Critical Appraisal of Devices for the Management of Hypertension Professor Atul PATHAK, MD, PhD. Head of Clinical Research Director Hypertension and Heart Failure unit Director of Hi-LAB Clinique Pasteur , Toulouse FRANCE

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company Grant/Research Support Consulting Fees/Honoraria Medtronic, CVRx, Recor, Ablative Solution, SJM

What is the most suitable patient population? Move from RH patient to uncontrolled patient. The RH population might not respond with the greatest fall in BP. Difficulty to find sufficient treatment-resistant severely HTN patients An alternative may be a trial in younger patients with mild hypertension. have greater sympathetic nervous system activation than older patients the arterial wall is more responsive to changes in sympathetic tone plea for extensive phenotyping not “just “ BP recording less treated patient Include option of patient’s preference in the study design. ( combo trial, patient with ADR, compliance issues) What if Isolated systolic HTN or renal disease (eGFR <30 ml/min/1.73 m2)? take into account device specificity (ROX rather than RDN) Ott C et al. J Am Heart Assoc. 2016 Dec 21;5(12). pii: e004234. doi: 10.1161/JAHA.116.004234.

Variability of response RDN Control ? Azizi M Optimum and Stepped Care Standardised Antihypertensive Treatment with or without Renal Denervation for Resistant Hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial, Lancet 2015; 14: 1-9.

What is the most suitable device? Preclinical evaluation Animal model, with hypertension Follow up ( long term) Per procedural testing Easy to use Standardisation of the treatment Reduced operator variability Efficacy Safe : Follow up Type of Safety Standardization : VARC type

Technical success verifiable Critical Appraisal Devices Preclinical Data (published) Strength of evidence Sham possible Technical success verifiable Reversible Specificity Potential AE Rox Coupler No RCT Yes ISH possibe Immediate BP reduction Venous stenosis RDN No ISH Anatomy Known GSR External Ultrasound Observational prospective trial Easy Ambuatory? ? Chemical RDN Case Report Yes and No Like RDN BAT CHF also Titration possible Procedure Pacemaker like Adapted from Curr Hypertens Rep (2016) 18: 61

How to measure outcome ? Efficacy ? BP Dose response ? BP related surrogate Morbidity Mortality Follow up for BP lowering effect BP lowering effect is a must. Clinical meaningful

ABPM, HBP, office BP, unattended BP ? ABPM more informative (large number of readings, variability, nocturnal BP) Strong prognostic value Detect different phenotypes and exclude pseudo resistance (white coat, stiff arteries, cuff problem in obese patient) interesting for selection Less bias and placebo effect (blind analysis) 5 mm Hg decrease in daytime SBP clinically meaningful (like in DENER HTN) ? Lack of recommandation (Standardize all device trial ? )

Critical Appraisal of Device Trials Feasible : external validity Need for control :What is the sham effect ? Sham procedure is an active treatment per se is it really the appropriate control ? Optimal procedure and material Optimize adherence: Stepped care approach, e-tools Follow up : BP, Surrogate, Imaging, Safety Alliance: Public funding, common data, health economics Use the Web to make the clinical trial faster,cheaper, and more efficient. Patient involvement Ott C et al. J Hypertens. 2016 Dec;34(12):2475-2479. Azizi M et al. Circulation. 2016 Sep 20;134(12):847-57. doi: 10.1161/CIRCULATIONAHA.116.022922.

Critical Appraisal of other devices Strength of evidence Sham Technical success verifiable Reversible Patient Specificity Potential AE Carotid Body Ablation Observational Feasibility study No Yes surgical resection High CB tone Verifiable surgical resection ? Deep Brain Stimulation Observational Non BP trial Yes ? Open loop , no titration Median Nerve Stimulation Sham Controlled RCT Inexpensive Less invasive Vagal Nerve Stimulation * Animal data and case report Not yet Heart Rate Other system. Titration *A study of selective VNS in patients undergoing carotid endarterectomy and coronary artery bypass grafting, with four patients enrolled, has been completed, but the results have not yet been published (clinicaltrials.gov: NCT00983632). Adapted from Curr Hypertens Rep (2016) 18: 61

Conclusion Expand Patient Phenotype (autonomic, psychological, physiology, brain –mind connexion) Standardize Device Evaluation (efficacy, safety) Improve Strength of Evidence (preclinical and clinical)