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Patients with Treatment-Resistant Hypertension The Symplicity HTN-2 - - PowerPoint PPT Presentation
Patients with Treatment-Resistant Hypertension The Symplicity HTN-2 - - PowerPoint PPT Presentation
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
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Rate of spillover of noradrenaline from the kidneys to plasma (ng/min)
100 200 300 400
Normal BP 20-39 40-59 60-79 Essential Hypertension
** *
- A. “Increased Spillover of Noradrenaline into the
Renal Veins in Essential Hypertension” M Esler, G Lambert, G Jennings
J Hypertension 1990; 8: S53- S57 (Updated)
- B. “Renal Denervation Delays or Prevents
Development of Many Experimental Forms of Hypertension”
- C. Renal Sympathetic Denervation
First in Man Study G F DiBona
Physiol Rev 1997;77:75-197
- H. Krum, et. al.
Lancet 2009; 373:1275-1281
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- 4-6 two-minute treatments
- Proprietary RF Generator
− Automated − Low power − Built-in safety algorithms
Catheter-Based Renal Sympathetic Denervation
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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
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- 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
Study Design
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Assessed for Eligibility (n=190) Excluded During Screening, Prior to Randomization (n=84)
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 (n=52)
All 52 received RDN
Allocation Screening Allocated to Control (n = 54) Follow-up No Six-Month Primary Endpoint Visit (n = 3)
Reasons: Withdrew consent (n=1) Missed visit (n=2)
No Six-Month Primary Endpoint Visit (n = 3)
Reasons: Withdrew consent (n=2) Lost to follow-up (n=1)
Analysis Analyzed (n = 49) Analyzed (n = 51)
Patient Disposition
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Baseline Characteristics
Renal Denervation (n=52) Control (n=54) p-value
Baseline Systolic BP (mmHg) 178 18 178 16 0.97 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/m2) 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/1.73m2) 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
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Baseline Medications
Renal Denervation (n=52) Control (n=54) p-value
Number Anti-HTN medications 5.2 1.5 5.3 1.8 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
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Primary Endpoint
6-Month Office BP
- 32
- 12
1
- 50
- 40
- 30
- 20
- 10
10 6M SBP 6M DBP
Renal Denervation (n=49) Control (n=51) 33/11 mmHg
difference between RDN and Control (p<0.0001)
††
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- 20
- 7
- 24
- 8
- 32
- 12
- 4
- 2
1
- 50
- 40
- 30
- 20
- 10
10 1M SBP 1M DBP 3M SBP 3M DBP 6M SBP 6M DBP
† p<0.0001 †† p=0.002 ††† p=0.005
Two-way repeated measures ANOVA, p=0.001
† † † † †† ††† BP Change (mmHg)
Time Course of BP Change
BP Change (mmHg)
- 20
- 12
- 11
- 7
2
- 3
- 1
- 30
- 25
- 20
- 15
- 10
- 5
5 10 Home SBP Home DBP ABPM SBP ABPM DBP
Renal Denervation Control
† p<0.0001 †† p=0.014 ††† p=0.006
All other p-values = NS † † † †† †††
Home & 24 Hour Ambulatory
Renal Denervation Control
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10% 84% 47% 35% 0% 20% 40% 60% 80% 100% No ↓ in SBP ≥10 mmHg ↓ in SBP Renal Denervation (N=49) Control (N=51)
p-value for all between-group comparisons <0.0001
Change in SBP distribution BP thresholds achieved at 6 months
39% 10% 43% 90% 19%
0% 20% 40% 60% 80% 100%
RDN Baseline RDN 6 Months
≥ 160 mmHg
6% 4% 18% 96% 76%
Control Baseline Control 6 Months
≥ 160 mmHg
0% 20% 40% 60% 80% 100%
≥ 160 mmHg
SBP ≥ 160 mmHg SBP 140 - 159 mmHg SBP < 140 mmHg
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Medication Changes
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)
Renal Denervation (n=49) Control (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
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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
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Other Safety
Renal Denervation (n=49) Control (n=51)
Composite CV Events Hypertensive event unrelated to non-adherence to medication Transient ischemic attack Other CV events 3 1 3 2 Other Serious AEs Hypertensive event after abruptly stopping clonidine Hypotensive episode resulting in reduction of medications Coronary stent for angina Nausea/edema 1 1 1 1 1
Δ Renal Function
(baseline - 6M) Renal Denervation Mean ± SD (n) Control Mean ± SD (n) Difference (95% CI) p-value
eGFR (MDRD)
(mL/min/1.73m2)
0 ± 11
(49)
1 ± 12
(51)
- 1
(-5, 4)
0.76 Serum Creatinine
(mg/dL)
0.0 ± 0.2
(49)
0.0 ± 0.1
(51)
0.0
(-0.1, 0.1)
0.66 Cystatin-C
(mg/L)
0.1 ± 0.2
(37)
0.0 ± 0.1
(40)
0.0
(-0.0, 0.1)
0.31
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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