Transcript (The Symplicity HTN-2 Trial): a randomised

RENAL SYMPATHETIC
DENERVATION
Anxiolytic for nervous kidneys???
HYPERTENSION
 Is according to the WHO the most frequent cause of
death worldwide.
 In 2025, 50% of the adult population will be
hypertensive.
 20-30% of patients are considered to have resistant
HTN despite availability of potent medications.
HYPERTENSION
 20/10mmHg increase in blood pressure doubles
cardiovascular mortality.
 Reduction of systolic blood pressure by only 10
mmHg reduces the risk of stroke by 30%.
 7.5 million deaths annually.
HYPERTENSION
30%
Untreated
35%
Treated but
Uncontrolled
35%
Treated &
Controlled
• Only half of all treated
hypertensives are controlled
to established BP targets.
• High prevalence:
• Affects 1 in 3 adults.
• 1B people worldwide 
1.6 B by 2025
Chobanian et al. Hypertension. 2003;42(6):1206–1252.
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Renal Sympathetic Activation: Efferent Nerves
Kidney as Recipient of Sympathetic Signals
Renal Efferent
Nerves
↑ Renin Release  RAAS activation
↑ Sodium Retention
↓ Renal Blood Flow
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Renal Sympathetic Activation: Afferent Nerves
Kidney as Origin of Central Sympathetic Drive
Vasoconstriction
Atherosclerosis
Insulin
Resistance
Sleep
Disturbances
Renal Afferent
Nerves
Hypertrophy
Arrhythmia
Oxygen Consumption
↑ Renin Release  RAAS activation
↑ Sodium Retention
↓ Renal Blood Flow
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Initial Cohort – Reported in the Lancet, 2009:
-First-in-man, non-randomized
-Cohort of 45 patients with resistant HTN (SBP ≥160 mmHg on
≥3 anti-HTN drugs, including a diuretic; eGFR ≥ 45 mL/min)
- 12-month data
Renal Nerve Anatomy
Nerves arise from T10-L2
Follow the renal artery to the kidney
Primarily lie within the adventitia.
Vessel
Lumen
Medi
a
Adventitia
Renal
Nerves
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Catheter-Based Approach
Spacing of
e.g. 5 mm.
• Renal artery access via standard
interventional technique
• Radiofrequency electrode tip
• 4-6 two-minute treatments per artery
• RF generator
– Automated
– Low power-max 8 Watts
– Built-in safety mechanisms
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Hypertension. 2011;57:911-917.
Expanded Cohort – This Report (Symplicity HTN-1):
-Expanded cohort of patients (n=153)
-36-month follow-up
-90% response rate, >20/10mmHg reduction.
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Lancet. 2010;376:1903-1909.
The simplicity HTN-2 Trial
• Purpose: To demonstrate the effectiveness of catheter-based
renal denervation for reducing blood pressure in patients with
uncontrolled hypertension.
• Study design: Randomized, controlled clinical trial.
• Patients: 106 patients randomized 1:1 to treatment with
renal denervation vs. control.
• Participating centres: 24 centers in Europe, Australia, & New
Zealand.
The simplicity HTN-2 Trial
Inclusion Criteria:
• -Office SBP ≥ 160 mmHg (≥ 150 mmHg with type II diabetes
mellitus)
• -3+ more anti-HTN medications
• -Age 18-85 years
Exclusion Criteria:
• -Significant renal artery abnormalities or prior renal artery
intervention
• -eGFR < 45 mL/min/1.73m2 (MDRD formula)
• -Type 1 diabetes
• -Contraindication to MRI
• -Significant stenotic valvular heart disease
• -MI, unstable angina, or CVA in the preceding 6 months
The simplicity HTN-2 Trial
Before randomisation and to assess eligibility:
•
Screening process required patients to record daily bd
automated BP measurements and to document drug compliance
for 2/52.
•
Renal artery anatomical screening, with renal duplex, CT, MRI or
renal angiography to confirm anatomical eligibility.
•
Baseline creatinine, Cystatin C, ACR.
•
24hr BP measurement.
June 09 – jan 10
RDN
(n = 52)
Control
(n = 54)
Baseline systolic BP (mmHg)
178 ± 18
178 ± 16
Baseline diastolic BP (mmHg)
97 ± 16
98 ± 17
Number anti-HTN medications
5.2 ± 1.5
5.3 ± 1.8
Age
58 ± 12
58 ± 12
Gender (female) (%)
35%
50%
Race (Caucasian) (%)
98%
96%
31 ± 5
31 ± 5
Type 2 diabetes
40%
28%
Coronary artery disease
19%
7%
Hypercholesterolemia
52%
52%
eGFR (MDRD, ml/min/1.73m2)
77 ± 19
86 ± 20
Serum creatinine (mg/dL)
1.0 ± 0.3
0.9 ± 0.2
Urine alb/creat ratio (mg/g)*
128 ± 363
109 ± 254
Cystatin C (mg/L)†
0.9 ± 0.2
0.8 ± 0.2
Heart rate (bpm)
75 ± 15
71 ± 15
BMI (kg/m2)
Follow up
• At 1, 3 and 6 months, with rpt creat, Cystatin C, BP, ACR.
• Office and home BP readings, average of 3.
• Daily home BP and drug compliance diary 2/52 prior to the 6
month FU.
• At 6 months: 24hr BP monitor and renal imaging in the renal
denervation group.
. 84% of RDN patients had ≥10 mmHg reduction in SBP
. 10% of RDN patients had no reduction in SBP
. p <0.001 for difference between RDN and Control
Adverse events
• No significant change in renal function.
• One renal artery dissection from injection of contrast into renal arter
wall during dye angiography. The lesion was stented without further
consequences.
Minor adverse events (n=52)
•1 femoral artery pseudoaneurysm  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
6-month renal imaging (n=43)
•No vascular abnormality at any RF treatment site
•1 MRA indicates possible progression of a pre-existing stenosis unrelated to RF
treatment (no further therapy)
Conclusions
• Catheter-based renal denervation, done in a multicentre,
randomised trial in patients with treatment-resistant
essential hypertension, resulted in significant reductions in
BP.
• The technique was applied without major complications.
• This therapeutic innovation, based on the described neural
pathophysiology of essential hypertension, affirms the
crucial relevance of renal nerves in the maintenance of BP
in patients with hypertension.
• Catheter-based renal denervation may be beneficial for
patients with treatment-resistant essential hypertension.
Limitations
• Non-blinded trial.
• ?long-term benefit, ?evidence of reinnervation
• Small number of patients.
• Was the population truly treatment resistant?
• Adjustments in medications, unclear effect on pill burden
• Effect in patients with more severe CKD.
Simplicity HTN-3 trial on way
Discussion