The safety and long-term effect of renal artery denervation on blood pressure and renal function

in real world patients with uncontrolled hypertension from the Global SYMPLICITY Registry

Felix Mahfoud, MD1

M. Böhm1, K. Narkiewicz2, L. Ruilope3, M. Schlaich4, R. Schmieder5, B. Williams6, G. Mancia7

on behalf of the GSR Investigators

1 Saarland University Hospital, Homburg/Saar, Germany2 Medical University of Gdansk, Gdansk, Poland; 3 Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain; 4 Royal Perth Hospital Unit, The University of Western Australia, Perth, Australia; 5 Universität Erlangen Nürnberg, Nürnberg, Germany; 6 Institute of Cardiovascular Sciences,

University College London, London, United Kingdom; 7 University of Milano Bicocca, St Gerardo Hospital, Monza, Italy

Potential conflicts of interest

Speaker's name: Felix MahfoudI have the following potential conflicts of interest to report:

Research Grants• Deutsche Hochdruckliga• Deutsche Gesellschaft für Kardiologie• Saarländisches Ministerium für Wissenschaft und Forschung

Consultant/Lecture fee/Travel support: • Medtronic, St. Jude, Boston Scientific, Cordis, Berlin Chemie,

Boehringer Ingelheim

Institutional grant/Research support: • Medtronic, St. Jude, Recor, Boston Scientific

Background

• The Global SYMPLICITY Registry was designed to assess the procedural and long-term safety and effectiveness of the Symplicity™ renal denervation system in a real-world patient population of– patients with uncontrolled hypertension alone or – patients with concomitant conditions also characterized by

sympathetic nervous system overdrive

• Follow-up results of the first 2037 enrolled patients are available through 6 months, and 2-year outcomes are available for 608 enrolled patients.

Global SYMPLICITY Registry (GSR) Current Activated Site Locations

CA: 5

MEA: 39

WE: 131

C&EEU: 19

ASEAN: 19

Korea: 10

247 sites in 37 countriesEnrollment to date: 2385 pts ANZ: 14

LA: 10

• 5000 real world patients with uncontrolled hypertension or other conditions associated with increased sympathetic activity

• >18 years

Global SYMPLICITY Registry (GSR) Clinical Trial Design

• 40% randomly assigned to 100% monitoring

Max. 5000 patients

Böhm,M, et al. Hypertension. 2015

GREAT Registry

N=1000

Korea Registry

N=102

South Africa RegistryN=400

Canada & Mexico1

Rest of GSR

N≈3500

Prospective, open-label, single-arm, all-comer observational registry

6M 3Y2Y1YFollow-up 3M 4Y 5Y

1601

NCT01534299

2037 608Patient data availableto date

Patient DispositionBaseline (N=2037)OBP: 1979 (97%)

ABPM: 1403 (69%)

6 Month Follow-up eligible (N=2037)Safety: 1983 pts (97%)OBP: 1571 pts (77%)

ABPM: 1045 pts (51%)

1 Year Follow-up eligible (N=1601)Safety: 1396 pts (87%)

OBP: 1444 pts (90%)ABPM: 932 pts (58%)

Analysis on BP change performed on patients with matching baseline and follow-up values

2 Year Follow-up eligible (N=608)Safety: 451 pts (74%)

OBP: 508 pts (84%)ABPM: 257 pts (42%)

Baseline Patient Characteristics

% or mean ± SD N=2037

Male gender 59.1Age (years) 61 ± 12BMI (kg/m2) 31 ± 6Current smoking 9.6History of cardiac disease 48.2Chronic kidney disease (eGFR <60ml/min/1.73m2) 21.8Obstructive sleep apnea 11.0Sleep apnea (AHI≥5) 4.1Atrial fibrillation 12.8Diabetes, Type 2 38.11 co-morbidity 39.42 co-morbidities 36.93+ co-morbidities 23.7

Baseline Patient Characteristics

% or mean ± SD N=2037

Office BP (Systolic/Diastolic), mmHg 165/89 ± 25/16

24-h BP (Systolic/Diastolic), mmHg 154/86 ± 18/14

True hypertension 82

Masked hypertension 12

Pseudo-hypertension 4

Procedural Details

mean ± SD N=2037

Number of renal arteries 2.1 ± 0.5

Treatment time (min) 48.9 ± 20.4

Number of ablations 13.3 ± 4.0

Number of 120 sec ablations 11.3 ± 3.4

Contrast volume used (cc) 128.2 ± 77.8

Anti-hypertensive Medication Use

% or mean ± SD Baseline 1 Year 2 Years P

Anti-hypertensive medication classes 4.5 ± 1.4 4.4 ± 1.4 4.4 ± 1.4 <0.0001

Beta-blockers 77.4 75.0 77.1 0.04

ACE inhibitors 34.2 31.1 28.9 <0.0001

Angiotensin Receptor blockers 65.5 65.1 66.7 NS

Calcium Channel blockers 78.3 76.1 76.9 NS

Diuretic 79.4 77.1 77.2 NS

Aldosterone antagonists 23.6 26.4 25.4 <0.0001

Spironolactone 20.1 22.1 20.9 0.006

Alpha-adrenergic blockers 34.3 32.1 32.6 0.002

Direct-acting vasodilators 13.7 13.4 14.7 NS

Centrally-acting sympatholytics 38.3 34.7 30.3 <0.0001

Direct renin inhibitors 6.3 5.0 5.6 0.0002

P-values calculated by Friedman test to compare medication rates across time points on repeated measures of patient level data.

Safety Results to 2 Years% 6 Months

n=19271 Yearn=1383

2 Yearsn=425

Composite safety endpoint 2.3 4.0 8.0

Cardiovascular events

Cardiovascular death * 0.3 0.9 1.2

Stroke 0.8 1.4 2.6

Hospitalization for new onset heart failure 0.7 1.2 2.6

Hospitalization for atrial fibrillation 0.7 1.7 2.6Hospitalization for hypertensive crisis/hypertensive emergency * 0.8 1.5 3.8

Myocardial infarction 0.8 1.1 2.4

Renal events

New onset end-stage renal disease * 0.2 0.5 1.4

Serum creatinine elevation >50% 0.5 1.2 2.8

New artery stenosis >70% * 0.1 0.2 0.0

Post-procedural events

Non-cardiovascular death 0.1 0.4 1.4

Renal artery reintervention * 0.3 0.4 0.5

Vascular complication * 0.7 0.5 0.9

* Included in composite safety endpoint at 30 days

BP Change at 6 Months

-20

-15

-10

-5

0

-12.3

-6.8

-4.5 -4.0

systolicdiastolic

Syst

olic

Blo

od P

ress

ure

Chan

ge

(mm

Hg)

Office BP 24h ABPM N = 1531 n=877

P < 0.0001 P < 0.0001

Baseline BP 165/89 ± 25/16 154/86 ± 18/14

n=878N = 1526

Office Systolic BP Change

-20

-15

-10

-5

0

-12.3 -12.5-13.5

-14.8

Syst

olic

Blo

od P

ress

ure

Chan

ge

(mm

Hg)

All patients with ≥ 6mo f/u

n=1531

Baseline OSBP 164 ± 24 P < 0.0001

n=447n=447

Baseline OSBP 163 ± 22P < 0.0001

n=400

Change at 6 monthsChange at 1 yearChange at 2 years

All patients with 2yr follow-up

24-h Ambulatory BP Change

-20

-15

-10

-5

0

-6.6 -7.1-8.1 -8.0

Syst

olic

Blo

od P

ress

ure

Chan

ge

(mm

Hg)

n=787 n=171n=195

Baseline ABPM 153 ± 18P < 0.0001

Baseline ABPM 152 ± 18P < 0.0001

n=186

All patients with ≥ 6mo f/u

All patients with 2yr follow-up

Change at 6 monthsChange at 1 yearChange at 2 years

Office BP by Stratified GroupsChange to 2 Years

-40

-20

0

2013

-4

-15

-33

12

-4

-16

-34

10

-5

-19

-35

Syst

olic

Blo

od P

ress

ure

Chan

ge

(mm

Hg) OSBP <140

(N=271)

OSBP ≥180(N=513)206

128 ± 10P < 0.0001 at all timepoints

216

368179

168 ± 6P < 0.0001 at all timepoints

OSBP 160-179(N=654)

OSBP 140-159(N=541)

150 ± 6P ≤0.005 at

all timepoints

197 ± 15P < 0.0001 at all timepoints

418 529

66

384 140 476 116345

Change at 6 monthsChange at 1 yearChange at 2 years

Baseline OSBPP-value compared

to baseline BP

24-h ABPM by Stratified GroupsChange to 2 Years

-20

-10

0

10

-5-6

-7-8

-4

-6-8

-11

-4

-8

-10-11

Syst

olic

Blo

od P

ress

ure

Chan

ge

(mm

Hg)

OSBP <140(N=271)

OSBP ≥180(N=513)

144 ± 16P <0.001 at 6M,

P=0.03 at 1yrP=NS at 2yrs

19364

155 ± 17P < 0.0001 at all timepoints

OSBP 160-179(N=654)

OSBP 140-159(N=541)

148 ± 15P <0.005 at

all timepoints

164 ± 19P < 0.005 at

all timepoints

246 269231 67 227 42162

Change at 6 monthsChange at 1 yearChange at 2 years

129145 36

Baseline ABPMP-value compared

to baseline BP

Office Systolic BP

-30

-20

-10

0

-22.0

-12.8

-22.4

-16.7

-21.3

-17.3

Syst

olic

Blo

od P

ress

ure

Chan

ge

(mm

Hg)

Severe resistant HTNOSBP ≥ 160, ABPM ≥ 135

and 3+ meds(N=681)

Less severe HTNOSBP 150 – 180, ABPM 140 – 170

and DBP ≥ 90(N=213)

Baseline OSBP 181 ± 18P < 0.0001

n=531 n=165 n=51n=146

Baseline OSBP 165 ± 8P < 0.0001

n=484 n=153

Change at 6 monthsChange at 1 yearChange at 2 years

Ambulatory Systolic BP

-20

-10

0

-8.5-7.4

-11.0 -10.9-11.0 -10.7

Syst

olic

Blo

od P

ress

ure

Chan

ge

(mm

Hg)

Baseline ABPM 161 ± 16P < 0.0001

n=403 n=133 n=36n=116

Baseline ABPM 154 ± 8P < 0.0001

n=344 n=93

Change at 6 monthsChange at 1 yearChange at 2 years

Severe resistant HTNOSBP ≥ 160, ABPM ≥ 135

and 3+ meds(N=681)

Less severe HTNOSBP 150 – 180, ABPM 140 – 170

and DBP ≥ 90(N=213)

Conclusions

• The Global SYMPLICITY Registry is largest available real world database and has enrolled over 2300 patients to date.

• No long-term safety concerns have been observed following the denervation procedure.

• Renal denervation in a large real world population resulted in significant blood pressure reductions at 6 months that were sustained in the cohort that was followed out to 2 years post-procedure.