Impact of Renal SympAthetic DenerVation on Chronic HypErtension (SAVE)
|First Received Date ICMJE||June 12, 2012|
|Last Updated Date||February 18, 2015|
|Start Date ICMJE||May 2012|
|Estimated Primary Completion Date||December 2015 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||change in ambulatory blood pressure [ Time Frame: baseline and 6 months ] [ Designated as safety issue: No ]
The change in blood pressure as measured by 24 hour ambulatory monitoring at 6 months as compared to from baseline.
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT01628198 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Impact of Renal SympAthetic DenerVation on Chronic HypErtension|
|Official Title ICMJE||Impact of Renal SympAthetic DenerVation on Chronic HypErtension|
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.
|Study Type ICMJE||Interventional|
|Study Phase||Not Provided|
|Study Design ICMJE||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Condition ICMJE||Uncontrolled Hypertension|
|Intervention ICMJE||Device: Celcius Thermacool Catheter or Chilli II Cooled Ablation Catheter
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
Chilli II Cooled Ablation Catheter Boston Scientific Corporation San Jose, California
|Study Arm (s)||Experimental: Renal denervation group
Celcius Thermacool Catheter or Chilli II Cooled Ablation Catheter
Intervention: Device: Celcius Thermacool Catheter or Chilli II Cooled Ablation Catheter
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE||500|
|Estimated Completion Date||December 2019|
|Estimated Primary Completion Date||December 2015 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||18 Years to 85 Years|
|Accepts Healthy Volunteers||No|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT01628198|
|Other Study ID Numbers ICMJE||GCO 12-0740|
|Has Data Monitoring Committee||Yes|
|Responsible Party||Vivek Reddy, Mount Sinai School of Medicine|
|Study Sponsor ICMJE||Vivek Reddy|
|Collaborators ICMJE||Not Provided|
|Information Provided By||Icahn School of Medicine at Mount Sinai|
|Verification Date||February 2015|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP