Giuliano Tocci, MD, PhD, ESH Hypertension Specialist

Centro per la Diagnosi e la Cura dell’Ipertensione Arteriosa, Cattedra di Cardiologia,

Dipartimento di Medicina Clinica e Molecolare, Facoltà di Medicina e PsicologiaUniversità di Roma Sapienza, Azienda Ospedaliera Sant’Andrea, Roma, Italia.

E-mail: giuliano.tocci@uniroma1.itE-mail: centro.ipertensione@ospedalesantandrea.it

BP Stratification in Hypertensive Patients enrolled in Hypertension Surveys in Italy

n=1.831 n=3.739 n=3.374 n=15.904 n=13.297 n=2.081

N=52.71571%

22%

Volpe M, Tocci G, et al. J Hypertens 2007 Jul;25(7):1491-8

Resistant Hypertension

• Hypertension is usually defined resistant or refractory to treatment when a therapeutic plan that has included attention to lifestyle measures and the prescription of at least three drugs (including a diuretic) in adequate doses has failed to lower systolic and diastolic blood pressure to goal.

• According to this definition prevalence of resistant hypertension is relatively high (in ALLHAT 8% pts with 4 drugs and 15% with resistant hypertension).

• In such situations, referral to a specialist or a hypertension center should be considered, because resistant hypertension is recognized to be often associated with subclinical organ damage and a high or very high cardiovascular risk.

2007 ESH/ESC Hypertension Guidelines

Mancia G, et al. J Hypertens 2007;25:1105–1187

Epidemiologia dell‘Ipertensione Arteriosa in Italia

Schematic Representation of the Catheter Ablation of Renal Arteries

The Renal Denervation Procedure

• 4-6 focal treatments are delivered– 120 seconds per treatment– ≥5 mm between locations– Stable, unique locations– Circumferential coverage

• The catheter is pulled, rotated, and new location and prior treatment site are assessed

The blood pressure lowering effects of renal denervation in a real world population

of patients with uncontrolled hypertension: Early outcomes from the Global SYMPLICITY Registry

Felix Mahfoud et al. Expert consensus document from the ESC on

catheter-based RD, Eur Heart J April 2013

Michael Böhm, on behalf of the Global SYMPLICITY Registry Investigators Oral Comunication at ESC 2013 Congress

Purpose of the Registry

To document:• Long-term safety & effectiveness • Real world patient population with: • Hypertension and/or • Other diseases characterized by elevated sympathetic

drive

• Procedural technique

Global SYMPLICITY Registry

RationaleRationaleGlobal SYMPLICITY Registry

LA: 6

CA: 5

MEA: 11

WE: 116

ANZ: 11

C&EEU: 10

ASEAN: 10

Korea: 10

Current Activated Site LocationsGlobal SYMPLICITY Registry

Primary Objective

• Safety Parameters–Peri-procedural safety–Long-term safety• Vascular effect• Renal effect• Hemodynamic effect

Global SYMPLICITY Registry

Secondary Objectives

• Patient characterization• Effect on blood pressure levels• Effects on major cardiovascular endpoints

(MACE), including death, stroke, MI, renal function, CHF.

• Changes in baseline antihypertensive medication

Global SYMPLICITY Registry

Consecutive patients treated in real world population

~ 5000 patients

GREAT RegistryN=1000

~ 200 sites InternationalMin. 10% randomly assigned to 100% monitoring

Korea Registry*N=102

South Africa Registry*N=400

Canada and Mexico*

Rest of GSRN~3500

*: limited to resistant hypertension only

Global SYMPLICITY Registry

Patients’ Allocation and Follow-Up

6mo6mo 3yr3yr2yr2yr12mo12mo

Follow-up schedule

3mo3mo 4yr4yr 5yr5yr

Mahfoud F et al. Expert consensus document from the ESC on catheter-based RD, Eur Heart J April 2013

Patients’ characteristics at baseline• 1097 patients treated as of June

26, 2013• 86% with SBP ≥140 mmHg• 66% of patients treated according

to ESC Consensus paper on Renal Denervation1

– SBP ≥ 160 mm Hg (≥ 150 mmHg Diabetes II), 3+ meds, including diuretic

• 13% with BP ≥180/100 mmHg

Co-Morbidities Include:• Diabetes II 38.2%• Renal Disease 30.1%• Sleep Apnea 16.9%• Hx of Cardiac Disease 49%• Heart Failure 9.2%• Atrial Fibrillation 12.6%• LVH 15.9%

Global SYMPLICITY Registry

Patients’ characteristics at baselineDemographic Value

Age (years) 60 ± 12

Gender (% male) 60%

Race (% African Dissent) 1.3%

BMI (kg/m2) 31 ± 5.7

History of Renal Insufficiency (eGFR<60) 21%

eGFR (ml/min/1.73 m2) n=1061 79 ± 44

-eGFR > 45 mL/min/1.73 m2 90%

Serum Creatinine (mg/dl) n=896 1.02 ± 0.79

Global SYMPLICITY Registry

Blood Pressure levels and Antihypertensive Tx at baseline

Drugs Proportions

Baseline BP (mm Hg) 164/89 ± 24/16

Number of classes anti-HTN meds (mean) 4.39 ± 1.33

Diuretic (%) 76%

Aldosterone blocker (%) 21%

ACE (%) 34%

ARB (%) 65%

Beta-Blocker (%) 77%

Calcium Channel Blocker (%) 75%

Alpha adrenergic Blocker(%) 34%

Vasodilator (%) 14%

Direct Renin Inhibitor (%) 7%

Global SYMPLICITY Registry

Presence of Comorbidities according to SBP stratification

Patients (%)All

(n=1162)<140 mmHg

(n=150)140-159 mmHg

(n=313)160-179 mmHg

(n=370)>180 mmHg

(n=264)

SBP (mmHg) 164.1 ± 24.0 127.4 ± 10.1 150.4 ± 5.8 167.6 ± 5.6 196.3 ± 14.3

1 co-morbidity 33.1% 33.3% 28.9% 36.5% 34.8%

2 co-morbidities 36.8% 34.7% 39.2% 36.2% 35.6%

3+ co-morbidities 29.9% 32.0% 31.5% 27.0% 29.5%

Global SYMPLICITY Registry

Distribution of Patients according to 2013 ESH/ESC Global Cardiovascular Risk Stratification

Other risk factors, asymptomatic organ damage or disease

Blood pressure (mmHg)

High normal SBP 130-139 or

DBP 85-89(n=71)

Grade 1 HT SBP 140-159 or

DBP 90-99(n=292)

Grade 2 HT SBP 160-179 or

DBP 100-109(n=373)

Grade 3 HT SBP ≥ 180 or

DBP ≥ 110(n=295)

No other RF 0.0% 5.6% 6.7% 11.4%

1-2 RF 93.8% 51.9% 49.5% 45.7%

≥ 3 RF 6.3% 42.6% 43.8% 42.9%

OD, CKD stage 3 or diabetes 71.8% 72.9% 64.9% 66.4%

Symptomatic CVD, CKD stage ≥ 4 or diabetes with OD/RFs 54.9% 62.7% 55.5% 56.6%

Global SYMPLICITY Registry

Procedural Details

• 98% anatomically eligible • Mean length: 42 ± 14 mm• Mean diameter: 5.8 ± 3.4 mm• Mean Symplicity procedure time: 50 min– Mean # bilateral ablations: 13.5

• Mean contrast volume used: 128 ± 80 cc

Global SYMPLICITY Registry

Procedural Safety(safety population N=1,162)

• Renal artery re-intervention due to dissection 0.09% (n=1)

• Vascular complication• Vascular complication, pseudoaneurysm 0.34% (n=4)• Vascular complication, hematoma 0.09% (n=1)

Global SYMPLICITY Registry

Change in Office BP levels according to baseline BP

≥ 140 ≥ 140 ≥ 140≥ 180†≥ 160* ≥ 160*≥ 160*≥ 180† ≥ 180†

3 months 6 months 12 months

* ≥ 150 mm Hg in Diabetes† ≥ 100 mm Hg DBP

n=612 n=468 n=78 n=391 n=313 n=51 n=91 n=79 n=9-37

p < 0.001 for all values except;P = 0.001 SBP ≥ 180, 12m; p = 0.0005 DBP ≥ 180, 12m

Global SYMPLICITY Registry

Change in 24-hour ABP levels according to baseline BP

≥ 140 ≥ 140 ≥ 140≥ 180†≥ 160* ≥ 160*≥ 160*≥ 180† ≥ 180†

3 months 6 months 12 months

* ≥ 150 mm Hg in Diabetes† ≥ 100 mm Hg DBP

n=288 n=196 n=35 n=181 n=132 n=25 n=24 n=18

**

p < 0.0001 for all time points except; p=0.0456 SBP ≥ 140 mm Hg, p=0.7611 DBP ≥ 140 mm Hg (12m);p=0.0677 SBP ≥ 160/150 mm Hg, p=0.7838 DBP ≥ 160/150 mm Hg (12m); p=0.0001 and p=0.0036 SBP ≥ 180/100 mm Hg (3m + 6m) and p=0.0007 and p=0.0017 DBP ≥ 180/100 mm Hg (3m + 6m) ** Sample size for >180/100 at 12 months too small to be shown (n=2)

Global SYMPLICITY Registry

Renal Function

Stage I

Stage II

Stage III

Stage IV

ESRDStage V

100

eGFR

(mL/

min

/1.7

3m2 )

Global SYMPLICITY Registry

Antihypertensive Medications AnalysisGlobal SYMPLICITY Registry

Antihypertensive Medications Analysis

Baseline(n=1108)

3 months(n=764)

6 months(n=480)

12 months(n=107)

Number of anti-hypertensive medication classes 4.39 ± 1.33 4.27 ± 1.35* 4.25 ± 1.41* 4.05 ± 1.44

Diuretic (%) 76% 76% 76% 72%

Spironolactone (%) 18% 17% 18% 22%

ACE (%) 35% 32% 29% 22%

ARB (%) 65% 66% 68% 74%

Beta-Blocker (%) 78% 77% 76% 79%

Calcium Channel Blocker (%) 75% 76% 78% 79%

Alpha adrenergic Blocker(%) 34% 32% 30% 24%

Vasodilator (%) 14% 13% 13% 12%

Centrally-acting sympatholytics 34% 29% 27% 12%

* Indicates a significant change from baseline

Global SYMPLICITY Registry

Chronic Safety DataEvent Patients (num) Incidence (patient/year) •Major CV Events•Hospitalization for hypertensive crisis 6 1.46%•Death, deemed unrelated to device or procedure 5 1.22%•Stroke 6 1.46%•MI 4 0.97%•Hospitalization for Afib 6 1.46%•Hospitalization for new onset HF 5 1.22%

•Renal Events:•Serum creatinine elevations 4 0.97%•New onset of end-stage renal disease 1 0.24%•(Nephrotoxic overdose)

•Post-Procedural Events:•Renal artery re-intervention 1 0.24%•Hematoma 1 0.24%

Data on patients reaching 3 or 6 or 12 month follow up

Global SYMPLICITY Registry

Conclusions

• Excellent procedural and clinical safety profile in real world

• Treatment resembles current consensus

• Significant reduction in both Office and ambulatory BP

• Enrolment and analyses continue

Global SYMPLICITY Registry

Take-Home Message• Il trattamento dell’ipertensione arteriosa non controllata (o resistente) richiede l’impiego di

terapie di combinazione con diverse classi di farmaci.

• Tali terapie di combinazione dovrebbero essere:– Semplici– Razionali– A dosaggio “adeguato” (pieno)

• Studi clinici disponibili dimostrano come l’impiego di terapie di combinazione duplici o triplici (farmaco bloccante RAS, diuretico tiazidico e CCB diidropiridinico a dosaggio pieno) consentono di ottenere il controllo dei valori di PAS/PAD in oltre 70-80% dei pazienti trattati.

• Nel rimanente 20-30% l’impiego di farmaci di 4 scelta (antialdosteronici o inibitori diretti della renina) può consentire di ridurre ulteriormente i valori pressori e raggiungere il controllo dei valori pressori.

• Nei casi non responsivi alla terapia (o con documentate allergie o intolleranze), l’impiego della denervazione delle arterie renali rappresenta una opzione efficace, sicura e ben tollerata per ridurre i valori pressori e contribuire a raggiungere il controllo della pressione arteriosa.

How to improve BP control in daily clinical practice of hypertension?

Volpe M, et al. G Ital Cardiol (Rome) 2012 Dec;13(12):853-60Ipertensione Prev Cardiovasc 2013; in press

High Blood Press Cardiovasc Prev 2013 March: in press

How to manage difficult-to-treat patients with resistant hypertension?

Volpe M, et al. G Ital Cardiol (Rome) 2012 Dec;13(12):846-5Ipertensione Prev Cardiovasc 2013; in press

High Blood Press Cardiovasc Prev 2012 Dec;19(4):237-44

Grazie per la Vostra Attenzione!

E: giuliano.tocci@uniroma1.itE: centro.ipertensione@ospedalesantandrea.it