Michael Bhm, MD on behalf of the GSR Investigators March 30, 2014 - - PowerPoint PPT Presentation

The Global SYMPLICITY Registry: Safety and Effectiveness of Renal Artery Denervation In Real World Patients With Uncontrolled Hypertension Michael Böhm, MD

• n behalf of the GSR Investigators

March 30, 2014

Universitätskliniken des Saarlandes, Klinik für Innere Medizin III, Homburg/Saar, Germany

Conflicts of Interest – M. Böhm

• 1. Study Support:

Astra Zeneca, Bayer AG, Boehringer Ingelheim, Medtronic, Novartis, Pfizer, Sanofi-Aventis, Servier, St. Jude

• 2. Advisory Boards:

Astra Zeneca, Bayer AG, Boehringer Ingelheim, Cordis, Daiichi-Sankyo, Medtronic, MSD, Novartis, Pfizer, Sanofi-Aventis, Servier,

• 3. Speaker:

Astra Zeneca, Bayer, Boehringer Ingelheim, Berlin-Chemie, Daiichi-Sankyo, Medtronic, MSD, Novartis, Pfizer, Sanofi-Aventis, Servier, St. Jude

• Deutsche Forschungsgemeinschaft
• Federal State of the Saarland (Ministry of Science and Economy
• BMBF
• European Union

Global SYMPLICITY Registry

Co-Chairs

• Prof. Michael Böhm; Prof. Giuseppe

Mancia Executive Committee

• Prof. Bryan Williams; Prof. Krzysztof

Narkiewicz; Prof. Luis Ruilope; Prof. Markus Schlaich Steering Committee Executive committee and Dr. Mostafa Adel Youssef; Dr. Ashok Seth r. Brett Egan; Dr. Dong-Ju Choi; Dr. Phillip L’Allier Prof. Bert Andersson; Prof. Chaim Lotan; Prof. Iris Baumgartner;

• Prof. Massimo Volpe; Prof. Roland

Schmieder; Prof. Thierry Lefevre;

• Prof. Uta Hoppe; Prof. Uwe Zeymer;
• Dr. Robaayah Zambahari

Independent Clinical Events Committee Steven Marx, MD; Clive Rosendorff, MD, PhD, DsC Med, FRCP, FACC; Michele H. Mokrzycki, MD; Ladan Golestaneh, MD; Joel Neugarten, MD (Non-voting members: Roxana Mehran, MD and Sorin Brener, MD) Data Analysis Institut für Herzinfarktforschung, IHF, Ludwigshafen, Germany Sponsor Medtronic, Inc.

Background

• Sympathetic nervous

system overdrive is implicated in many diseases

• RDN has been studied

extensively in subjects with uncontrolled hypertension

• Published reports describe

the clinical benefit of renal denervation in several co- morbid conditions

• Safety and treatment effect

in real life could differ

• Primary: Safety

– Peri-procedural safety – Long-term safety

• Vascular
• Renal

– Hemodynamic

• Secondary

– Patient characterization – Effect on blood pressure – Changes in baseline antihypertensive medication

• New

– Relationship of registry vs RCT (SYMPLICITY HTN-3)

Objectives

Design and Rationale

• Prospective, open label, multi-center, international

registry

• Up to 5000 real world patients with uncontrolled

hypertension and some with conditions associated with sympathetic nervous system activation

• Key Inclusion:

– Older than 18 years – Candidates for renal denervation as defined by local regulations for use of the Symplicity™ catheter.

• NCT01534299

LA: 6 CA: 5 MEA: 11 WE: 116 ANZ: 11 C&EEU: 10 ASEAN: 10

Global SYMPLICITY Registry – Current Activated Site Locations

Korea: 10

Consecutive patients treated in real world population 5000 patients

Global SYMPLICITY Registry

GREAT Registry N=1000 Korea Registry* N=102 South Africa Registry* N=400 Canada and Mexico* Rest of GSR N~3500 6M 3Y 2Y 1Y

Follow-up schedule

3M 4Y 5Y

* Limited to resistant hypertension only 231 international sites in 37 countries

• Min. 10% randomly assigned to 100% monitoring

Patient Disposition

Baseline (N=1000 ) OBP: 982/1000 (98.2%) ABPM: 693/1000 (69.3%) 3 Month Follow-up (N=996 in study) Safety: 965/998 (96.7%) OBP: 779/996 (78.2%) ABPM: 474/996 (47.6%)

• 2 patients died
• 2 patients withdrew

6 Month Follow-up (N=992 in study) Safety: 913/996 (91.7%) OBP: 760/992 (76.6%) ABPM: 487/992 (49.1%)

• 2 patients died
• 2 patients withdrew

Analysis on BP change performed on patients with matching baseline and FUP values

Baseline Patient Characteristics

All Patients (N = 1000) SBP ≥160 mm Hg & Ambulatory SBP ≥135* mm Hg (N = 327)

Gender, (% male) 61.2% 63.9% Age (years) 60.7 ± 12.0 61.0 ± 10.9 BMI (kg/m2) 30.5 ± 5.5 30.9 ± 5.5 Current smoking 10.0% 11.0% History of cardiac disease 50.5% 52.9% Renal impairment (eGFR <60 ml/min/1.73m2) 23.4% 27.9% Sleep apnea (AHI≥5) 4.2% 5.9% Diabetes, Type 1 3.2% 2.5% Diabetes, Type 2 38.5% 42.6% 1 co-morbidity 39.7% 36.7% 2 co-morbidities 35.5% 34.6% 3+ co-morbidities 24.6% 28.4%

* With ≥3 antihypertensive medication classes

Antihypertensive Medication Use

All Patients (N = 1000) SBP ≥160 mm Hg & Ambulatory SBP ≥135 mm Hg* (N = 327)

Antihypertensive medication classes 4.5 ± 1.3 4.7 ± 1.2 Beta-blockers 78.9% 81.0% ACE inhibitors 33.8% 38.5% Angiotensin-receptor blockers 67.3% 67.9% Calcium channel blockers 76.3% 78.9% Diuretics 78.2% 79.8% Aldosterone antagonists 21.1% 19.3% Spironolactone 18.6% 15.9% Alpha adrenergic blockers 35.2% 40.1% Direct-acting vasodilators 15.1% 19.0% Centrally acting sympatholytics 33.2% 37.6% Direct renin inhibitor 7.4% 7.7%

* With ≥3 antihypertensive medication classes

# renal arteries 2.2 ± 0.5 Length 41.5 ± 13.1 mm Diameter left renal artery 5.6 ± 1.2 mm Diameter right renal artery 5.7 ± 1.2 mm Treatment time 50 min # bilateral ablations 13.5 ± 4.1 # 120 sec bilateral ablations 11.3 ± 3.4 Contrast volume used 127.6 ± 81.1 cc

Procedural Detail

values are mean ± SD

Safety at 1 and 6 Months

1 Month n=967 6 Month n=913

Cardiovascular events Cardiovascular death 0.0% (0) 0.2% (2) Stroke 0.2% (2) 0.9% (8) Hospitalization for new onset heart failure 0.3% (3) 0.7% (6) Hospitalization for atrial fibrillation 0.1% (1) 0.9% (8) Hypertensive crisis/emergency 0.2% (2) 1.0% (9) Myocardial infarction 0.0% (0) 0.6% (5) Renal events New onset end stage renal disease 0.1% (1) 0.2% (2) Serum creatinine elevation > 50% 0.1% (1) 0.2% (2) New renal artery stenosis >70% 0.0% (0) 0.0% (0) Post-procedural events Non-cardiovascular death 0.0% (0) 0.2% (2) Renal artery re-intervention 0.1% (1) 0.2% (2) Vascular complication 0.4% (4) 0.4% (4)

Safety in HTN-3 and GSR

HTN-3 RDN arm (N=364) GSR All Patients (N=1000) GSR OSBP≥160 and ABPM≥135* (N=327)

MAE 1.4% 0.8% 1.3% At 6 month Death 0.6% 0.4% 0.3% New onset end stage renal disease 0.0% 0.2% 0.3% Significant embolic event resulting in end-organ damage 0.3% 0.0% 0.0% Renal artery re-intervention 0.0% 0.2% 0.0% Vascular complication 0.3% 0.4% 0.7% Hypertensive crisis/emergency 2.6% 1.0% 1.7% New renal artery stenosis > 70% 0.3% 0.0% 0.0%

* With ≥3 antihypertensive medication classes

Change in Office Systolic BP for All Patients and Subgroups

• 10.0

12.9

• 2.0
• 18.9
• 11.9

14.2

• 4.6
• 21.4
• 25
• 20
• 15
• 10
• 5

5 10 15 20

3 Mo 6 Mo

All Patients* <140 mm Hg* 140-159 mm Hg † ≥160 mm Hg* N=222 N=227 N=96 N=94 N=751 N=769 N=433 N=448 *P<0.0001 for both 3 and 6 month change from baseline †P=0.14 at 3 months and P=0.0006 at 6 months

Change in Office SBP at 6 Months for GSR and SYMPLICITY HTN-3 Patients

• 11.9
• 20.2
• 17.3
• 25
• 20
• 15
• 10
• 5

GSR All Pts GSR (≥160 office/≥135 ABPM) GSR (≥160 office/≥135 ABPM) *

N=244 N=62

*with ≥3 antihypertensive medication classes † with ≥3 antihypertensive meds at maximum tolerated dose

†

N=751

Change in Office SBP (mm Hg)

Change in Office SBP at 6 Months for GSR and SYMPLICITY HTN-3 Patients

• 11.9
• 20.2
• 17.3
• 25
• 20
• 15
• 10
• 5

GSR All Pts GSR (≥160 office/≥135 ABPM) GSR (≥160 office/≥135 ABPM) HTN-3 RDN HTN-3 Sham *

N=244 N=62

*with ≥3 antihypertensive medication classes † with ≥3 antihypertensive meds at maximum tolerated dose

†

N=751 N=353 N=171

• 14.1
• 11.7

Change in Office SBP (mm Hg)

Change in Office SBP at 6 Months for GSR and Non-African American Patients in SYMPLICITY HTN-3

• 20.2
• 17.3
• 15.2
• 8.6
• 25
• 20
• 15
• 10
• 5

Change in Mean 24-Hour SBP (mm Hg)

GSR (≥160 office/≥135 ABPM) GSR (≥160 office/≥135 ABPM) HTN-3 RDN non-African American HTN-3 Sham non-African American

N=62 N=120 N=264 N=244

*

*with ≥3 antihypertensive medication classes † with ≥3 antihypertensive meds at maximum tolerated dose †

Change in Ambulatory Systolic BP for All Patients and Subgroups

• 6.9
• 6.3
• 6.6
• 7.1
• 7.9
• 6.9
• 7.9
• 8.2
• 12
• 10
• 8
• 6
• 4
• 2

3 Mo 6 Mo

All Patients* <140 mm Hg† 140-159 mm Hg* ≥160 mm Hg* N=130 N=139 N=67 N=55 N=404 N=401 N=203 N=199 *P<0.0001 for both 3 and 6 month change from baseline †P=0.007 at 3 months and P=0.004 at 6 months

Change in Ambulatory SBP for GSR and SYMPLICITY HTN-3 Patients

• 7.9
• 9.1
• 10.3
• 12
• 10
• 8
• 6
• 4
• 2

Change in Mean 24-Hour SBP (mm Hg)

GSR All Pts GSR (≥160 office/≥135 ABPM) GSR (≥160 office/≥135 ABPM) N=176 N=52 *with ≥3 antihypertensive medication classes † with ≥3 antihypertensive meds at maximum tolerated dose N=404

*

†

Change in Ambulatory SBP for GSR and SYMPLICITY HTN-3 Patients

• 7.9
• 9.1
• 10.3
• 12
• 10
• 8
• 6
• 4
• 2

Change in Mean 24-Hour SBP (mm Hg)

GSR All Pts GSR (≥160 office/≥135 ABPM) GSR (≥160 office/≥135 ABPM) HTN-3 RDN HTN-3 Sham

• 6.8
• 4.8

N=176 N=52

*with ≥3 antihypertensive medication classes † with ≥3 antihypertensive meds at maximum tolerated dose

N=404 N=325 N=159

*

†

Response Rates* for Patients with Office SBP ≥160 mm Hg / Ambulatory SBP ≥135 mm Hg at Baseline†

43% 50% 62% 68% 69% 77% 0% 20% 40% 60% 80% 100% 3 months 6 months >20 mm Hg >10 mm Hg >5 mm Hg

Response rate

*Reduction in mean office SBP of at least 5, 10, or 20 mm Hg

†with ≥3 antihypertensive medication classes

Distribution of SBP in Patients With Office SBP≥160 mm Hg and Ambulatory SBP ≥135 mm Hg* at Baseline

0% 25% 50% 75% 100% Baseline 3 Months 6 Months >180mmHg 160 - <180 mm Hg 150 - <160 mm Hg 140- <150 mm Hg 110 - <140 mm Hg 90 - <110 mm Hg <90 mm Hg

% Patients

*with ≥3 antihypertensive medication classes

• Excellent procedural and clinical safety profile in

the largest dataset of real world RDN patients to date

• Significant reductions in both office and ambulatory

BP from baseline

– Differences with SYMPLICITY HTN-3 include randomization, blinding, sham control, BP inclusion criteria, antihypertensive-drug treatment intensity, and African-American inclusion in HTN-3 – Despite the limitations of comparing a registry with a randomized, blinded, controlled study, the reduction in blood pressure is numerically larger in the GSR at 6 months after treatment – Due to the registry nature of the GSR, it is difficult to account for the magnitude of a possible placebo effect.

Conclusions

Future Research

• Define appropriate treatment populations

– Key subgroups – Optimal BP inclusion criteria

• Interaction with drug treatments
• Time course
• Technical issues
• Operator experience

– Optimal training and proctoring

• M. Böhm

Klinik für Innere Medizin III Universitätsklinikum des Saarlandes Homburg/Saar, Germany

• Tel. 06841-16-23372
• Fax. 06841-16-23369

michael.boehm@uks.eu

Thank you!