Study of Renal Denervation in Patients With Heart Failure

Over the past decades, clinical trials in HF have been unable to alter the natural history
of cardio-renal compromise. Fluid retention accounts for the majority of admissions for
acute decompensated heart failure, and salt and water removal using intravenous (IV)
diuretics has been the mainstay of therapy applied to this population.1 Over 20% of
hospitalized patients in the Acute Decompensated Heart Failure National Registry (ADHERE)
had serum creatinine values greater than 2.0 mg/dL2 with the majority of congested patients
presenting with significantly elevated systolic blood pressures rather than low-output
states.1 Administration of IV loop diuretics further produces intravascular volume depletion
and reduction in glomerular filtration rates3 as well as an increase in neurohormonal
activation.4 This is true regardless of whether LVEF is impaired or preserved.5 However,
despite relieving symptoms, acute drug administrations (such as adenosine receptor
antagonists or natriuretic peptide analogues) for short durations have not changed the
long-term cardio-renal outcomes in large clinical trials.

Recent recognition of different phenotypes of cardio-renal syndrome has provided better
characterization of patient populations to evaluate specific treatment approaches or
interventions.6 There is now greater appreciation that patients with congestive HF depend
not only on an adequate glomerular function for renal glomerular filtration, but also on
adequate tubular function for effective sodium handling that may or may not be dependent on
glomerular filtration.7 Despite optimizing intracardiac filling pressures, many patients
with August 28, 2013 Page 10 of 58 cardio-renal compromise remain symptomatic, complaining
of breathlessness and fatigue often associated with concomitant increase in neurohormonal
up-regulation (e.g. natriuretic peptides) and poor outcomes.8 Since the majority of patients
present with hypertension, it points to the possibility that congestive HF is precipitated
by heightened sympathetic drive.

Animal models have demonstrated that both blood pressure control and renal tubular
function/glomerular filtration (as a function of renal blood flow) can be directly
influenced by renal sympathetic nerve activity,9-12 which has evolved to provide
cardiovascular support in the setting of hypovolemia or profound cardiovascular collapse.
Specifically, HF animal models with denervated kidneys have demonstrated improvement in
renal blood flow and natriuresis (with restoration of Na+-K+ ATPase at the loop of Henle, as
well as epithelial sodium pumps at the distal tubules). However, our understanding of how
persistently activated renal sympathetic outflow can lead to exaggerated neurohormonal
up-regulation and chemoreceptor regulation in humans is still evolving. As heightened
cardio-renal compromise leads to disease progression and congestive HF, it is conceivable
that an approach to selectively modulate renal sympathetic outflow may improve cardio-renal
compromise as well as the target mechanism leading to symptomatic improvement in at-risk
patients.

By establishing the mechanistic role of renal sympathetic outflow in patients with impaired
sodium handling as a contributor to congestion in HF, we may better understand why patients
with HF develop symptoms, retain salt and water, and activate neurohormonal systems. This
trial will be hypothesis generating and will serve to inform a larger clinical trial in
patients with congestion related to HF.

The Data Safety and Monitoring Board (DSMB), an independent committee assigned by the
sponsor to oversee the conduct and safety of this study, met on May 12, 2014 to review
information that had become available from another study of the renal artery denervation
procedure using the same investigational catheter as the PRESERVE study. Even though there
were no concerns for the safety of subjects that had the renal artery denervation, the DSMB
decided to stop the PRESERVE study.

Based upon agreement with the FDA, the protocol was amended to reduce subject participation
from 52 weeks to 13 weeks and to only collect limited safety information.

Inclusion Criteria:

- Male or female, aged 21-80 years old.

- History of chronic HF (>6 months) with current NYHA II-III symptoms.

- Left Ventricular Ejection Fraction ≤40% on a clinically indicated echocardiogram
obtained within 6 months prior to informed consent.

- Requires daily loop diuretic (≥40mg furosemide per day, or equivalent) to maintain
euvolemia (absence of congestive signs including jugular venous distension with
Jugular Venous Pressure > 7cm H20, ≥ moderate (2+) peripheral edema, S3).

- Optimized medical therapy for HF. Patients will be receiving guideline-recommended
therapy (per the 2013 ACCF/AHA HF Guidelines) including angiotensin-converting enzyme
(ACE) inhibitors and/or angiotensin receptor blocker, beta-blockers, and aldosterone
antagonists without changes in heart failure medication regimen (including diuretics)
for previous 14 days.

- Systolic blood pressure (BP) ≥110 mmHg at time of informed consent.

- Able to maintain stable medications for 52 weeks.

- Suitable renal artery anatomy for Renal Sympathetic Denervation (RSD) procedure. All
of the following criteria must be met, based on the screening renal Doppler
ultrasound:

- ≥ 20mm treatable length in each renal artery,

- Diameter in treatable segments must be ≥4mm,

- Lone main renal vessel feeding each kidney.

Exclusion Criteria:

- Unable to comply with protocol or procedures.

- Evidence of orthostatic hypotension or known dysautonomia. Orthostatic hypotension is
defined by ≥1 of the following feature(s) within 2-5 minutes of quiet standing:

- ≥ 20 mmHg fall in systolic pressure

- ≥ 10 mmHg fall in diastolic pressure

- Symptoms of cerebral hypoperfusion (e.g. dizziness or lightheadedness, visual
blurring or darkening of the visual fields, syncope).

- Evidence of or history of renal artery stenosis, nephrectomy, or renal transplant.

- Significant renal impairment as defined by estimated glomerular filtration rate
(eGFR) < 45 ml/min/1.73m2 determined by Modification of Diet in Renal Disease (MDRD)
equation.

- Significant proteinuria (>2g protein/daily protein excretion).

- Body mass index (BMI) >35 kg/m2.

- Acute coronary syndrome within last 4 weeks as defined by ECG changes and biomarkers
of myocardial necrosis (e.g. troponin) in an appropriate clinical setting (chest
discomfort or angina equivalent).

- Coronary revascularization procedures (percutaneous coronary intervention or cardiac
artery bypass graft) and or valve surgery within 30 days of screening or expected
procedures within the next 6 months.

- Cardiac resynchronization therapy, with or without implantable cardiac defibrillator
within 90 days of screening or expected procedures within the next 6 months.

- Hypertrophic or restrictive cardiomyopathy, constrictive pericarditis, active
myocarditis, active endocarditis, or complex congenital heart disease.

- Severe advanced HF, with ANY of the following features:

- Current or anticipated use of ventricular assist device within the next 6 months.

- Current or anticipated IV vasoactive drug therapy for HF management within the next 6
months.

- Listed cardiac transplant candidate, with transplantation likely within the next 6
months.

- Known allergic reactions to iodinated radiological contrast media or iodinated
antiseptics.

- Greater than moderate mitral or aortic stenosis, and/or severe tricuspid
regurgitation.

- Terminal illness (other than HF) with expected survival of less than 1 year.

- Female who is pregnant, nursing, or of childbearing potential not practicing
effective birth control.

- Enrollment or planned enrollment in another clinical trial within the next 12 months.

- History of urinary outflow tract obstruction, bladder retention and/ or moderate to
severe prostate hypertrophy.

- History of adrenal insufficiency

- History of untreated hypothyroidism

- Patients with non-cardiac dyspnea or fatigue due to frailty, motivational factors,
pulmonary disease or orthopedic problems that precludes them from performing 6MWT
(Six-Minute WalkTest).