Renal Sympathetic Denervation for the Treatment of Difficult-to-Control or Resistant Hypertension

Hypertension represents a major health problem with an appalling annual toll. Despite the plethora of antihypertensive drugs, hypertension remains resistant in a considerable number of patients, thus creating the need for alternative strategies, including interventional approaches. Recently, catheter-based renal sympathetic denervation has been shown to be fairly safe and effective in patients with resistant hypertension. Pathophysiology of kidney function, interaction and crosstalk between the kidney and the brain, justifies the use of renal sympathetic denervation in the treatment of hypertension. Data from older studies have shown that sympathectomy has effectively lowered blood pressure and prolonged life expectancy of hypertensive patients, but at considerable cost. Renal sympathetic denervation is devoid of the adverse effects of surgical sympathectomy, due to its localized nature, is minimally invasive, and provides short procedural and recovery times. This paper outlines the pathophysiological background for renal sympathetic denervation, describes the past and the present of this interventional approach, and considers several future potential applications

Benefits from Treatment and Control of Patients with Resistant Hypertension

Resistant hypertension is commonly found in everyday clinical practice. However, the risks of resistant hypertension, as well as the benefits of treatment and control of blood pressure in patients with resistant hypertension remain vaguely clarified. Data from small clinical studies and observational cohorts suggest that patients with resistant hypertension are at increased cardiovascular risk, while control of blood pressure offers substantial benefits. It has to be noted however that data from appropriate large randomized studies are missing, and resistant hypertension remains remarkably understudied. Resistant hypertension has attracted significant scientific interest lately, as new therapeutic modalities become available. The interventional management of resistant hypertension either by carotid baroreceptor stimulation or renal sympathetic denervation is currently under investigation with promising preliminary results. This review presents available evidence regarding the benefits of treatment and control of blood pressure in patients with resistant hypertension and offers a critical evaluation of existing data in this field

Implementing the Proclamation of Stroke and Potentially Preventable Dementias

Brain health plays a central role in wellbeing and in the management of chronic diseases. Stroke and dementia pose the two greatest threats to brain health, but recent developments suggest the possibility that preventing stroke may also prevent some dementias: 1. A large population study showed a 32% decrease in the incidence of stroke and a concomitant 7% reduction in the incidence of dementia; 2. Treatment of atrial fibrillation resulted not only in stroke reduction, but a 48% decrease in dementia; 3. A hypothesis free analyses has shown that the first phase of Alzheimer disease involves vascular dysregulation, opening the door to new therapeutic approaches; 4. Cognitive impairment, often treatable and reversible, accompanies heart and kidney failure. These developments, combined with the knowledge that stroke, dementia and heart disease share the same major treatable risk factors, particularly hypertension, offers an opportunity for their joint prevention. This aspiration is expressed by a Proclamation of the World Stroke Organization on Stroke and Potentially Preventable Dementias and endorsed by the World Heart Federation, the World Hypertension League, Alzheimer Disease International and 18 other international, regional and national organizations as a call for action

Rationale and design of two randomized sham-controlled trials of catheter-based renal denervation in subjects with uncontrolled hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) and presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications: a novel approach using Bayesian design.

BACKGROUND: The SPYRAL HTN clinical trial program was initiated with two 80-patient pilot studies, SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED, which provided biological proof of principle that renal denervation has a blood pressure-lowering effect versus sham controls for subjects with uncontrolled hypertension in the absence or presence of antihypertensive medications, respectively. TRIAL DESIGN: Two multicenter, prospective, randomized, sham-controlled trials have been designed to evaluate the safety and efficacy of catheter-based renal denervation for the reduction of blood pressure in subjects with hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) or presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications. The primary efficacy endpoint is baseline-adjusted change from baseline in 24-h ambulatory systolic blood pressure. The primary safety endpoint is incidence of major adverse events at 1 month after randomization (or 6 months in cases of new renal artery stenosis). Both trials utilize a Bayesian design to allow for prespecified interim analyses to take place, and thus, the final sample sizes are dependent on whether enrollment is stopped at the first or second interim analysis. SPYRAL HTN-OFF MED Pivotal will enroll up to 300 subjects and SPYRAL HTN-ON MED Expansion will enroll up to 221 subjects. A novel Bayesian power prior approach will leverage historical information from the pilot studies, with a degree of discounting determined by the level of agreement with data from the prospectively powered studies. CONCLUSIONS: The Bayesian paradigm represents a novel and promising approach in device-based hypertension trials. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02439749 (SPYRAL HTN-OFF MED Pivotal) and NCT02439775 (SPYRAL HTN-ON MED Expansion)

Rationale and design of two randomized sham-controlled trials of catheter-based renal denervation in subjects with uncontrolled hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) and presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications: a novel approach using Bayesian design

Background The SPYRAL HTN clinical trial program was initiated with two 80-patient pilot studies, SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED, which provided biological proof of principle that renal denervation has a blood pressure-lowering effect versus sham controls for subjects with uncontrolled hypertension in the absence or presence of antihypertensive medications, respectively. Trial design Two multicenter, prospective, randomized, sham-controlled trials have been designed to evaluate the safety and efficacy of catheter-based renal denervation for the reduction of blood pressure in subjects with hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) or presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications. The primary efficacy endpoint is baseline-adjusted change from baseline in 24-h ambulatory systolic blood pressure. The primary safety endpoint is incidence of major adverse events at 1 month after randomization (or 6 months in cases of new renal artery stenosis). Both trials utilize a Bayesian design to allow for prespecified interim analyses to take place, and thus, the final sample sizes are dependent on whether enrollment is stopped at the first or second interim analysis. SPYRAL HTN-OFF MED Pivotal will enroll up to 300 subjects and SPYRAL HTN-ON MED Expansion will enroll up to 221 subjects. A novel Bayesian power prior approach will leverage historical information from the pilot studies, with a degree of discounting determined by the level of agreement with data from the prospectively powered studies. Conclusions The Bayesian paradigm represents a novel and promising approach in device-based hypertension trials. Clinical trial registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02439749 (SPYRAL HTN-OFF MED Pivotal) and NCT02439775 (SPYRAL HTN-ON MED Expansion)