1. For OMA distribution only. Trademarks may be registered and are the property of their respective owners © 2015 Medtronic, Inc. All Rights Reserved. 10188475DOC_1A 3/15 Reduced Blood Pressure Lowering Effect of Catheter-Based Renal Denervation in Patients with Isolated Systolic Hypertension: Data from Pooled SYMPLICITY HTN Trials Felix Mahfoud*, George L. Bakris, Deepak L. Bhatt, Murray D Esler, David E. Kandzari, Kazuomi Kario, Henry Krum, Giuseppe Mancia, Ashok Seth, Michael A. Weber, Robert Whitbourn, Michael Boehm *Universitätskliniken des Saarlandes, Homburg/Saar, Germany

2. For OMA distribution only. Trademarks may be registered and are the property of their respective owners © 2015 Medtronic, Inc. All Rights Reserved. 10188475DOC_1A 3/15 Author Disclosures Ashok Seth, M.B.B.S., F.A.C.C.CONSULTANT FEES/HONORARIA - Abbott Vascular, Boston Scientific, Medicines Company, Medtronic, Meril life sciences. David E. Kandzari, MD, F.A.C.C.CONSULTANT FEES/HONORARIA - Boston Scientific, Medtronic, Micell Technologies, Thoratec. Deepak L. Bhatt, MD, MPH, F.A.C.C. CONSULTANT FEES/HONORARIA - Elsevier Practice Update Cardiology; RESEARCH/RESEARCH GRANTS - Amarin, Astra Zeneca, Bristol Myers Squibb, Eisai, Ethicon, FlowCo, Forest Laboratories, Ischemix, Inc, PLx Pharma, Roche, Sanofi Aventis, Takeda, The Medicines Company; OTHER - Belvoir Publications, Cardax, Clinical Cardiology, HMP communications, Journal of Invasive Cardiology, Medscape Cardiology, Regado Biosciences, Slack Publications/Cardiology Research Foundation, WebMD. Felix Mahfoud, M.D.Nothing to Disclose George L. Bakris, M.D.CONSULTANT FEES/HONORARIA - AbbVie, Vascular Dynamic, Janssen, Eli Lilly, Novartis, Takeda, DSI, Boeringher-Ingelheim, MedTronic, Relypsa, Bayer. Giuseppe Mancia, M.D.Nothing to Disclose Kazuomi Kario, M.D., Ph.D, F.A.C.C. CONSULTANT FEES/HONORARIA - Astellas Pharma Inc., AstraZeneca K.K., Bayer Yakuhin Ltd., Boehringer Ingelheim Japan Inc., Bristol-Myers K.K., Daiichi Sankyo Company, Limited., GlaxoSmithKline K.K., Kowa Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Medtronic Japan Co., Ltd., Mitsubishi Tanabe Pharma Corporation., Mochida Pharmaceutical Co., Ltd, Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Roche Diagnostics K.K., Sanofi K.K., SANWA KAGAKU KENKYUSHO CO.,LTD., Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited., Terumo corporation. Michael Boehm, MDCONSULTANT FEES/HONORARIA - Astra Zeneca, Bayer AG, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, MSD, Novartis, Pfizer, Sanofi-Aventis, Servier; RESEARCH/RESEARCH GRANTS - Astra Zeneca, Bayer AG, Boehringer Ingelheim, Novartis, Pfizer, Sanofi-Aventis, Medtronic, Servier; SPEAKER’S BUREAU - Astra Zeneca, Bayer, Boehringer Ingelheim, Berlin-Chemie, Daiichi-Sankyo, MSD, Novartis, Pfizer, Sanofi-Aventis, Servier, St Jude, Medtronic. Michael A. Weber, M.D., F.A.C.C. CONSULTANT FEES/HONORARIA - Boston Scientific, MEDTRONIC, Novartis, Recor; SPEAKER’S BUREAU - Arbor Murray D Esler, M.B.B.S., Ph.D.CONSULTANT FEES/HONORARIA - Medtronic/Ardian; RESEARCH/RESEARCH GRANTS - Medtronic/Ardian Robert WhitbournNothing to Disclose

3. For OMA distribution only. Trademarks may be registered and are the property of their respective owners © 2015 Medtronic, Inc. All Rights Reserved. 10188475DOC_1A 3/15 Abstract Background: Catheter-based renal artery denervation (RDN) has been shown to significantly lower blood pressure (BP) in certain patients with uncontrolled hypertension. Patients with isolated systolic hypertension (ISH; systolic BP [SBP] ≥140 mm Hg and diastolic BP<90 mmHg) are at higher risk for stroke and coronary events. Methods: Pooled data from denervated patients in SYMPLICITY HTN-3 and the Global SYMPLICITY Registry were used to compare baseline characteristics and SBP change at 6 months between patients with ISH and those with combined systo-diastolic hypertension (CH). Results: A total of 538 patients had ISH and 793 patients had CH. Patients with ISH were significantly older than those with CH (65 years vs 55 years), had more type 2 diabetes mellitus (52.4% vs 34.3%) and a lower estimated glomerular filtration rate (71.3 vs 78.6 ml/min/1.73m2); all p<0.001. Baseline office and 24-hour ambulatory BP was 166/78 ± 16/8 mmHg and 152/77 ± 15/10 mmHg, respectively for the ISH group and 177/104 ± 20/12 mmHg and 161/95 ± 17/12 mmHg, respectively for the CH group. Both the office and ambulatory BP changes were significantly less pronounced in ISH compared with CH, even when adjusted for differences in baseline SBP. Conclusions: Patients with ISH and CH appear to exhibit a reduction in SBP after RDN but this effect seems less pronounced in the ISH group

4. For OMA distribution only. Trademarks may be registered and are the property of their respective owners © 2015 Medtronic, Inc. All Rights Reserved. 10188475DOC_1A 3/15 Background Catheter-based renal artery denervation (RDN) has been shown to significantly lower blood pressure (BP) in certain patients with uncontrolled hypertension. However, information on the treatment effect in different types of hypertension is largely unknown. Patients with isolated systolic hypertension (ISH; systolic BP [SBP] ≥140 mm Hg and diastolic BP<90 mm Hg) are at higher risk for stroke and coronary events. A recent study comparing the effect of RDN in patients with ISH and patients with combined systo-diastolic hypertension (CH), indicated that the magnitude of office and ambulatory BP reduction was less pronounced in the patients with ISH. 1 The current analysis aims to further evaluate the BP-lowering effect of RDN in patients with ISH compared to patients with CH, using data from the SYMPLICITY HTN-3 and Global SYMPLICITY Registry (GSR) studies. 1 Ewen, S et al. Hypertension. Online ahead of print October 20, 2014. doi:10.1161/HYPERTENSIONAHA.114.04336.

5. For OMA distribution only. Trademarks may be registered and are the property of their respective owners © 2015 Medtronic, Inc. All Rights Reserved. 10188475DOC_1A 3/15 Methods For this post-hoc analysis, all patients from the SYMPLICITY HTN-3 Study were pooled with the patients from GSR who had a baseline office-based SBP ≥140 mm Hg while receiving at least 3 antihypertensive medications of different classes. Patients were stratified into 2 groups: – The ISH group included all patients with a baseline office SBP ≥140 mm Hg and office DBP <90 mm Hg. – The CH group included all patients with a baseline office SBP ≥140 mm Hg and office DBP ≥90 mm Hg. Changes in BP levels at 6 months relative to baseline by office BP and ambulatory BP measurements (ABPM) were compared between the ISH and CH groups. TrialISHCH HTN-3147318 GSR (OSBP>140 mm Hg)391475 Total538793

6. For OMA distribution only. Trademarks may be registered and are the property of their respective owners © 2015 Medtronic, Inc. All Rights Reserved. 10188475DOC_1A 3/15 Results Patient Baseline Characteristics % or mean ± SD CH N=793 ISH N=538 P-value Age, years55.38 ± 11.0365.40 ± 10.04< 0.001 Male sex62.459.50.302 BMI, kg/m 2 31.9 ± 6.630.9 ± 6.60.009 History of diabetes mellitus, type 234.352.4< 0.001 History of coronary artery disease11.313.80.173 History of obstructive sleep apnea20.313.80.003 History of stroke10.75.40.081 eGFR, ml/min/1.73m 2 78.6 ± 21.971.3 ± 22.9< 0.001 Heart Rate, bpm73.2 ± 14.165.1 ± 11.1< 0.001 Pulse Pressure74.7 ± 17.987.7 ± 17.1<0.001 Office systolic blood pressure178.8 ± 20.0165.8 ± 16.1< 0.001 Office diastolic blood pressure104.0 ± 11.678.1 ± 8.1< 0.001 24-hour systolic blood pressure160.8 ± 16.7152.5 ± 15.5< 0.001 24-hour diastolic blood pressure95.0 ± 12.177.4 ± 10.3< 0.001

7. For OMA distribution only. Trademarks may be registered and are the property of their respective owners © 2015 Medtronic, Inc. All Rights Reserved. 10188475DOC_1A 3/15 Antihypertensive Medications at Baseline % or mean ± SD CH (n=783) ISH (n=535) P-value No. of anti-hypertensive medication classes 4.62 ± 1.364.64 ± 1.19 0.80 ACE inhibitors 37.739.10.64 Angiotensin receptor blockers 61.063.90.30 Calcium channel blockers 74.576.10.52 Diuretics 86.386.70.87 Aldosterone antagonists 24.617.40.002 Alpha 2 Agonist 38.339.80.61 Direct renin inhibitors 9.15.60.02 Beta blockers 81.5 1.00 Alpha-adrenergic blocker 22.732.1< 0.001 Direct-acting vasodilators 25.220.40.046

8. For OMA distribution only. Trademarks may be registered and are the property of their respective owners © 2015 Medtronic, Inc. All Rights Reserved. 10188475DOC_1A 3/15 RDN n=225 -7.21 (-12.42, -2.01) P=0.007 Sham -2.92 (-11.83, 6.00) P=0.52 n=121 BL SBP 182175 182174 Age 5465 5266 Heart rate 73.863.6 75.363.5 P-values are unadjusted n=125n=48 Change in blood pressure (mm Hg) Office Systolic BP Change at 6 Months HTN-3

9. For OMA distribution only. Trademarks may be registered and are the property of their respective owners © 2015 Medtronic, Inc. All Rights Reserved. 10188475DOC_1A 3/15 -8.48 (-11.84, -5.13) P<0.001 BL SBP 176162 Age 5665 Heart rate 73.065.8 P-value is unadjusted Change in blood pressure (mm Hg) n=379n=304 Office Systolic BP Change at 6 Months GSR

10. For OMA distribution only. Trademarks may be registered and are the property of their respective owners © 2015 Medtronic, Inc. All Rights Reserved. 10188475DOC_1A 3/15 P<0.001 Adjusted P=0.031 n=680n=445 -8.0 [-10.6, -5.3] Office Systolic BP Change at 6 Months Pooled Dataset Change in blood pressure (mm Hg) BL SBP 176162 Age 5665 Heart rate 73.065.8

11. For OMA distribution only. Trademarks may be registered and are the property of their respective owners © 2015 Medtronic, Inc. All Rights Reserved. 10188475DOC_1A 3/15 P<0.001 Adjusted P=0.013 n=467n=293 -4.1 (-6.3, -1.7) Ambulatory Systolic BP Change at 6 Months Pooled Dataset Change in blood pressure (mm Hg)

12. For OMA distribution only. Trademarks may be registered and are the property of their respective owners © 2015 Medtronic, Inc. All Rights Reserved. 10188475DOC_1A 3/15 Conclusions Both patients with CH as well as ISH appear to exhibit a reduction in systolic BP after RDN, however this BP-lowering effect seems less pronounced in the ISH group.