Impact of Renal SympAthetic DenerVation on Chronic HypErtension (SAVE)

Despite the development of many drug therapies designed to treat high blood pressure (hypertension), it remains a considerable and poorly managed health, social and economic burden. For various reasons, including the high health care costs of treatment, there are estimates that up to 65% of patients with high blood pressure have untreated and/or uncontrolled blood pressure (BP). Aside from its effect on kidney function, chronic high blood pressure increases the risk for stroke, and heart disease. It is also thought to be involved in the formation of irregular heartbeats. This link between high blood pressure and heart health has been well described, as has their combined effect on the aging and the obesity-battling Western world. A recently published study (Symplicity HTN-2 trial) established the benefit of a new treatment procedure, catheter-based renal sympathetic denervation (RSDN) for hypertension, as having enormous potential for the treatment of patients with high blood pressure. This multi-center trial will attempt to confirm and expand on these promising data. Patients who enroll in the trial will be followed for 4 years.

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.

Saline-Irrigated Radiofrequency Ablation Catheter will be placed in the renal arteries in a circumferential manner and energy will be delivered to create 4 burn lesions. There are 2 devices that can be used---this is optional, based on physician preference: Celcius Thermacool Catheter Biosense Webster, Inc Diamond Bar, California or Chilli II Cooled Ablation Catheter Boston Scientific Corporation San Jose, California

The change in systolic blood pressure as measured by 24 hour ambulatory monitoring at 6 months as compared to from baseline.

The change in diastolic blood pressure as measured by 24 hour ambulatory monitoring at 6 months as compared to from baseline.

Renal artery blood flow as measured by Renal Aortic Ratio (RAR) = Peak systolic Velocity renal artery / Peak Systolic Velocity Aorta. A >60% stenosis is reported when there is a >3.5:1 Renal to Aortic Ratio.

Renal artery blood flow as measured by Resistive Index. RI = (peak systolic velocity - end diastolic velocity ) / peak systolic velocity. the normal value is ~ 0.60, with 0.70 being around the upper limits of normal

A blood urea nitrogen (BUN) test measures the amount of nitrogen in blood that comes from the waste product urea. Urea is made when protein is broken down in the body. Urea is made in the liver and passed out in the urine.

Creatinine measures the level of the waste product in the body. The amount of creatinine in the blood depends partly on the amount of muscle tissue you have. Men generally have higher creatinine levels than women.Normal levels of creatinine in the blood are approximately 0.6 to 1.2 milligrams (mg) per deciliter (dL) in adult males and 0.5 to 1.1 milligrams per deciliter in adult females. High levels of creatinine indicates kidney impairment.

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.

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