Update on therapy-resistant hypertension: Novel pharmacotherapy or renal denervation? Prof. Luis Ruilope Hospital 12 de Octubre Madrid, Spain

Incidence of RH in new hypertensives In new hypertensives, 2% present with RH after 18 months of pharmacological therapy Development of RH is followed by a 50% increase in risk of suffering CV events or death It takes place after similar duration of arterial hypertension. There must be a factor accelerating CV and probably renal damage in RH. Daugherty et al, Circulation 2012 Pimenta & Calhoun, Circulation 2012

Frequency of Resistant Hypertension in Treated Hypertensives: Spain True resistant hypertension (7.6% of total treated population) White-coat hypertension (4.6% of total treated population) KEY POINTS ADDITIONAL INFORMATION This study estimated the prevalence of resistant hypertension through both office and ambulatory blood pressure monitoring in a large cohort of treated hypertensive patients from the Spanish Ambulatory Blood Pressure Monitoring Registry The study also compared clinical features of patients with true or white-coat–resistant hypertension [Sierra 2011, p 898/abs] In 2009, the authors identified 68,045 treated patients with complete information for this analysis Among these patients, 8295 (12.2% of the database) had resistant hypertension (office blood pressure ≥140 and/or 90 mm Hg while being treated with ≥3 antihypertensive drugs, 1 of them being a diuretic) After ambulatory blood pressure monitoring, 62.5% of patients were classified as true resistant hypertensives, the remaining 37.5% having white-coat resistance REFERENCE de la Sierra A, Segura J, Banegas JR, et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension. 2011;57:898-902. Resistant Hypertension (12.2% of total treated population) Treated Patients With Hypertension de la Sierra A et al. Hypertension. 2011;57:898-902.

FACILITATORS OF BP UNRESPONSIVENESS TO STANDARD THERAPY Clinical inertia Poor compliance Inadequate diet (salt) Inadequate and late use of combinations Primary aldosteronism (10-12%) Inadequate control of SNS activity BP variability OSA Diabetes and obesity CKD Progression of arterial disease due to an inadequate BP control Solini a & Ruilope LM. Nat Rev Cardiol 2013

Diagnostic and Treatment Algorithm of RH Exclude Pseudoresistance Pharmacologic approach: # adherence Identify and Reverse Contributing Lifestyle Factors Discontinue or Minimize Interfering Substances Screen for Secondary Causes of HT Schmieder 2012 6

RESULTS ADEQUATE INTERVENTION IN RH N=197 RH patients with SBP > 160 mmHg ABPM normal in 108 (pseudoresistant) Spironolactone administered to 75 good response in 60 (80%) Remaining 29 (14 intolerant to spiro), 18 responded to other combinations 11 (12.3%) were denervated Fontela A et al, Rev Esp Cardiol 2012

Primary Endpoint: Change from Baseline to Week 6 in 24-Hour Mean SBP by ABPM Azilsartan Medoxomil in Combination with Amlodipine Placebo + AML 5 mg -4 AZL-M 40 mg + AML 5 mg AZL-M 80 mg + AML 5 mg -8 aP<0.001 vs placebo + AML 5 mg -12 Change from Baseline (mm Hg) -16 -13.6 TAK-491-010 poster for ASH Figure 2A. Change from Baseline to Week 6 in 24-Hour Mean SBP by ABPM (LS Mean±SE) Change in SBP and DBP by ABPM • For the primary efficacy endpoint, the combined regimens of AZL-M + AML lowered 24-hour mean SBP by ABPM significantly more than placebo + AML (Figure 2A). • Treatment differences compared with placebo + AML 5 mg were as follows: – For AZL-M 40 mg + AML 5 mg, -11.2 mm Hg (95% CI -13.3, -9.1) – For AZL-M 80 mg + AML 5 mg, -10.9 mm Hg (95% CI -13.0, -8.8) Source: Final CSR, 01-05-TL-491-010 Clinical Study Report Body.pdf, dated 15-Feb-2010, Table 11.a, Change from Baseline to Week 6 in 24-Hour Mean SBP (mm Hg) by ABPM (FAS), page 68 of 121. Data are the least-squares mean ± SE. For placebo + AML 5 mg, AZL-M 40 mg + AML 5 mg, and AZL-M 80 mg + AML 5 mg, respectively, standard error (SE) = 0.8, 0.8, 0.8. -20 -24 -24.8a -24.5a -28 Weber et al. Antihypertensive Efficacy of the New Angiotensin Receptor Blocker Azilsartan Medoxomil in Combination with Amlodipine. Poster session presented at: American Society of Hypertension Annual Scientific Meeting and Exposition; 2010 May 1-4; NYC,NY January 26, 2009

Change in SBP by ABPM CLD vs. HCTZ on background of AZL-M Change in Mean 24-Hour SBP (mmHg) by ABPM -25.7a -19.9 -26.6a -22.4 -30 -20 -10 Week 6 Week 10 AZL-M–CLD AZL-M + HCTZ a P<0.001 Baseline 146.5± 0.89 145.4± 0.88 Axis – mmHg by ABPM Source: Final TLGs dated 29-Mar-2010, Table 15.2.3.1.2 Analysis of ABPM SBP Measurements (mm Hg) by Study Visit, LOCF, FAS, pages 1, 4, and 6 of 11. For the primary efficacy endpoint of trough sitting clinic SBP, N=295 for AZL-M--CLD and N=292 for AZL-M + HCTZ at baseline, week 6, and week 10. (Source: Final TLGs dated 29-Mar-2010, Table 15.2.1.1.2 Analysis of Trough Sitting Clinic SBP (mm Hg) by Study Visit, LOCF, FAS, pages 1, 4, and 6 of 6.)   (FYI: For the study overall, subjects randomized were N=303 for AZL-M--CLD and N=306 for AZL-M + HCTZ, but 1 and 3 subjects, respectively, were randomized but not treated. Therefore, total randomized and treated were N=302 for AZL-M--CLD and N=303 for AZL-M + HCTZ; however, not all of these subjects had the required baseline value and post baseline value. Therefore, final analyzed were N=295 and N=292.) Data are least-squares mean ± SE. Bakris et al. Results of a double-blind randomized study comparing CLD and HCTZ combined with the new ARB Azilsartan Medoxomil in primary HTN. Late breaking Clinical Trial session presented at:: American Society of Hypertension Annual Scientific Meeting and Exposition; 2010 May 1-4; NYC,NY January 26, 2009 9

Patients should be evaluated by a hypertension specialist. Schmieder RE, Redon J, Grassi G, Kjeldsen SE, Mancia G, Narkiewicz, Parati G, Ruilope L, van der Borne P, Tsioufis C. ESH POSITION PAPER: RENAL DENERVATION-AN INTERVENTIONAL THERAPY OF RESISTANT HYPERTENSION. J HYPERTENS (IN PRESS) Hypertensive patients are elegible for RDN if they have treatment resistant hypertension defined by office SBP >= 160 mmHg (150 mm Hg if type 2 diabetes) despite treatment with 3 or more drugs og different types in adequate doses, including one diuretic, which is equivalent to stage 2 or 3 hypertension. Patients should be evaluated by a hypertension specialist.

SYMPLICITY RDN Global Clinical Program Enrollment Complete / In Follow Up Series of non-randomized pilot studies (n =153) Symplicity HTN-1 3 yr Symplicity HTN-2 1:1 Randomization Symplicity Catheter System vs control (n = 106) >1 yr 2 yr Randomized Controlled Trial (2:1), (530 randomized) Enroll completed SYMPLICITY HTN-3 Planning / Enrolling SYMPLICITY-HF Feasibility Study, 40 subjects Enroll Global SYMPLICITY Registry Prospective, non-interventional Registry, ~5,000 subjects Enroll Randomized Controlled Trial (1:1) n=100 SYMPLICITY HTN-Japan Enroll Randomized Controlled Trial SYMPLICITY HTN-4 Plan Symplicity HTN-India Single-arm, Controlled Trial Plan 11

BP reduction sustains over 3 years for all changes compared to baseline BP changes (mmHg) Krum H, ACC 2013

Symplicity HTN-2 – cross over 6m Primary Endpoint Control Crossover† Randomization 6m post procedure 12m post procedure 18m post procedure 24m post procedure mm Hg 6m post randomization 12m post randomization 18m post randomization 24m post randomization 30m post randomization Esler M, ASH 2013

Predictors of response Mahfoud F et al, Circulation in press

SBP DBP All patients (n=346) -10 -20 BP changes (mm Hg) -30 -40 3M -8.9 -9.5 -10 -11.7 p<0.0001 p<0.0001 p<0.0001 -20 -21.5 BP changes (mm Hg) -23.7 p<0.0001 -27.3 p<0.0001 -30 p<0.0001 ANOVA SBP p<0.0001 ANOVA DBP p<0.0001 -40 3M (n=245) 6M (n=236) 12M (n=90) SBP DBP

SBP DBP True resistant hypertension (n=303) All patients (n=346) -10 -8.9 -9.5 -9.1 -9.4 -10 -11.7 -11.6 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 -20 -21.5 -21.5 BP changes (mm Hg) -23.7 -23.8 p<0.0001 -27.3 p<0.0001 -26.8 p<0.0001 p<0.0001 -30 p<0.0001 p<0.0001 ANOVA SBP p<0.0001 ANOVA DBP p<0.0001 ANOVA SBP p<0.0001 ANOVA DBP p<0.0001 -40 3M (n=245) 6M (n=236) 12M (n=90) 3M (n=213) 6M (n=206) 12M (n=80) SBP DBP

SBP DBP True resistant hypertension (n=303) Pseudo-resistant All patients (n=346) -8.9 -7.8 -9.5 -9.1 -9.4 -10.2 -10 -11.7 -11.6 -12.3 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.0001 -20 -21.5 -21.5 -21.3 p<0.0001 -23.7 -23.8 -22.8 BP changes (mm Hg) p<0.0001 -27.3 p<0.0001 -26.8 p<0.0001 p<0.0001 p<0.0001 p<0.0001 -30.9 -30 p<0.0001 p<0.0001 ANOVA SBP p<0.0001 ANOVA DBP p<0.0001 ANOVA SBP p<0.0001 ANOVA DBP p<0.0001 ANOVA SBP p<0.0001 ANOVA DBP p=0.013 -40 p<0.0001 3M (n=245) 6M (n=236) 12M (n=90) 3M (n=213) 6M (n=206) 12M (n=80) 3M (n=32) 6M (n=30) 12M (n=11) SBP DBP

ABP changes SBP DBP Mahfoud F et al, Circulation in press All patients (n=346) 10 5 BP changes (mm Hg) -4.2 -4.3 -5 -6.6 -8.4 p<0.0001 p<0.0001 -8.7 -9.9 p<0.0001 -10 p<0.0001 p<0.0001 p<0.0001 -15 ANOVA SBP p<0.0001 ANOVA DBP p<0.0001 3M (n=245) 6M (n=236) 12M (n=90) SBP DBP Mahfoud F et al, Circulation in press

ABP changes SBP DBP Mahfoud F et al, Circulation in press True resistant hypertension (n=303) All patients (n=346) 10 5 ANOVA SBP p<0.0001 ANOVA DBP p<0.0001 BP changes (mm Hg) -4.2 -4.3 -4.8 -4.9 -5 -6.6 -7.4 -8.4 p<0.0001 p<0.0001 -8.7 p<0.0001 p<0.0001 -9.9 p<0.0001 -10.1 -10.2 -10 p<0.0001 p<0.0001 -11.7 p<0.0001 p<0.0001 p<0.0001 p<0.0001 -15 ANOVA SBP p<0.0001 ANOVA DBP p<0.0001 p<0.0001 3M (n=245) 6M (n=236) 12M (n=90) 3M (n=213) 6M (n=206) 12M (n=80) SBP DBP Mahfoud F et al, Circulation in press

ABP changes SBP DBP Mahfoud F et al, Circulation in press -15 -10 -5 5 5 10 BP changes (mm Hg) 3M (n=245) 6M (n=236) 12M (n=90) p<0.0001 -8.4 -8.7 -9.9 -4.2 -4.3 -6.6 ANOVA SBP p<0.0001 ANOVA DBP p<0.0001 (n=213) (n=206) (n=80) -4.8 -4.9 -7.4 -10.1 -10.2 -11.7 (n=32) (n=30) (n=11) p=0.906 p=0.757 p=0.465 p=0.991 p=0.386 p=0.362 2.7 0.3 1.2 -0.3 -4.4 -0.2 ANOVA SBP p=0.568 ANOVA DBP p=0.754 All patients (n=346) True resistant hypertension (n=303) Pseudo-resistant hypertension (n=43) SBP DBP Mahfoud F et al, Circulation in press

Correlation in ABPM and office BP reductions – data from drug trials Mancia G, J Hypertension 2004

? Open questions Long-term safety and efficacy Influence of BP reduction on CV morbidity/mortality Predictors of response and non-response Pleiotropic effects Glucose metabolism Structural changes Renal function Arrhythmias ... ?