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

3. 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

4. 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:
Resistant Hypertension (12.2% of total treated population)
Treated Patients With Hypertension
de la Sierra A et al. Hypertension. 2011;57:

5. 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

6. 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

7. 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

8. 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 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, mm Hg (95% CI -13.3, -9.1)
– For AZL-M 80 mg + AML 5 mg, mm Hg (95% CI -13.0, -8.8)
Source: Final CSR, TL 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

9. 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 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 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

10. 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.

11. 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

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

13. 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

15. Predictors of response
Mahfoud F et al, Circulation in press

16. 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

17. 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

18. 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

19. 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

20. 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

21. ABP changes SBP DBP Mahfoud F et al, Circulation in press -15 -10 -5 55 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

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

23. ? 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
... ?