardiography

- Nonischemic etiology confirmed by coronary angiography within two years of enrollment

- Listed for heart transplantation or plan to list for heart transplantation pending
successful LVAD implantation in one of the participating centers, as per usual
transplant listing policy at each participating center

- >= 18 years of age

- Body surface area >= 1.5 m2

- Have an implantable defibrillator in place or a commitment to implant an ICD prior to
hospital discharge

- Have undergone insertion within prior 2 weeks or will be inserted with a Heartmate XVE
LVAD with use of antimicrobial prophylaxis and drive line restraining belt

Exclusion Criteria:

- Not a heart transplant candidate

- Evidence of active acute myocarditis

- Pulmonary Vascular Resistance > 6 Wood Units

- History of previous CVA resulting in significant fixed motor deficit limiting ability
to perform exercise testing

- Previous prosthetic replacement of aortic and/or mitral valve(s)

- Hypertrophic obstructive cardiomyopathy

- LVIDD < 5 cm by surface echocardiogram (restrictive cardiomyopathy)

- Irreversible multi-organ failure

- Underlying bleeding disorder, or platelet count < 75,000, INR > 2.5 (without
Coumadin), or Hgb < 8.0.

- Pregnant or lactating women or unwilling to utilize two reliable methods of birth
control for women of childbearing age

- Receipt of other investigational drug therapy during LVAD support