CRT 2014 Washington DC, Feb 22-25, 2014 Renal Denervation with a Percutaneous Bipolar Radiofrequency Balloon Catheter in Patients with Resistant Hypertension: 6-Month Efficacy and Safety Results from the REDUCE-HTN Trial 13.53-14.01 Horst Sievert On behalf of the REDUCE-HTN Investigators CardioVascular Center Frankfurt CVC Frankfurt, Germany

Horst Sievert, MD Consulting: AccessClosure, Inc., AGA Medical Corporation, Ardian, Inc., Arstasis, Inc., Atritech Atrium Medical Corporation, Avinger, Inc., Bard Peripheral Vascular, Inc., Boston Scientific Corporation, Bridgepoint, CardioKinetix Inc., CardioMEMS, Inc., Coherex, Inc., Contego, CSI, EndoCross, Endotex Interventional Systems, Epitek, Evalve, Inc., ev3, Inc.

Horst Sievert, MD Consulting: FlowCardia, Inc., Gore, Guidant, Lumen Biomedical, Inc., HLT, Kensey Nash Corporation, Kyoto Medical, Lifetech, Lutonix, Inc., Medinol, Medtronic, Inc., NDCNMT Medical, Inc., OAS, Occlutech Osprey Medical, Inc., Ovalis, Inc., Pathway Medical Technologies, Inc., PendraCare International B.V., Pfm Medical, Inc., Rox Medical, Recor, Sadra Medical, Sorin Biomedica Cardio S.R.L.,and Spectranetics Corporation, Trireme, Trivascular, Viacor, Inc.

Horst Sievert, MD Honoraria: Viacor, Inc., HLT, Lifetech, Recor, Trivascular, Veryan, CVRx, GDS, InSeal Medical.

Renal Denervation for Resistant Hypertension More than 25% of adults have hypertension1-4 Between 5%-30% of these patients have elevated blood pressure despite aggressive medical treatment5,6 It has been shown that renal denervation reduces blood pressure in patients with resistant hypertension5 Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. Jul 2013;31(7):1281-1357. Persell SD. Prevalence of resistant hypertension in the United States, 2003-2008. Hypertension. Jun 2011;57(6):1076-1080. Kearney et al. Lancet 2005;365:217-23 Lloyd-Jones et al. Circulation 2010;121:e46–e215 Wolf-Meier et al. JAMA 2003;289:2363–2369 Sekikawa and Hayakawa. J Hum Hypertens 2004;18:911-912 Mancia et al. J Hypertens 2013;31(7):1281-1357 Persell. Hypertension 2011;57(6):1076-1080

Vessix Renal Denervation System Balloon-based technology 4 - 7 mm diameters Bipolar radiofrequency electrodes 30 second treatment time All electrodes are activated simultaneously Bipolar energy delivery, ~1 Watt Temperature-controlled algorithm ensures energy delivery at 68°C One button operation Approved in Europe (CE mark) and Australia

REDUCE-HTN Clinical Sites Institution Principal Investigator Parcelsus Medical University Prof. Dr. Uta C. Hoppe Allgemein Affentliches Krankenhaus der Stad Linz Prof. Dr. Clemens Steinwender Onze-Lieve-Vrouwziekenhuis, (OLVZ) Dr. Eric Wyffels Monash Heart Southern Health Prof. Dr. Ian Meredith CardioVasculares Centrum (CVC) Frankfurt Prof. Dr. med Horst Sievert George Pompidou Hospital Prof. Dr. Michel Azizi The Prince Charles Hospital Associate Prof. Darren Walters Cardiology Center Geneva university Hospitals Dr. Georg Ehret Auckland City Hospital Dr. Mark Webster Flinders Medical Centre Dr. Ajay Sinhal Erasmus Medical Center Dr. Joost Daemen Vascular Center Berlin Dr. Ralf Langhoff Main Tanus Kliniken Prof. Dr. med. Nicolaus Reifart St. Vincent's Dr. David Muller Zentrum für Gefäßmedizin Prof. Dierk Scheinert Academic Medical Center Prof. Robbert-Jan de Winter Cliniques Universitaires Saint Luc Prof. dr. Alexandre Persu Clinique Pasteur Prof. Jean Fajadet German Heart Centre Prof. Dr. med. Ilka Ott Universitäres Herz- und Gefäßzentrum Hamburg Prof. Dr. med. Joachim Schofer Zentralklinik Bad Berka GmbH Dr. med. Ahmed Farah Royal Adelaide Hospital Prof. Steven Worthley Mercy Angiography - Auckland Dr. John Ormiston

REDUCE-HTN FIM + PMS Key Inclusion Criteria PMS (N=128) FIM (N=18) REDUCE-HTN FIM + PMS (N=146) Office-based blood pressure (average of 3 readings): First in Man (FIM): SBP ≥ 160 mmHg Post-Market Study (PMS): SBP/DBP ≥ 160/90 mmHg ≥ 3 antihypertensive drugs at maximally tolerated doses with stable regimen for at least 2 weeks prior to enrollment Renal artery length: FIM: ≥ 20 mm PMS: ≥ 15 mm Renal artery without significant stenosis (i.e., baseline diameter stenosis <30%) Main renal artery diameter of ≥ 3.5 mm and ≤ 7.0 mm for each kidney: FIM: Single renal artery PMS: Subjects with accessory renal arteries were enrolled

REDUCE-HTN FIM + PMS Study Endpoints Efficacy Reduction of office-based blood pressures at 6 months Reduction of 24-hour ambulatory blood pressure at 6 months Safety Endpoints Acute Safety Renal artery dissection or perforation during the procedure that requires stenting or surgery Renal artery infarction or embolus Periprocedural cerebrovascular accident Periprocedural myocardial infarction Periprocedural sudden cardiac death Long-term Safety Renal stenosis requiring an intervention, documented by angiography Duplex ultrasound required at 6 months to assess absence of flow limiting stenosis in the renal artery (core lab analysis) Renal function (eGFR) Primary endpoint analysis includes 142 patients who have completed 6 months of follow-up (97% of enrolled patients)

Baseline Demographic and Clinical Characteristics Demographic Characteristics Age (years) 58.6±10.5 Gender (male) 61.0% Ethnic origin (white) 92.5% Comorbidities Type 2 diabetes 28.1% Coronary artery disease 37.7% Dyslipidemia 58.2% Congestive heart failure 2.1% Blood Pressure Systolic blood pressure (mmHg) 182.4±18.4 Diastolic blood pressure (mmHg) 100.2±14.0 Kidney Function eGFR (mL/min/1.73 m2) 83.9±24.1 Serum creatinine (μmol/L) 82.1±19.8 eGFR=estimated glomerular filtration rate

Baseline Antihypertensive Medications Number of antihypertensive medications per patient 5.3±1.9 ≥5 Medications 61.6% 4 Medications 21.9% 3 Medications 13.0% Percentage of Patients Receiving: ACE Inhibitors or ARBs 93.2% β Blockers 78.1% Diuretics 76.7% Calcium Channel Blockers 75.3% Centrally Acting Sympatholytic 39.7% α-1 Blockers 34.2% Aldosterone Antagonist 29.5% Nitrate and Other Vasodilators 15.1% Direct Renin Inhibitors 11.0% Other Antihypertensive 2.7% ACE=angiotensin-converting enzyme; ARB=angiotensin-receptor blocker

Significant Office Blood Pressure Reductions Over Time Mean reduction in office-based BP was 24.7/10.3 mmHg at 6 months (P<.0001) P<.0001 for each timepoint vs baseline. Error bars represent 95% confidence bounds. BP=blood pressure

Blood Pressure Response 85% of patients had a clinically meaningful response to treatment1 based on office systolic BP at 6 months Whelton PK, He J, Appel LJ, et al. Primary prevention of hypertension: clinical and public health advisory from the National High Blood Pressure Education Program. JAMA. 2002; 288: 1882–1888. BP=blood pressure Whelton et al. JAMA 2002;288:1882-8 (National High Blood Pressure Education Program).

Target Office Pressure Achievement Office-based systolic BP <140 mmHg was reached by 18% of patients at 6 months BP=blood pressure

Significant Reductions in 24-hour Ambulatory Blood Pressures Baseline mean 24-hour ambulatory blood pressure was 153/88 mmHg (n=103) Mean reduction at 6 months was 8.4/5.9 mmHg (P<.0001; n=69) P<.0001 vs baseline. Error bars represent 95% confidence bounds. ABP=ambulatory blood pressure

Target Ambulatory Blood Pressure Achievement Ambulatory systolic BP <140 mmHg was reached by 34% of patients at 6 months BP=blood pressure

24-hour Ambulatory Blood Pressure Reductions 85% of patients who had ambulatory BP measurements (88/103) had ambulatory systolic BP >140 mmHg at baseline The reduction in ambulatory systolic BP at 6 months was greatest for patients with higher baseline pressure Change in Ambulatory Systolic BP at 6 Months Error bars represent 95% confidence bounds. BP=blood pressure

Significant Office Blood Pressure Reductions for Patients with Accessory Renal Arteries (n=24) P<.0005 for each timepoint vs baseline. Error bars represent 95% confidence bounds. BP=blood pressure

Significant Office Blood Pressure Reductions for Men (n=89) and Women (n=57) P<.0001 for each timepoint vs baseline (within subgroup). Error bars represent 95% confidence bounds.

Diabetes Subgroup (n=34) Significant Office Blood Pressure Reduction for Diabetes and Age ≥65 Subgroups Diabetes Subgroup (n=34) Age ≥65 Years (n=43) P<.0001 for each timepoint vs baseline P<.0001 for each timepoint vs baseline Change in Office Systolic BP Change in Office Diastolic BP Error bars represent 95% confidence bounds. BP=blood pressure

Renal Function Mean eGFR changed -0.9±16.4 mL/min/1.73 m2 at 6 months At 6 months, 10.9% (15/138) of patients had a reduction in eGFR >25% from baseline Only 2 of these patients had kidney-related adverse events, and neither of them were determined to be related to the procedure by the Data Safety Monitoring Board: Renal insufficiency at 3 months Acute renal failure at 6 months eGFR=estimated glomerular filtration rate

No Acute Safety Events and Low Rate of Procedure-Related SAEs No patient experienced prespecified acute safety events Low rate of procedure-related serious adverse eventsa (5.5%) among the 146 patients Hematoma (1) Bilateral flank pain (1) Vomiting (1) Access site infection (2) Pseudoaneurysm at access site (1) Femoral artery thrombus (1) Renal artery stenosis requiring treatment (1) Baseline stenosis was 17% based on core lab assessment of angiogram; stenosis of 60% noted by angiography at 6 month follow-up; patient received percutaneous transluminal angioplasty/stent and continues to be monitored. 6-month patencyb 99.2% by DUS (248/250 arteries) aSerious adverse events (SAEs) defined according to International Organization for Standardization ISO14155. bPatency defined as stenosis <60%. DUS=duplex ultrasound

Conclusions The Vessix System is a safe and effective method for the treatment of resistant hypertension Significant office blood pressure reductions through 6 months Significant reductions for patients with accessory renal arteries Significant reductions for patients ≥65 years of age, those with diabetes, and both sexes 85% of patients had an office systolic BP reduction of at least 5 mmHg at 6 months Ambulatory systolic BP was below 140 mmHg at 6 months in 34% of the patients

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