1. Giuliano Tocci, MD, PhD, ESH Hypertension Specialist Centro per la Diagnosi e la Cura dell’Ipertensione Arteriosa, Cattedra di Cardiologia, Dipartimento di Medicina Clinica e Molecolare, Facoltà di Medicina e Psicologia Università di Roma Sapienza, Azienda Ospedaliera Sant’Andrea, Roma, Italia. E-mail: giuliano.tocci@uniroma1.it E-mail: centro.ipertensione@ospedalesantandrea.it

2. BP Stratification in Hypertensive Patients enrolled in Hypertension Surveys in Italy n=1.831n=3.739n=3.374n=15.904n=13.297n=2.081 N=52.715 71% 22% Volpe M, Tocci G, et al. J Hypertens 2007 Jul;25(7):1491-8

3. Resistant Hypertension Hypertension is usually defined resistant or refractory to treatment when a therapeutic plan that has included attention to lifestyle measures and the prescription of at least three drugs (including a diuretic) in adequate doses has failed to lower systolic and diastolic blood pressure to goal. According to this definition prevalence of resistant hypertension is relatively high (in ALLHAT 8% pts with 4 drugs and 15% with resistant hypertension). In such situations, referral to a specialist or a hypertension center should be considered, because resistant hypertension is recognized to be often associated with subclinical organ damage and a high or very high cardiovascular risk. 2007 ESH/ESC Hypertension Guidelines Mancia G, et al. J Hypertens 2007;25:1105–1187

4. Epidemiologia dell‘Ipertensione Arteriosa in Italia

5. Schematic Representation of the Catheter Ablation of Renal Arteries

6. The Renal Denervation Procedure 4-6 focal treatments are delivered – 120 seconds per treatment – ≥5 mm between locations – Stable, unique locations – Circumferential coverage The catheter is pulled, rotated, and new location and prior treatment site are assessed

7. The blood pressure lowering effects of renal denervation in a real world population of patients with uncontrolled hypertension: Early outcomes from the Global SYMPLICITY Registry Felix Mahfoud et al. Expert consensus document from the ESC on catheter-based RD, Eur Heart J April 2013 Michael Böhm, on behalf of the Global SYMPLICITY Registry Investigators Oral Comunication at ESC 2013 Congress

8. Purpose of the Registry To document : Long-term safety & effectiveness Real world patient population with: Hypertension and/or Other diseases characterized by elevated sympathetic drive Procedural technique Global SYMPLICITY Registry

9. Rationale Global SYMPLICITY Registry

10. LA: 6 CA: 5 MEA: 11 WE: 116 ANZ: 11 C&EEU: 10 ASEAN: 10 Korea: 10 Current Activated Site Locations Global SYMPLICITY Registry

11. Primary Objective Safety Parameters – Peri-procedural safety – Long-term safety Vascular effect Renal effect Hemodynamic effect Global SYMPLICITY Registry

12. Secondary Objectives Patient characterization Effect on blood pressure levels Effects on major cardiovascular endpoints (MACE), including death, stroke, MI, renal function, CHF. Changes in baseline antihypertensive medication Global SYMPLICITY Registry

13. Consecutive patients treated in real world population ~ 5000 patients GREAT Registry N=1000 ~ 200 sites International Min. 10% randomly assigned to 100% monitoring Korea Registry* N=102 South Africa Registry* N=400 Canada and Mexico* Rest of GSR N~3500 *: limited to resistant hypertension only Global SYMPLICITY Registry Patients’ Allocation and Follow-Up 6mo3yr2yr12mo Follow-up schedule 3mo 4yr 5yr

14. Mahfoud F et al. Expert consensus document from the ESC on catheter-based RD, Eur Heart J April 2013 Patients’ characteristics at baseline 1097 patients treated as of June 26, 2013 86% with SBP ≥140 mmHg 66% of patients treated according to ESC Consensus paper on Renal Denervation 1 – SBP ≥ 160 mm Hg (≥ 150 mmHg Diabetes II), 3+ meds, including diuretic 13% with BP ≥180/100 mmHg Co-Morbidities Include: Diabetes II 38.2% Renal Disease 30.1% Sleep Apnea 16.9% Hx of Cardiac Disease 49% Heart Failure 9.2% Atrial Fibrillation 12.6% LVH 15.9% Global SYMPLICITY Registry

15. Patients’ characteristics at baseline DemographicValue Age (years)60 ± 12 Gender (% male)60% Race (% African Dissent)1.3% BMI (kg/m 2 )31 ± 5.7 History of Renal Insufficiency (eGFR<60)21% eGFR (ml/min/1.73 m 2 ) n=106179 ± 44 -eGFR > 45 mL/min/1.73 m 2 90% Serum Creatinine (mg/dl) n=8961.02 ± 0.79 Global SYMPLICITY Registry

16. Blood Pressure levels and Antihypertensive Tx at baseline DrugsProportions Baseline BP (mm Hg)164/89 ± 24/16 Number of classes anti-HTN meds (mean)4.39 ± 1.33 Diuretic (%)76% Aldosterone blocker (%)21% ACE (%)34% ARB (%)65% Beta-Blocker (%)77% Calcium Channel Blocker (%)75% Alpha adrenergic Blocker(%)34% Vasodilator (%)14% Direct Renin Inhibitor (%)7% Global SYMPLICITY Registry

17. Presence of Comorbidities according to SBP stratification Patients (%) All (n=1162) <140 mmHg (n=150) 140-159 mmHg (n=313) 160-179 mmHg (n=370) >180 mmHg (n=264) SBP (mmHg) 164.1 ± 24.0127.4 ± 10.1150.4 ± 5.8167.6 ± 5.6196.3 ± 14.3 1 co-morbidity33.1%33.3%28.9%36.5%34.8% 2 co-morbidities36.8%34.7%39.2%36.2%35.6% 3+ co-morbidities29.9%32.0%31.5%27.0%29.5% Global SYMPLICITY Registry

18. Distribution of Patients according to 2013 ESH/ESC Global Cardiovascular Risk Stratification Other risk factors, asymptomatic organ damage or disease Blood pressure (mmHg) High normal SBP 130-139 or DBP 85-89 (n=71) Grade 1 HT SBP 140-159 or DBP 90-99 (n=292) Grade 2 HT SBP 160-179 or DBP 100-109 (n=373) Grade 3 HT SBP ≥ 180 or DBP ≥ 110 (n=295) No other RF0.0%5.6%6.7%11.4% 1-2 RF93.8%51.9%49.5%45.7% ≥ 3 RF6.3%42.6%43.8%42.9% OD, CKD stage 3 or diabetes71.8%72.9%64.9%66.4% Symptomatic CVD, CKD stage ≥ 4 or diabetes with OD/RFs 54.9%62.7%55.5%56.6% Global SYMPLICITY Registry

19. Procedural Details 98% anatomically eligible Mean length: 42 ± 14 mm Mean diameter: 5.8 ± 3.4 mm Mean Symplicity procedure time: 50 min – Mean # bilateral ablations: 13.5 Mean contrast volume used: 128 ± 80 cc Global SYMPLICITY Registry

20. Procedural Safety (safety population N=1,162) Renal artery re-intervention due to dissection0.09% (n=1) Vascular complication Vascular complication, pseudoaneurysm 0.34% (n=4) Vascular complication, hematoma0.09% (n=1) Global SYMPLICITY Registry

21. Change in Office BP levels according to baseline BP ≥ 140 ≥ 180† ≥ 160* ≥ 180† 3 months 6 months 12 months * ≥ 150 mm Hg in Diabetes † ≥ 100 mm Hg DBP n=612 n=468 n=78 n=391 n=313 n=51 n=91 n=79 n=9 -37 p < 0.001 for all values except; P = 0.001 SBP ≥ 180, 12m; p = 0.0005 DBP ≥ 180, 12m Global SYMPLICITY Registry

22. Change in 24-hour ABP levels according to baseline BP ≥ 140 ≥ 180† ≥ 160* ≥ 180† 3 months 6 months 12 months * ≥ 150 mm Hg in Diabetes † ≥ 100 mm Hg DBP n=288 n=196 n=35 n=181 n=132 n=25 n=24 n=18 ** p < 0.0001 for all time points except; p=0.0456 SBP ≥ 140 mm Hg, p=0.7611 DBP ≥ 140 mm Hg (12m); p=0.0677 SBP ≥ 160/150 mm Hg, p=0.7838 DBP ≥ 160/150 mm Hg (12m); p=0.0001 and p=0.0036 SBP ≥ 180/100 mm Hg (3m + 6m) and p=0.0007 and p=0.0017 DBP ≥ 180/100 mm Hg (3m + 6m) ** Sample size for >180/100 at 12 months too small to be shown (n=2) Global SYMPLICITY Registry

23. Renal Function Stage I Stage II Stage III Stage IV ESRD Stage V 100 eGFR ( mL/min/1.73m 2 ) Global SYMPLICITY Registry

24. Antihypertensive Medications Analysis Global SYMPLICITY Registry

25. Antihypertensive Medications Analysis Baseline (n=1108) 3 months (n=764) 6 months (n=480) 12 months (n=107) Number of anti-hypertensive medication classes 4.39 ± 1.334.27 ± 1.35*4.25 ± 1.41*4.05 ± 1.44 Diuretic (%)76% 72% Spironolactone (%)18%17%18%22% ACE (%)35%32%29%22% ARB (%)65%66%68%74% Beta-Blocker (%)78%77%76%79% Calcium Channel Blocker (%)75%76%78%79% Alpha adrenergic Blocker(%)34%32%30%24% Vasodilator (%)14%13% 12% Centrally-acting sympatholytics34%29%27%12% * Indicates a significant change from baseline Global SYMPLICITY Registry

26. Chronic Safety Data EventPatients (num)Incidence (patient/year) Major CV Events Hospitalization for hypertensive crisis61.46% Death, deemed unrelated to device or procedure51.22% Stroke61.46% MI40.97% Hospitalization for Afib61.46% Hospitalization for new onset HF51.22% Renal Events: Serum creatinine elevations40.97% New onset of end-stage renal disease10.24% (Nephrotoxic overdose) Post-Procedural Events: Renal artery re-intervention10.24% Hematoma10.24% Data on patients reaching 3 or 6 or 12 month follow up Global SYMPLICITY Registry

27. Conclusions Excellent procedural and clinical safety profile in real world Treatment resembles current consensus Significant reduction in both Office and ambulatory BP Enrolment and analyses continue Global SYMPLICITY Registry

28. Take-Home Message Il trattamento dell’ipertensione arteriosa non controllata (o resistente) richiede l’impiego di terapie di combinazione con diverse classi di farmaci. Tali terapie di combinazione dovrebbero essere: – Semplici – Razionali – A dosaggio “adeguato” (pieno) Studi clinici disponibili dimostrano come l’impiego di terapie di combinazione duplici o triplici (farmaco bloccante RAS, diuretico tiazidico e CCB diidropiridinico a dosaggio pieno) consentono di ottenere il controllo dei valori di PAS/PAD in oltre 70-80% dei pazienti trattati. Nel rimanente 20-30% l’impiego di farmaci di 4 scelta (antialdosteronici o inibitori diretti della renina) può consentire di ridurre ulteriormente i valori pressori e raggiungere il controllo dei valori pressori. Nei casi non responsivi alla terapia (o con documentate allergie o intolleranze), l’impiego della denervazione delle arterie renali rappresenta una opzione efficace, sicura e ben tollerata per ridurre i valori pressori e contribuire a raggiungere il controllo della pressione arteriosa.

29. How to improve BP control in daily clinical practice of hypertension? Volpe M, et al. G Ital Cardiol (Rome) 2012 Dec;13(12):853-60 Ipertensione Prev Cardiovasc 2013; in press High Blood Press Cardiovasc Prev 2013 March: in press

30. How to manage difficult-to-treat patients with resistant hypertension? Volpe M, et al. G Ital Cardiol (Rome) 2012 Dec;13(12):846-5 Ipertensione Prev Cardiovasc 2013; in press High Blood Press Cardiovasc Prev 2012 Dec;19(4):237-44

31. Grazie per la Vostra Attenzione! E: giuliano.tocci@uniroma1.it E: centro.ipertensione@ospedalesantandrea.it