Impact of Renal SympAthetic DenerVation on Chronic HypErtension

Aside from its obvious impact on renal function, chronic hypertension significantly increases
the risk for stroke, coronary artery disease, heart failure, and vascular disease, and it is
believed to mediate the pathogenesis and progression of cardiac arrhythmias via its
remodeling effects on cardiac anatomy. This inextricable link between hypertension and
cardiovascular health has been well described, as has their combined effect on up to 40% of
the aging, obesity-battling Western world.

Despite the development of numerous anti-hypertensive drug therapies—diuretics,
angiotensin-converting enzyme inhibitors, alpha-adrenergic blockers, angiotensin-receptor
blockers, calcium-channel blockers, beta blockers, and vasodilators—designed to block various
and multiple avenues of the complex renal-cardiovascular circuit, hypertension remains a
considerable, and poorly managed, social and economic burden. For various reasons, including
the enormous health care costs of treatment, up to 65% of hypertensive patients have
untreated and/or uncontrolled blood pressure (BP). Of those with uncontrolled blood pressure,
~10% have resistant hypertension—defined as elevated BP refractory to treatment with 3
antihypertensive agents of different classes.

But an even greater problem than the ineffectiveness of available therapies is their
applicability. As has been observed with other illnesses, patients are often the greatest
obstacles to their own care. Convincing patients to adhere to a life-long regimen of
expensive medication for something which causes no immediate, palpable impact to their lives,
is a challenging feat for today's pressed-for-time physician.

Therefore, of particular interest and profound promise is a recent study examining the
effects on chronic blood pressure management of catheter-based renal sympathetic denervation
(Symplicity HTN-1, Krum et al, Lancet 373:1275, 2009). This proof-of-principle study revealed
that the procedure could be performed safely and without any procedure-related sequelae in 50
patients with baseline office blood pressure of 177±20 / 101±15, on 4.7 anti-hypertensive
medications. At 12 months post-procedure, the mean reduction in office blood pressures was a
remarkable -27/-17 mm Hg, with a concurrent 47% reduction in renal noradrenaline spillover.
Importantly, these favorable blood pressure results were maintained over 2 years (see Fig).

Then, Esler et al performed a multicenter, randomized controlled trial comparing catheter
based renal denervation to optimal medication therapy in patients with drug-resistant
hypertension (Symplicity HTN-2, Lancet 2010; 376:1903-1909). In this study of 106 randomized
patients, the 6-month office BPs in the denervation group decreased by 32/12 mmHg (SD 23/11,
baseline of 178/96 mmHg, p<0.0001), whereas they did not differ from baseline in the control
group (change of 1/0 mmHg [SD 21/10], baseline 178/97 mmHg, p=N.S.). There were no serious
procedure-related or device-related complications. And most recently, besides the hydrostatic
effect on blood pressure, it was recently demonstrated that RSDN significantly reduces LV
mass and improves diastolic function in patients with refractory hypertension (J Am Coll
Cardiol 2012; 59:901-9). Together, these favorable effects all suggest that there may
important beneficial prognostic implications for RSDN in patients with resistant hypertension
at high cardiovascular risk.

But of note, in both Lancet studies, the catheter used for the renal ablation procedure was a
specialized radiofrequency ablation catheter that is not yet FDA-approved. To this end, it
has been demonstrated that RSDN can be safely performed in patients using an off-the-shelf
solid-tip radiofrequency ablation catheter typically used for cardiac ablation
(EuroIntervention 2012; 7(9):1077-80). In addition, we have recently demonstrated that a
standard off-the-shelf irrigated radiofrequency ablation catheters can also be used to
achieve a similar effect (H.Ahmed / P.Neuzil / V.Reddy, JACC-Cardiovasc Interven, in press).
Briefly, in drug-refractory hypertension patients, an irrigated radiofrequency ablation
catheter (Celsius Thermocool catheter, Biosense-Webster Inc, Diamond Bar, California) was
used to perform bilateral renal arterial sympathetic denervation. Briefly, over a 6 month
period, 1) the systolic/diastolic BPs (as determined by 24-hour blood pressure monitoring)
decreased by -21/-11 mmHg (for comparison, the change in the 24-hour blood pressure change in
Symplicity HTN-2 was -11/-7 mm Hg); 2) all patients experienced a decrease in systolic BP of
at least 10 mm Hg (range: 10-40 mm Hg); 3) there was no evidence of renal artery stenosis or
aneurysm at repeat angiography; and 4) there was a significant decrease in renal sympathetic
activity at 3 months: including metanephrine (-12±4, p=0.003), normetanephrine (-18±4,
p=0.0008) levels, and aldosterone levels (-60±33 ng/l, p=0.02). There was also no evidence of
worsening renal function (change in serum creatinine was -1 mmol/L, p=0.4). These data
provide the proof-of-principle that RSDN can be performed using an off-the-shelf
saline-irrigated radiofrequency ablation catheter. [Of note, there were two major reasons
that this off-the-shelf catheter was used: i) the lack of availability of the specialized RF
ablation catheter used in the Lancet studies, and ii) unlike this specialized RF catheter,
the catheter we employed had a saline-irrigated ablation element. In theory,
saline-irrigation has the advantage of being less likely to cause thrombus or char formation
during catheter ablation, and is also more likely to cause tissue surface sparing while
ablating deeper tissue.] The purpose of this trial will be to evaluate the long term safety
and efficacy of catheter-based renal sympathetic denervation in 500 hypertensive patients by
following them for 2 years.

Study Rationale The recently published results of the Symplicity HTN-2 trial (Renal
sympathetic denervation in patients with treatment resistant hypertension) establishing the
therapeutic benefit of catheter-based renal sympathetic denervation for hypertension, have
enormous potential for the management of a large and challenging patient population. The
proposed prospective non-randomized multi-center trial will attempt to confirm and expand on
these promising data by evaluating the long-term efficacy (and safety) of renal sympathetic
denervation in patients with chronic hypertension. Patients who enroll in the trial will be
followed for 4 years.

Inclusion Criteria:

- ≥ 18 and ≤ 85 years of age.

- Refractory hypertension (per JNC-7, this is defined as BP ≥ 140/90 mmHg despite
treatment with at least 3 anti-hypertensive drugs, at least one of which is a
diuretic, or treatment by ≥ 4 anti-hypertensive drugs)

- Stable anti-hypertensive drug regimen, where no modifications have occurred for at
least 2 weeks.

- Accessibility of renal vasculature.

- Ability to understand the requirements of the study.

- Willingness to adhere to study restrictions and comply with all post-procedural
follow-up requirements.

Exclusion Criteria:

- Subject has a known secondary cause of hypertension.

- Subject has isolated White coat hypertension.

- Subject has Type 1 Diabetes.

- Subject has known significant renovascular abnormalities (e.g., significant renal
artery stenosis, previous renal artery stenting or angioplasty that precludes the RSDN
procedure because of no sites for ablation treatment, or the presence of an accessory
renal artery in which the main renal artery is estimated to supply <75% of the kidney
)

- Significant renal artery stenosis is defined as > 50% diameter stenosis on renal
angiography. Per the guidelines for noninvasive vascular laboratory testing: a report
from the American Society of Echocardiography and the Society for Vascular Medicine
and Biology, significant renal artery stenosis is defined by any one of the following
criteria on renal duplex ultrasound; i) Renal artery to aorta peak systolic velocity
ratio ≥ 3.5; ii) Peak Systolic Velocity > 200 cm/s with evidence of post-stenotic
turbulence; iii) end diastolic velocity >150 cm/s ; iv) Resistive Index (RI) > 0.8; v)
An occluded renal artery demonstrates no flow in the affected vessel.

- Subject has hemodynamically significant valvular heart disease for which reduction of
blood pressure would be considered hazardous.

- Subject has New York Heart Association (NYHA) Class III or IV congestive heart
failure, due to either systolic or diastolic dysfunction.

- Subject has an eGFR<45 ml/min/1.73m2 (calculated by using the modified diet in renal
disease (MDRD) formula), and is not receiving dialysis.

- Subject has orthostatic hypotension. (per the American Academy of Neurology/American
Autonomic Society Conesus Statement, this is defined as a sustained reduction of
systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of 10 mm Hg
within 3 min of standing or head-up tilt to at least 60° on a tilt table)

- Subject has a life expectancy < 1 year for any medical condition.

- Subject is currently enrolled in another investigational drug or device trial that
would interfere with this study.