1. 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

2. 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

3. 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.

4. Global SYMPLICITY Registry (GSR) Current Activated Site Locations CA: 5 MEA: 39 WE: 131 C&EEU: 19 ASEAN: 19 Korea: 10 247 sites in 37 countries Enrollment to date: 2385 pts ANZ: 14 LA: 10 5000 real world patients with uncontrolled hypertension or other conditions associated with increased sympathetic activity >18 years

5. Global SYMPLICITY Registry (GSR) Clinical Trial Design 40% randomly assigned to 100% monitoring Max. 5000 patients Böhm,M, et al. Hypertension. 2015 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 NCT01534299 2037 608 Patient data available to date ✔ ✔

6. 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%)

7. 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 238.1 1 co-morbidity39.4 2 co-morbidities36.9 3+ co-morbidities23.7

8. 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

9. 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

10. Anti-hypertensive Medication Use % or mean ± SD Baseline1 Year2 YearsP Anti-hypertensive medication classes4.5 ± 1.44.4 ± 1.4 <0.0001 Beta-blockers77.475.077.1 0.04 ACE inhibitors34.231.128.9 <0.0001 Angiotensin Receptor blockers65.565.166.7 NS Calcium Channel blockers78.376.176.9 NS Diuretic79.477.177.2 NS Aldosterone antagonists23.626.425.4 <0.0001 Spironolactone20.122.120.9 0.006 Alpha-adrenergic blockers34.332.132.6 0.002 Direct-acting vasodilators13.713.414.7 NS Centrally-acting sympatholytics38.334.730.3 <0.0001 Direct renin inhibitors6.35.05.6 0.0002 P-values calculated by Friedman test to compare medication rates across time points on repeated measures of patient level data.

11. Safety Results to 2 Years % 6 Months n=1927 1 Year n=1383 2 Years n=425 Composite safety endpoint2.34.08.0 Cardiovascular events Cardiovascular death *0.30.91.2 Stroke0.81.42.6 Hospitalization for new onset heart failure0.71.22.6 Hospitalization for atrial fibrillation0.71.72.6 Hospitalization for hypertensive crisis/hypertensive emergency * 0.81.53.8 Myocardial infarction0.81.12.4 Renal events New onset end-stage renal disease *0.20.51.4 Serum creatinine elevation >50%0.51.22.8 New artery stenosis >70% *0.10.20.0 Post-procedural events Non-cardiovascular death0.10.41.4 Renal artery reintervention *0.30.40.5 Vascular complication *0.70.50.9 * Included in composite safety endpoint at 30 days

12. BP Change at 6 Months Systolic Blood Pressure Change (mm Hg) Office BP24h ABPM N = 1531 n=877 P < 0.0001 Baseline BP165/89 ± 25/16154/86 ± 18/14 n=878N = 1526

13. Office Systolic BP Change Systolic Blood Pressure Change (mm Hg) All patients with ≥ 6mo f/u n=1531 Baseline OSBP 164 ± 24 P < 0.0001 n=447 Baseline OSBP 163 ± 22 P < 0.0001 n=400 Change at 6 months Change at 1 year Change at 2 years All patients with 2yr follow-up

14. 24-h Ambulatory BP Change Systolic Blood Pressure Change (mm Hg) n=787n=171n=195 Baseline ABPM 153 ± 18 P < 0.0001 Baseline ABPM 152 ± 18 P < 0.0001 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

15. Office BP by Stratified Groups Change to 2 Years Systolic Blood Pressure Change (mm Hg) OSBP <140 (N=271) OSBP ≥180 (N=513) 206 128 ± 10 P < 0.0001 at all timepoints 216 368179 168 ± 6 P < 0.0001 at all timepoints OSBP 160-179 (N=654) OSBP 140-159 (N=541) 150 ± 6 P ≤0.005 at all timepoints 197 ± 15 P < 0.0001 at all timepoints 418529 66 384140476116345 Change at 6 months Change at 1 year Change at 2 years Baseline OSBP P-value compared to baseline BP

16. 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 19364 155 ± 17 P < 0.0001 at all timepoints OSBP 160-179 (N=654) OSBP 140-159 (N=541) 148 ± 15 P <0.005 at all timepoints 164 ± 19 P < 0.005 at all timepoints 2462692316722742162 Change at 6 months Change at 1 year Change at 2 years 12914536 Baseline ABPM P-value compared to baseline BP

17. 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 < 0.0001 n=531n=165n=51n=146 Baseline OSBP 165 ± 8 P < 0.0001 n=484 n=153 Change at 6 months Change at 1 year Change at 2 years

18. Ambulatory Systolic BP Systolic Blood Pressure Change (mm Hg) Baseline ABPM 161 ± 16 P < 0.0001 n=403n=133n=36n=116 Baseline ABPM 154 ± 8 P < 0.0001 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)

19. 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.