Renal denervation in
resistant hypertension,
with target organ
damage
Darrel Francis
Reader in Cardiology
Imperial College, London
BHS,
Cambridge 2011
REACH – pilot study
REnal Artery denervation in Chronic Heart failure
Imperial College London
55 female
Hypertension for over 20 years since the birth of her first child
15 years blood pressure >180 mm Hg
tolerated well
no evidence of secondary organ involvement
REACH – pilot study
REnal Artery denervation in Chronic Heart failure
Imperial College London
Extensive review
tertiary (Newcastle)
and at national specialist centres (Cambridge)
Excluded secondary causes of hypertension
Renal artery stenosis
Congenital causes
Malignancy
Tests
Normal renal function
No proteinuria
CT/MRI
Renal vein sampling
Progressive worsening of hypertension
18 months blood pressure sustained >230 mm Hg (250-270mm Hg)
episodes of blood pressure exceeding 300 mmHg
6 months heart failure – moderate-severe systolic impairment
Marked decrease in exercise capacity (200 yards)
3 in-patient admissions
1 ITU admission (Pulmonary oedema)
pre-syncope when blood pressure <170 mmHg
Pharmacological regime
Primary Endpoint: 6-Month Office BP
∆ from
Baseline
to
6 Months
(mmHg)
Systolic
Diastolic
Diastolic
Systolic
•
•
33/11 mmHg
difference between RDN and Control
(p<0.0001)
84% of RDN patients had ≥ 10 mmHg reduction in SBP
10% of RDN patients had no reduction in SBP
Symplicity HTN-2 Investigators. The Lancet 2010: 376:1903-1909
7
Primary Endpoint: 6-Month Office BP
∆ from
Baseline
to
6 Months
(mmHg)
Systolic
Diastolic
Diastolic
Systolic
•
•
33/11 mmHg
difference between RDN and Control
(p<0.0001)
84% of RDN patients had ≥ 10 mmHg reduction in SBP
10% of RDN patients had no reduction in SBP
Symplicity HTN-2 Investigators. The Lancet 2010: 376:1903-1909
8
Primary Endpoint: 6-Month Office BP
∆ from
Baseline
to
6 Months
(mmHg)
Systolic
Diastolic
Diastolic
Systolic
•
•
33/11 mmHg
difference between RDN and Control
(p<0.0001)
84% of RDN patients had ≥ 10 mmHg reduction in SBP
10% of RDN patients had no reduction in SBP
Symplicity HTN-2 Investigators. The Lancet 2010: 376:1903-1909
9
Primary Endpoint: 6-Month Office BP
∆ from
Baseline
to
6 Months
(mmHg)
Systolic
Diastolic
Diastolic
Systolic
•
•
33/11 mmHg
difference between RDN and Control
(p<0.0001)
84% of RDN patients had ≥ 10 mmHg reduction in SBP
10% of RDN patients had no reduction in SBP
Symplicity HTN-2 Investigators. The Lancet 2010: 376:1903-1909
10
Primary Endpoint: 6-Month Office BP
∆ from
Baseline
to
6 Months
(mmHg)
Systolic
Diastolic
Diastolic
Systolic
•
•
33/11 mmHg
difference between RDN and Control
(p<0.0001)
84% of RDN patients had ≥ 10 mmHg reduction in SBP
10% of RDN patients had no reduction in SBP
Symplicity HTN-2 Investigators. The Lancet 2010: 376:1903-1909
11
Primary Endpoint: 6-Month Office BP
∆ from
Baseline
to
6 Months
(mmHg)
Systolic
Diastolic
Diastolic
Systolic
•
•
33/11 mmHg
difference between RDN and Control
(p<0.0001)
84% of RDN patients had ≥ 10 mmHg reduction in SBP
10% of RDN patients had no reduction in SBP
Symplicity HTN-2 Investigators. The Lancet 2010: 376:1903-1909
12
Primary Endpoint: 6-Month Office BP
∆ from
Baseline
to
6 Months
(mmHg)
Systolic
Diastolic
Diastolic
Systolic
•
•
33/11 mmHg
difference between RDN and Control
(p<0.0001)
84% of RDN patients had ≥ 10 mmHg reduction in SBP
10% of RDN patients had no reduction in SBP
Symplicity HTN-2 Investigators. The Lancet 2010: 376:1903-1909
13
Renal Denervation – practicalities of the technique
Symplicity® Catheter System™
• Low profile, electrode-tipped catheter
• Delivers RF energy to treatment site
• Proprietary RF generator
- Low power
- Automated
- Built-in safety control algorithms
• Standard interventional technique
Multiple Discrete Treatments
Maximize Nerve Coverage Without Applying Circumferential Energy in a Single
Segment
6-Month Histology (Porcine Model)
Movat’s pentachrome stain
cutting
artifact
Zone of
energy
delivery
20X magnification
100X magnification
Findings: Minimal intimal thickening and minimal IEL injury overlying areas of mild full
thickness medial fibrosis (yellow with green [proteoglycan deposition]), and adventitial
fibrosis (yellow). No significant inflammatory cells are present suggesting that the healing
process is complete.
REACH Phase 1
7-patient safety study
Investigator-led study
Academic Health Science Centre, Cardiovascular Practice Group
Aim
Determine first-in-man safety of procedure
in 7 patients with CHF
Inpatient monitoring for 5 days afterwards
Weekly and then monthly outpatient
monitoring for 6 months
REACH Phase 1
7-patient safety study
Day Minus 1
Admission
Clinical assessment
QoL
Bloods
Electrolytes, Creatinine,
NT-ProBNP
Renin, aldosterone
Fasting glucose, insulin
24-hour Urine
Sodium output
Creatinine output
Chemoreflex testing
Dynamic sinusoidal CO2 stimulus
Rebreathing CO2 stimulus
Exercise
6 minute walk test
Cardiopulmonary exercise test
Echocardiography
Heart rate / BP variability
Recumbent spontaneous
Controlled breathing
24-hour ambulatory monitors
BP
ECG
REACH Phase 1
Day 0
7-patient safety study
Post-procedure
Procedure
Research Cath Lab
Anaesthetist
On standby:
Interventional Radiologist
Vascular surgeon
Nephrologist
Care plan designed with Head of Nursing
Patient returns to ward
Team of Specialist Research
Nursing Sisters
Dr Justin Davies and Dr Darrel Francis
are first point of contact
for ward team if any queries
5-day postprocedure stay planned,
with option to extend
REACH Phase 1
Day +1
Clinical assessment
Bloods
Electrolytes,
Creatinine,
NT-ProBNP
Renin,
aldosterone
Fasting glucose,
insulin
7-patient safety study
24-hour Urine
Sodium output
Creatinine output
Metanephrines
24-hour ambulatory monitors
BP
ECG
REACH Phase 1
Day +2 .. +4
Clinical assessment
Bloods
Electrolytes,
Creatinine,
NT-ProBNP
Renin,
aldosterone
Fasting glucose,
insulin
7-patient safety study
24-hour Urine
Sodium output
Creatinine output
Metanephrines
24-hour ambulatory monitors
BP
ECG
REACH Phase 1
7-patient safety study
Week +1
Chemoreflex testing
Dynamic sinusoidal CO2 stimulus
Rebreathing CO2 stimulus
Bloods
Electrolytes, Creatinine,
NT-ProBNP
Renin, aldosterone
Fasting glucose, insulin
24-hour Urine
Sodium output
Creatinine output
Exercise
6 minute walk test
Cardiopulmonary exercise test
Echocardiography
Heart rate / BP variability
Recumbent spontaneous
Controlled breathing
24-hour ambulatory monitors
BP
ECG
REACH Phase 1
7-patient safety study
Week +2
Chemoreflex testing
Dynamic sinusoidal CO2 stimulus
Rebreathing CO2 stimulus
Bloods
Electrolytes, Creatinine,
NT-ProBNP
Renin, aldosterone
Fasting glucose, insulin
24-hour Urine
Sodium output
Creatinine output
Exercise
6 minute walk test
Cardiopulmonary exercise test
Echocardiography
Heart rate / BP variability
Recumbent spontaneous
Controlled breathing
24-hour ambulatory monitors
BP
ECG
REACH Phase 1
7-patient safety study
Month +1
Chemoreflex testing
Dynamic sinusoidal CO2 stimulus
Rebreathing CO2 stimulus
Bloods
Electrolytes, Creatinine,
NT-ProBNP
Renin, aldosterone
Fasting glucose, insulin
24-hour Urine
Sodium output
Creatinine output
Exercise
6 minute walk test
Cardiopulmonary exercise test
Echocardiography
Heart rate / BP variability
Recumbent spontaneous
Controlled breathing
24-hour ambulatory monitors
BP
ECG
REACH Phase 1
7-patient safety study
Month +2
Chemoreflex testing
Dynamic sinusoidal CO2 stimulus
Rebreathing CO2 stimulus
Bloods
Electrolytes, Creatinine,
NT-ProBNP
Renin, aldosterone
Fasting glucose, insulin
24-hour Urine
Sodium output
Creatinine output
Exercise
6 minute walk test
Cardiopulmonary exercise test
Echocardiography
Heart rate / BP variability
Recumbent spontaneous
Controlled breathing
24-hour ambulatory monitors
BP
ECG
REACH Phase 1
7-patient safety study
Month +3
Chemoreflex testing
Dynamic sinusoidal CO2 stimulus
Rebreathing CO2 stimulus
Bloods
Electrolytes, Creatinine,
NT-ProBNP
Renin, aldosterone
Fasting glucose, insulin
24-hour Urine
Sodium output
Creatinine output
Exercise
6 minute walk test
Cardiopulmonary exercise test
Echocardiography
Heart rate / BP variability
Recumbent spontaneous
Controlled breathing
24-hour ambulatory monitors
BP
ECG
REACH Phase 1
7-patient safety study
Month +4
Chemoreflex testing
Dynamic sinusoidal CO2 stimulus
Rebreathing CO2 stimulus
Bloods
Electrolytes, Creatinine,
NT-ProBNP
Renin, aldosterone
Fasting glucose, insulin
24-hour Urine
Sodium output
Creatinine output
Exercise
6 minute walk test
Cardiopulmonary exercise test
Echocardiography
Heart rate / BP variability
Recumbent spontaneous
Controlled breathing
24-hour ambulatory monitors
BP
ECG
REACH Phase 1
7-patient safety study
Month +5
Chemoreflex testing
Dynamic sinusoidal CO2 stimulus
Rebreathing CO2 stimulus
Bloods
Electrolytes, Creatinine,
NT-ProBNP
Renin, aldosterone
Fasting glucose, insulin
24-hour Urine
Sodium output
Creatinine output
Exercise
6 minute walk test
Cardiopulmonary exercise test
Echocardiography
Heart rate / BP variability
Recumbent spontaneous
Controlled breathing
24-hour ambulatory monitors
BP
ECG
REACH Phase 1
7-patient safety study
Month +6
Chemoreflex testing
Dynamic sinusoidal CO2 stimulus
Rebreathing CO2 stimulus
Bloods
Electrolytes, Creatinine,
NT-ProBNP
Renin, aldosterone
Fasting glucose, insulin
24-hour Urine
Sodium output
Creatinine output
Exercise
6 minute walk test
Cardiopulmonary exercise test
Echocardiography
Heart rate / BP variability
Recumbent spontaneous
Controlled breathing
24-hour ambulatory monitors
BP
ECG
REACH – pilot patient
REnal Artery denervation in Chronic Heart failure
Extensive pre-procedural preparation
Admission
Review by clinical pharmacology team
Anaesthetic review
Biochemistry / Imaging performed
Echo – severe LV systolic function
Detailed review of notes from previous investigations
REACH – pilot patient
REnal Artery denervation in Chronic Heart failure
Procedure
Anaesthetic input to maintain SBP at 180 mmHg
Uncomplicated denervation procedure
Immediate after-care
Immediate fall in blood pressure overnight to 150 mm Hg
Medications temporary reduced,
and then slowly restored to original levels
REACH – pilot patient
REnal Artery denervation in Chronic Heart failure
Discharge
Reduction in 2 of her anti-hypertensive agents
Blood pressure 190-200 mmHg
Felt well
REACH – pilot patient
REnal Artery denervation in Chronic Heart failure
Follow-up (2 weeks)
Large symptomatic improvement in breathlessness
Blood pressure 190-200 mmHg
Exercise tolerance increased from 200 m to 1 mile
Medications re-introduced at full dose with the aim to slowly
reduce her blood pressure
REACH – pilot study
REnal Artery denervation in Chronic Heart failure
Follow-up (4 months)
Continues to feels well
Improvement in exercise capacity persists
250-280
mmHg
systolic
200-205
mmHg
systolic
Close enough
to target
most of the time
Close enough
to target
most of the time
~2 x
~2 x
~2 x
REACH – pilot study
REnal Artery denervation in Chronic Heart failure
Follow-up (4 months)
Continues to feels well
Improvement in exercise capacity persists
250-280
mmHg
systolic
200-205
mmHg
systolic