Randomized, Controlled Trial of Renal Sympathetic Denervation in Patients with Treatment-Resistant Hypertension The Symplicity HTN-2 Trial The Symplicity HTN-2 Investigators (Simultaneous Lancet Publication) Murray D. Esler Baker IDI Heart and Diabetes Institute, Melbourne, Australia Sponsor: Ardian, Inc. Mountain View CA
Disclaimer Speaker is the Chief Investigator of the multi- centre international trial of therapeutic endovascular renal denervation with the Symplicity catheter in resistant hypertension presented here today (HTN-2 trial), and is a recipient of research grant, travel and consultancy funding from Ardian Inc.
A. “Increased Spillover of Noradrenaline into the Renal Veins in Essential Hypertension” 400 from the kidneys to plasma (ng/min) Rate of spillover of noradrenaline 300 M Esler, G Lambert, G Jennings 200 ** * J Hypertension 1990; 8: S53- 100 S57 (Updated) 0 Normal 20-39 40-59 60-79 BP Essential Hypertension B. “Renal Denervation Delays or Prevents G F DiBona Development of Many Experimental Physiol Rev 1997;77:75-197 Forms of Hypertension ” C. Renal Sympathetic Denervation H. Krum, et. al. Lancet 2009; 373:1275-1281 First in Man Study
Catheter-Based Renal Sympathetic Denervation • 4-6 two-minute treatments • Proprietary RF Generator − Automated − Low power − Built-in safety algorithms
Symplicity HTN-2 • International, multi-center, prospective, randomized, controlled study of the safety & effectiveness of renal denervation in patients with treatment-resistant hypertension • 190 patients enrolled in 24 centers in Europe, Australia, & New Zealand between June 2009 & January 2010 • Principal Investigator: – Murray D. Esler: Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia • Independent DSMB Chairman: – David P. Lee, Stanford University, Stanford, CA, USA • Sponsor: – Ardian, Inc. Mountain View, CA, USA
Study Design • Patient Population − Inclusion Criteria: Adults, office SBP ≥160 mmHg (≥150 mmHg with type 2 diabetics), stable drug regimen of ≥3 anti -HTN medications, bilateral single main renal artery of >20 mm length & 4 mm diameter − Exclusion Criteria: Renal artery stenosis or prior renal artery intervention, eGFR < 45 mL/min/1.73m2, type 1 diabetes, MI, unstable angina, or CVA in the prior 6M • Primary Endpoint – Automated office systolic BP change from baseline to 6M • Secondary Endpoints – Acute & chronic procedural safety, cardiovascular events through 6M, other measures of BP reduction at 6M • Enrolled patients underwent screening for: – Medication compliance, 2 weeks of twice-daily home monitoring – Renal artery anatomical suitability • Eligible patients were randomized 1:1 to either catheter-based renal denervation or to control, which did not undergo intervention • Background anti-HTN medication was held constant in both arms
Patient Disposition Assessed for Eligibility (n=190) Excluded During Screening, Prior to Randomization (n=84) Screening BP < 160 at Baseline Visit (after 2-weeks of medication compliance confirmation) (n=36; 19%) Ineligible anatomy (n=30; 16%) Declined participation (n=10; 5%) Other exclusion criteria discovered after consent (n=8; 4%) Randomized (n=106) Allocated to RDN Allocated to Control Allocation (n=52) (n = 54) All 52 received RDN No Six-Month Primary No Six-Month Primary Endpoint Visit (n = 3) Endpoint Visit (n = 3) Follow-up Reasons: Reasons: Withdrew consent (n=1) Withdrew consent (n=2) Missed visit (n=2) Lost to follow-up (n=1) Analyzed (n = 49) Analyzed (n = 51) Analysis
Baseline Characteristics Renal Denervation Control p-value (n=52) (n=54) 178 18 178 16 0.97 Baseline Systolic BP (mmHg) Baseline Diastolic BP (mmHg) 97 16 98 17 0.80 Age 58 12 58 12 0.97 Gender (% female) 35% 50% 0.12 Race (% Caucasian) 98% 96% >0.99 BMI (kg/m 2 ) 31 5 31 5 0.77 Type 2 diabetes 40% 28% 0.22 Coronary Artery Disease 19% 7% 0.09 Hypercholesterolemia 52% 52% >0.99 eGFR (MDRD, ml/min/1.73m 2 ) 77 19 86 20 0.013 eGFR 45-60 (% patients) 21% 11% 0.19 Serum Creatinine (mg/dL) 1.0 0.3 0.9 0.2 0.003 UACR (mg/g) † 128 363 109 254 0.64 Cystatin C (mg/L) †† 0.9 0.2 0.8 0.2 0.16 Heart rate (bpm) 75 15 71 15 0.23
Baseline Medications Renal Denervation Control p-value (n=52) (n=54) 5.2 1.5 5.3 1.8 Number Anti-HTN medications 0.75 % patients on HTN meds >5 years 71% 78% 0.51 % percent patients on ≥5 medications 67% 57% 0.32 % patients on drug class: ACEi/ARB 96% 94% >0.99 Direct renin inhibitor 15% 19% 0.80 Beta-blocker 83% 69% 0.12 Calcium channel blocker 79% 83% 0.62 Diuretic 89% 91% 0.76 Aldosterone antagonist 17% 17% >0.99 Vasodilator 15% 17% >0.99 Alpha-1 blocker 33% 19% 0.12 Centrally acting sympatholytic 52% 52% >0.99
Primary Endpoint 6-Month Office BP 6M 6M SBP DBP 10 1 0 0 †† -10 -12 -20 -30 33/11 mmHg -32 difference between RDN and Control -40 (p<0.0001) -50 Renal Denervation (n=49) Control (n=51)
Time Course of BP Change 1M 1M 3M 3M 6M 6M SBP DBP SBP DBP SBP DBP 10 1 0 0 0 0 -2 -4 †† -10 -7 -8 ††† -12 † BP Change -20 -20 † (mmHg) -24 † -30 † -32 † p<0.0001 †† p=0.002 -40 ††† p=0.005 Two-way repeated measures ANOVA, p=0.001 Renal Denervation -50 Control Home & 24 Hour Ambulatory Home Home ABPM ABPM SBP DBP SBP DBP 10 5 2 0 0 -1 -5 -3 BP -7 ††† Change -10 † (mmHg) †† -11 † -12 -15 -20 † -20 † p<0.0001 -25 †† p=0.014 ††† p=0.006 -30 All other p-values = NS Renal Denervation Control
Change in SBP distribution 100% 100% ≥ 160 mmHg ≥ 160 mmHg ≥ 160 mmHg 19% SBP ≥ 160 mmHg 80% 80% SBP 140 - 159 mmHg 60% 60% 76% 43% SBP < 140 mmHg 90% 96% 40% 40% 20% 20% 39% 18% 10% 0% 0% 6% 4% RDN RDN Control Control Baseline 6 Months Baseline 6 Months BP thresholds achieved at 6 months Renal Denervation (N=49) 100% 84% Control (N=51) 80% 60% 47% 35% 40% p-value for all between-group comparisons <0.0001 20% 10% 0% No ↓ ≥10 mmHg ↓ in SBP in SBP
Medication Changes Renal Denervation Control (n=49) (n=51) # Med Dose Decrease (%) 10 (20%) 4 (8%) # Med Dose Increase (%) 4 (8%) 5 (10%) Medication Escape • A medication change considered medically necessary due to at least one of: − an adverse event or symptom change, OR, − a SBP < 115 mmHg, OR − a SBP increase > 15 mmHg above baseline SBP Censoring after medication increases: • Renal Denervation Reduction of 29/11 20/11 mmHg (p<0.0001 for SBP & DBP) • Control Change of 0/-1 20/10 mmHg (p=0.97 & p=0.58 for SBP & DBP, respectively)
Procedural Safety Bilateral denervation performed in all patients randomized to treatment • No serious device or procedure related adverse events • Minor adverse events • – 1 femoral artery pseudoaneurysm treated with manual compression – 1 post-procedural drop in BP resulting in a reduction in medication – 1 urinary tract infection – 1 prolonged hospitalization for evaluation of paraesthesias – 1 back pain treated with pain medications & resolved after one month 43 patients have renal imaging available at 6 month follow-up • – No RF related observations – 1 MRA indicates possible progression of a pre-existing stenosis
Other Safety Renal Denervation Control (n=49) (n=51) Composite CV Events 3 3 Hypertensive event unrelated to non-adherence to medication 1 2 Transient ischemic attack 0 0 Other CV events Other Serious AEs 1 0 Hypertensive event after abruptly stopping clonidine 1 0 Hypotensive episode resulting in reduction of medications 1 1 Coronary stent for angina 1 0 Nausea/edema Δ Renal Function Renal Denervation Control Difference Mean ± SD Mean ± SD p-value (baseline - 6M) (95% CI) (n) (n) eGFR (MDRD) 0 ± 11 1 ± 12 -1 0.76 (51) (mL/min/1.73m 2 ) (49) (-5, 4) Serum Creatinine 0.0 ± 0.2 0.0 ± 0.1 0.0 0.66 (mg/dL) (49) (51) (-0.1, 0.1) Cystatin-C 0.1 ± 0.2 0.0 ± 0.1 0.0 0.31 (mg/L) (37) (40) (-0.0, 0.1)
Conclusions • Catheter-based renal denervation in patients with treatment-resistant essential hypertension results in significant reductions in BP • The magnitude of BP reduction can be predicted to have material impact on the development of hypertension related diseases and mortality • The technique was applied without significant complications • This experiment affirms the crucial relevance of renal nerves in the maintenance of elevated BP in patients with hypertension
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