1. Renal artery denervation for treatment of patients with obstructive sleep apnea and resistant hypertension: Results from the Global SYMPLICITY Registry Dominik Linz, MD 1 G. Mancia 2, F. Mahfoud 1, K. Narkiewicz 3, L. Ruilope 4, M. Schlaich 5, R. Schmieder 6, B. Williams 7, Böhm 1 on behalf of the GSR Investigators 1 Saarland University Hospital, Homburg/Saar, Germany; 2 University of Milano Bicocca, St Gerardo Hospital, Monza, Italy; 3 Medical University of Gdansk, Gdansk, Poland; 4 Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain; 5 Royal Perth Hospital Unit, The University of Western Australia, Perth, Australia; 6 Universität Erlangen Nürnberg, Nürnberg, Germany; 7 Institute of Cardiovascular Sciences, University College London, London, United Kingdom.

2. Potential conflicts of interest Speaker's name: Dominik Linz I have the following potential conflicts of interest to report: Research Grants Deutsche Gesellschaft für Kardiologie, Else Kröner Fresenius Stiftung, Deutsche Hochdruckliga Institutional grant/Research support: Medtronic, St. Jude, Recor, Boston Scientific

3. Abstract (for reference only) AIMS The Global SYMPLICITY Registry has prospectively enrolled over 2000 patients with uncontrolled hypertension and with a high proportion of multiple comorbidities from around the world including obstructive sleep apnea, which, like hypertension, is associated with increased sympathetic tone. This analysis of patients with and without obstructive sleep apnea aimed to determine if there is a difference in the blood pressure lowering effect of renal denervation based on the presence of obstructive sleep apnea. METHODS AND RESULTS Patients have been enrolled at the discretion of their treating physician according to local guidelines and treated per the Symplicity™ renal denervation system Instructions for Use. Office and 24hour ambulatory blood pressure was collected for all patients and analyzed for those with and without obstructive sleep apnea. In 998 patients the mean age was 61±12years, 60% were male and mean body mass index was 31 ± 6 kg/m. A history of obstructive sleep apnea was reported in 116 patients who were more likely to be male than the 752 patients without obstructive sleep (83% vs 56%, p<0.0001), had a larger body mass index (34 ± 6 kg/m vs 30 ± 5 kg/m, p<0.0001) more atrial fibrillation (19% vs 11%, p=0.020), more left ventricular hypertrophy (25% vs 15%, p=0.008) and more diabetes (52% vs 39%, p=0.008). Additionally, obstructive sleep apnea patients were taking more antihypertensive medications (4.9 ± 1.4 vs 4.4 ± 1.3, p<0.001) including a higher proportion of aldosterone antagonists (39% vs 20%, p<0.0001), alpha 2 agonists (54% vs 36%, p<0.001) and vasodilators (24% vs 13%, p=0.001). Overall baseline office blood pressure was 164/89 ± 24/17 mm Hg and baseline 24hour blood pressure was 152/85 ±17/13 mm Hg. At 6 months, office systolic blood pressure reduction was 11.6 ± 25.3 mm Hg (p<0.001) and was 6.6 ±18.0 mm Hg (p<0.001) for 24hr systolic blood pressure change. Among obstructive sleep patients the baseline office systolic blood pressure was 166 ± 23 mm Hg which was reduced by 15.5 ± 24.4 mm Hg at 6 month (p<0.0001). Ambulatory 24hr systolic blood pressure was reduced by 4.6 ± 17.1 mm Hg (n=73, p=0.024) from 156 ± 20 mm Hg at baseline. The 6 month change from baseline was not statistically different at 6 months between obstructive sleep apnea and no obstructive sleep apnea patients. CONCLUSIONS Renal artery denervation resulted in significant blood pressure reductions at 6 months in patients with and without obstructive sleep apnea. The absence of a difference in BP change between obstructive sleep apnea and nonobstructive sleep apnea patients is surprising and it will be of interest to determine if this result is confirmed in the larger cohort of 2100 patients that will be available for presentation in May. Confirmation of a significant blood pressure reduction may be particularly important for obstructive sleep apnea patients who have a much higher proportion of comorbidities that put them at greater risk for cardiovascular events.

4. 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 including obstructive sleep apnea (OSA). OSA is associated with sympathovagal disbalance, atrial fibrillation (AF), and postapneic blood pressure (BP) rises. 1,2 Preclinical research indicated that renal denervation (RDN) suppressed postapneic BP rises and AF in a model for sleep apnea, 3 however further clinical evidence is lacking. The current analysis of patients with and without OSA aimed to determine if there is a difference in the blood pressure lowering effect of renal denervation based on the presence of OSA. 1 Kohler M, Stradling JR. Nat Rev Cardiol. 2010;7:677–685 2 Kasai T, Bradley TD. J Am Coll Cardiol. 2011;57:119–127 3 Linz D, et al. Hypertension. 2012;60:172-178

5. Global SYMPLICITY Registry (GSR) Clinical Trial Design Primary objective: assess procedural and long-term safety of RDN in a real world population Min. 10% randomly assigned to 100% monitoring GSR inclusion criteria: any candidate for renal denervation by the Symplicity™ catheter GSR exclusion criteria: none Max. 5000 consecutive “real-world” patients treated with Symplicity™ renal denervation system for uncontrolled hypertension and/or conditions associated with sympathetic nervous system activation 1 Limited to resistant hypertension only Böhm,M, et al. Hypertension. 2015; online ahead of print. doi: 10.1161/HYPERTENSIONAHA.114.05010 GREAT Registry N=1000 Korea Registry 1 N=102 South Africa Registry 1 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 2037608 Patient data available to date:

6. Methods We report blood pressure results and changes for patients enrolled to date with 6-month data available. 205 Patients with history of OSA as reported by the study sites were identified from the broader GSR cohort. All other patients were grouped into the non-OSA cohort. The method of OSA diagnosis was performed per standard of care. Repeat OSA assessment during follow-up was not mandated by the study protocol and left at physician discretion. Furthermore, we evaluated outcomes specifically for the 57.6% of OSA patients who were currently treated with CPAP or BiPAP-therapy.

7. Baseline Patient Characteristics I % or mean ± SD Non-OSA (n=1663) OSA (n=205) P Male gender56.875.6<0.001 Age (years)61 ± 1262 ± 100.69 BMI (kg/m 2 )30 ± 534 ± 6<0.001 Current smoking9.49.80.86 Diabetes, Type 236.150.2<0.001 Chronic kidney disease (eGFR <60ml/min/1.73m 2 ) 21.130.20.003 Heart rate70 ± 13 0.57 History of cardiac disease46.953.90.06 Atrial fibrillation11.819.10.003 Heart Failure9.113.20.06 Left ventricular hypertrophy15.225.0<0.001

8. Baseline Patient Characteristics II % or mean ± SD Non-OSA (n=1663) OSA (n=205) P Comorbidities : 142.518.0 <0.001 Comorbidities : 236.040.0 0.26 Comorbidities : 3+21.542.0 <0.001 Office Systolic BP (mm Hg)165.1 ± 24.0166.1 ± 26.0 0.50 Office Diastolic BP (mm Hg)89.5 ± 16.489.5 ± 18.0 0.85 24-h Systolic BP (mm Hg) 153.3 ± 17.9 155.5 ± 18.90.11 24-h Diastolic BP (mm Hg)86.0 ± 13.988.2 ± 14.0 0.03

9. Procedural Details mean ± SD Non-OSA (n=1663) OSA (n=205) P Number of renal arteries2.1 ± 0.52.2 ± 0.50.01 Renal artery length (mm)40.6 ± 14.244.0 ± 15.50.01 Renal artery diameter (mm): right 5.7 ± 2.75.7 ± 1.20.48 Renal artery diameter (mm): left 5.7 ± 2.55.7 ± 1.30.44 Number of ablations13.1 ± 3.914.0 ± 3.7<0.001 Number of 120 sec ablations11.1 ± 3.412.1 ± 3.4<0.001

10. Anti-hypertensive Medication Use Baseline % or mean ± SD Non-OSA (n=1641) OSA (n=202) P Anti-hypertensive medication classes4.5 ± 1.34.9 ± 1.4<0.001 Beta-blockers77.974.80.31 ACE inhibitors32.737.60.16 Angiotensin receptor blockers66.166.30.95 Calcium channel blockers78.277.70.88 Diuretic79.581.20.58 Aldosterone antagonists22.034.2<0.001 Spironolactone18.830.7<0.001 Alpha-adrenergic blockers33.742.10.02 Direct-acting vasodilators13.121.30.002 Centrally-acting sympatholytics37.047.00.006 Direct renin inhibitors6.010.40.02

11. All GSR Patients Systolic BP Change at 6 Months Systolic Blood Pressure Change (mm Hg) Office BP24h ABPM N = 1531N = 787 -12.3 P < 0.0001 -6.6 P < 0.0001 Baseline BP164.2 ± 24.3153.3 ± 17.6

12. Office Systolic BP at 6 Months Office SBP (mm Hg) Non-OSAOSA Baseline6MBaseline6M n = 1617n = 1268n = 201n = 175 165.1 ± 24.4 151.8 ± 22.2 166.1 ± 26.0 151.2 ± 22.3 Δ -12.4 P < 0.001 Δ -14.0 P < 0.001 P = 0.46

13. 24-h Ambulatory BP at 6 Months Non-OSAOSA Baseline6MBaseline6M n = 1120n = 815n = 167n = 130 155.5 ± 18.9 144.0 ± 17.4 153.3 ± 17.9 147.4 ± 19.2 Δ -7.3 P < 0.001 Δ -4.9 P = 0.005 P = 0.63 ABPM (mm Hg)

14. OSA Treatment BP Change at 6 Months Systolic Blood Pressure Change (mm Hg) Non-OSA OSA without CPAP n=1235n=102 Baseline OSBP165 ± 24168 ± 29165 ± 24 n=70n=45n=69n=673 OSA with CPAP P-value for OSBP across groups: 0.11 P-value for ABPM across groups: 0.36

15. Conclusions In this analysis from the Global SYMPLICITY Registry, OSA patients had significantly more comorbidities compared to patients without history of OSA. Confirmation of a significant BP reduction may be particularly important for OSA patients who are at greater risk for cardiovascular events. Renal artery denervation resulted in significant blood pressure reductions at 6 months in patients with and without OSA. Furthermore, CPAP/BiPAP treatment of OSA did not seem to have an impact on BP reduction in this population. The absence of a difference in BP change between OSA and non-OSA patients is surprising. Further studies are needed to evaluate the effect of RDN on OSA, and should further investigate any impact on OSA severity.