The Global SYMPLICITY Registry: Safety and Effectiveness of Renal Artery Denervation In Real World Patients With Uncontrolled Hypertension Michael Böhm, MD on behalf of the GSR Investigators March 30, 2014 Universitätskliniken des Saarlandes, Klinik für Innere Medizin III, Homburg/Saar, Germany
Conflicts of Interest M. Böhm Deutsche Forschungsgemeinschaft Federal State of the Saarland (Ministry of Science and Economy BMBF European Union 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
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 comorbid 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 Objectives Changes in baseline antihypertensive medication New Relationship of registry vs RCT (SYMPLICITY HTN-3)
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
Global SYMPLICITY Registry Current Activated Site Locations CA: 5 WE: 116 C&EEU: 10 Korea: 10 MEA: 11 LA: 6 ASEAN: 10 ANZ: 11
Global SYMPLICITY Registry Consecutive patients treated in real world population 5000 patients GREAT Registry N=1000 Korea Registry* N=102 South Africa Registry* N=400 Canada and Mexico* Rest of GSR N~3500 231 international sites in 37 countries Min. 10% randomly assigned to 100% monitoring Follow-up schedule 3M 6M 1Y 2Y 3Y 4Y 5Y * Limited to resistant hypertension only
Patient Disposition Baseline (N=1000 ) OBP: 982/1000 (98.2%) ABPM: 693/1000 (69.3%) 2 patients died 2 patients withdrew 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%) 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/m 2 ) 30.5 ± 5.5 30.9 ± 5.5 Current smoking 10.0% 11.0% History of cardiac disease 50.5% 52.9% Renal impairment 23.4% 27.9% (egfr <60 ml/min/1.73m 2 ) 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
Procedural Detail # 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 values are mean ± SD
Safety at 1 and 6 Months Cardiovascular events 1 Month n=967 6 Month n=913 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 20 All Patients* <140 mm Hg* 140-159 mm Hg 160 mm Hg* 15 10 12.9 14.2 5 0-5 -10-15 N=769 N=751 N=227 N=222 N=448 N=433 N=94 N=96-2.0-4.6-10.0-11.9 3 Mo 6 Mo -20-25 *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 -18.9-21.4
Change in Office SBP (mm Hg) Change in Office SBP at 6 Months for GSR and SYMPLICITY HTN-3 Patients 0 N=751 N=244 N=62-5 GSR All Pts -10-15 -11.9 GSR ( 160 office/ 135 ABPM) * GSR ( 160 office/ 135 ABPM) -20-20.2-17.3-25 *with 3 antihypertensive medication classes with 3 antihypertensive meds at maximum tolerated dose
Change in Office SBP (mm Hg) Change in Office SBP at 6 Months for GSR and SYMPLICITY HTN-3 Patients 0 N=751 N=244 N=62 N=353 N=171-5 GSR All Pts -10-15 -11.9-14.1-11.7 GSR ( 160 office/ 135 ABPM) * GSR ( 160 office/ 135 ABPM) HTN-3 RDN -20-20.2-17.3 HTN-3 Sham -25 *with 3 antihypertensive medication classes with 3 antihypertensive meds at maximum tolerated dose
Change in Mean 24-Hour SBP (mm Hg) 0 Change in Office SBP at 6 Months for GSR and Non-African American Patients in SYMPLICITY HTN-3 N=244 N=62 N=264 N=120-5 -10-8.6 GSR ( 160 office/ 135 ABPM) * GSR ( 160 office/ 135 ABPM) -15-20 -20.2-17.3-15.2 HTN-3 RDN non-african American HTN-3 Sham non-african American -25 *with 3 antihypertensive medication classes with 3 antihypertensive meds at maximum tolerated dose
Change in Ambulatory Systolic BP for All Patients and Subgroups All Patients* <140 mm Hg 140-159 mm Hg* 160 mm Hg* 0 N=401 N=404 N=55 N=67 N=139 N=130 N=199 N=203-2 -4-6 -8-6.9-7.9-6.3-6.9-6.6-7.9-7.1-8.2 3 Mo 6 Mo -10-12 *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 Mean 24-Hour SBP (mm Hg) Change in Ambulatory SBP for GSR and SYMPLICITY HTN-3 Patients 0 N=404 N=176 N=52-2 GSR All Pts -4-6 -8-10 -12-7.9-9.1-10.3 GSR ( 160 office/ 135 ABPM) GSR ( 160 office/ 135 ABPM) *with 3 antihypertensive medication classes with 3 antihypertensive meds at maximum tolerated dose *
Change in Mean 24-Hour SBP (mm Hg) Change in Ambulatory SBP for GSR and SYMPLICITY HTN-3 Patients 0 N=404 N=176 N=52 N=325 N=159-2 GSR All Pts -4-6 -4.8 GSR ( 160 office/ 135 ABPM) * GSR ( 160 office/ 135 ABPM) -8-10 -7.9-9.1-10.3-6.8 HTN-3 RDN HTN-3 Sham -12 *with 3 antihypertensive medication classes with 3 antihypertensive meds at maximum tolerated dose
Response rate Response Rates* for Patients with Office SBP 160 mm Hg / Ambulatory SBP 135 mm Hg at Baseline 100% 80% 60% 40% 43% 62% 69% 50% 68% 77% >20 mm Hg >10 mm Hg >5 mm Hg 20% 0% 3 months 6 months *Reduction in mean office SBP of at least 5, 10, or 20 mm Hg with 3 antihypertensive medication classes
% Patients Distribution of SBP in Patients With Office SBP 160 mm Hg and Ambulatory SBP 135 mm Hg* at Baseline 100% 75% 50% 25% >180mmHg 160 - <180 mm Hg 150 - <160 mm Hg 140- <150 mm Hg 110 - <140 mm Hg 90 - <110 mm Hg <90 mm Hg 0% Baseline 3 Months 6 Months *with 3 antihypertensive medication classes
Conclusions 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.
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
Thank you! 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