The safety and long-term effect of renal artery denervation on blood pressure and renal function in real world patients with uncontrolled hypertension from the Global SYMPLICITY Registry Felix Mahfoud, MD 1 M. Böhm 1, K. Narkiewicz 2, L. Ruilope 3, M. Schlaich 4, R. Schmieder 5, B. Williams 6, G. Mancia 7 on behalf of the GSR Investigators 1 Saarland University Hospital, Homburg/Saar, Germany 2 Medical University of Gdansk, Gdansk, Poland; 3 Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain; 4 Royal Perth Hospital Unit, The University of Western Australia, Perth, Australia; 5 Universität Erlangen Nürnberg, Nürnberg, Germany; 6 Institute of Cardiovascular Sciences, University College London, London, United Kingdom; 7 University of Milano Bicocca, St Gerardo Hospital, Monza, Italy

Potential conflicts of interest Speaker's name: Felix Mahfoud I have the following potential conflicts of interest to report: Research Grants Deutsche Hochdruckliga Deutsche Gesellschaft für Kardiologie Saarländisches Ministerium für Wissenschaft und Forschung Consultant/Lecture fee/Travel support: Medtronic, St. Jude, Boston Scientific, Cordis, Berlin Chemie, Boehringer Ingelheim Institutional grant/Research support: Medtronic, St. Jude, Recor, Boston Scientific

Background The Global SYMPLICITY Registry was designed to assess the procedural and long-term safety and effectiveness of the Symplicity ™ renal denervation system in a real-world patient population of – patients with uncontrolled hypertension alone or – patients with concomitant conditions also characterized by sympathetic nervous system overdrive Follow-up results of the first 2037 enrolled patients are available through 6 months, and 2-year outcomes are available for 608 enrolled patients.

Global SYMPLICITY Registry (GSR) Current Activated Site Locations CA: 5 MEA: 39 WE: 131 C&EEU: 19 ASEAN: 19 Korea: sites in 37 countries Enrollment to date: 2385 pts ANZ: 14 LA: real world patients with uncontrolled hypertension or other conditions associated with increased sympathetic activity >18 years

Global SYMPLICITY Registry (GSR) Clinical Trial Design 40% randomly assigned to 100% monitoring Max patients Böhm,M, et al. Hypertension GREAT Registry N=1000 Korea Registry N=102 South Africa Registry N=400 Canada & Mexico 1 Rest of GSR N≈3500 Prospective, open-label, single-arm, all-comer observational registry 6M3Y2Y1Y Follow-up 3M4Y5Y 1601 NCT Patient data available to date ✔ ✔

Patient Disposition Baseline (N=2037) OBP: 1979 (97%) ABPM: 1403 (69%) 6 Month Follow-up eligible (N=2037) Safety: 1983 pts (97%) OBP: 1571 pts (77%) ABPM: 1045 pts (51%) 1 Year Follow-up eligible (N=1601) Safety: 1396 pts (87%) OBP: 1444 pts (90%) ABPM: 932 pts (58%) Analysis on BP change performed on patients with matching baseline and follow-up values 2 Year Follow-up eligible (N=608) Safety: 451 pts (74%) OBP: 508 pts (84%) ABPM: 257 pts (42%)

Baseline Patient Characteristics % or mean ± SD N=2037 Male gender59.1 Age (years)61 ± 12 BMI (kg/m 2 )31 ± 6 Current smoking9.6 History of cardiac disease48.2 Chronic kidney disease (eGFR <60ml/min/1.73m 2 )21.8 Obstructive sleep apnea11.0 Sleep apnea (AHI≥5)4.1 Atrial fibrillation12.8 Diabetes, Type co-morbidity co-morbidities co-morbidities23.7

Baseline Patient Characteristics % or mean ± SD N=2037 Office BP (Systolic/Diastolic), mmHg165/89 ± 25/16 24-h BP (Systolic/Diastolic), mmHg154/86 ± 18/14 True hypertension82 Masked hypertension12 Pseudo-hypertension4

Procedural Details mean ± SDN=2037 Number of renal arteries2.1 ± 0.5 Treatment time (min)48.9 ± 20.4 Number of ablations13.3 ± 4.0 Number of 120 sec ablations11.3 ± 3.4 Contrast volume used (cc)128.2 ± 77.8

Anti-hypertensive Medication Use % or mean ± SD Baseline1 Year2 YearsP Anti-hypertensive medication classes4.5 ± ± 1.4 < Beta-blockers ACE inhibitors < Angiotensin Receptor blockers NS Calcium Channel blockers NS Diuretic NS Aldosterone antagonists < Spironolactone Alpha-adrenergic blockers Direct-acting vasodilators NS Centrally-acting sympatholytics < Direct renin inhibitors P-values calculated by Friedman test to compare medication rates across time points on repeated measures of patient level data.

Safety Results to 2 Years % 6 Months n= Year n= Years n=425 Composite safety endpoint Cardiovascular events Cardiovascular death * Stroke Hospitalization for new onset heart failure Hospitalization for atrial fibrillation Hospitalization for hypertensive crisis/hypertensive emergency * Myocardial infarction Renal events New onset end-stage renal disease * Serum creatinine elevation >50% New artery stenosis >70% * Post-procedural events Non-cardiovascular death Renal artery reintervention * Vascular complication * * Included in composite safety endpoint at 30 days

BP Change at 6 Months Systolic Blood Pressure Change (mm Hg) Office BP24h ABPM N = 1531 n=877 P < Baseline BP165/89 ± 25/16154/86 ± 18/14 n=878N = 1526

Office Systolic BP Change Systolic Blood Pressure Change (mm Hg) All patients with ≥ 6mo f/u n=1531 Baseline OSBP 164 ± 24 P < n=447 Baseline OSBP 163 ± 22 P < n=400 Change at 6 months Change at 1 year Change at 2 years All patients with 2yr follow-up

24-h Ambulatory BP Change Systolic Blood Pressure Change (mm Hg) n=787n=171n=195 Baseline ABPM 153 ± 18 P < Baseline ABPM 152 ± 18 P < n=186 All patients with ≥ 6mo f/u All patients with 2yr follow-up Change at 6 months Change at 1 year Change at 2 years

Office BP by Stratified Groups Change to 2 Years Systolic Blood Pressure Change (mm Hg) OSBP <140 (N=271) OSBP ≥180 (N=513) ± 10 P < at all timepoints ± 6 P < at all timepoints OSBP (N=654) OSBP (N=541) 150 ± 6 P ≤0.005 at all timepoints 197 ± 15 P < at all timepoints Change at 6 months Change at 1 year Change at 2 years Baseline OSBP P-value compared to baseline BP

24-h ABPM by Stratified Groups Change to 2 Years Systolic Blood Pressure Change (mm Hg) OSBP <140 (N=271) OSBP ≥180 (N=513) 144 ± 16 P <0.001 at 6M, P=0.03 at 1yr P=NS at 2yrs ± 17 P < at all timepoints OSBP (N=654) OSBP (N=541) 148 ± 15 P <0.005 at all timepoints 164 ± 19 P < at all timepoints Change at 6 months Change at 1 year Change at 2 years Baseline ABPM P-value compared to baseline BP

Office Systolic BP Systolic Blood Pressure Change (mm Hg) Severe resistant HTN OSBP ≥ 160, ABPM ≥ 135 and 3+ meds (N=681) Less severe HTN OSBP 150 – 180, ABPM 140 – 170 and DBP ≥ 90 (N=213) Baseline OSBP 181 ± 18 P < n=531n=165n=51n=146 Baseline OSBP 165 ± 8 P < n=484 n=153 Change at 6 months Change at 1 year Change at 2 years

Ambulatory Systolic BP Systolic Blood Pressure Change (mm Hg) Baseline ABPM 161 ± 16 P < n=403n=133n=36n=116 Baseline ABPM 154 ± 8 P < n=344 n=93 Change at 6 months Change at 1 year Change at 2 years Severe resistant HTN OSBP ≥ 160, ABPM ≥ 135 and 3+ meds (N=681) Less severe HTN OSBP 150 – 180, ABPM 140 – 170 and DBP ≥ 90 (N=213)

Conclusions The Global SYMPLICITY Registry is largest available real world database and has enrolled over 2300 patients to date. No long-term safety concerns have been observed following the denervation procedure. Renal denervation in a large real world population resulted in significant blood pressure reductions at 6 months that were sustained in the cohort that was followed out to 2 years post-procedure.