Resistant hypertension trials: Can renal denervation therapy lower - - PowerPoint PPT Presentation

CVCT 2012

Resistant hypertension trials: Can renal denervation therapy lower blood pressure?

Felix Mahfoud

Klinik für Innere Medizin III Kardiologie, Angiologie und Internistische Intensivmedizin Universitätsklinikum des Saarlandes

Conflicts of interest

Research funding

• Deutsche Hochdruckliga e. V.
• Deutsche Forschungsgemeinschaft (KFO 196)
• Ardian/Medtronic
• Vessix
• ReCor
• St. Jude

Advisory/speaker honorarium

• Ardian/Medtronic
• St. Jude

Resistant hypertension Failure to achieve target blood pressure values despite triple drug regimen (including a diuretic)

Calhoun DA. Circulation 2008

Prevalence ranges from 3-15%

• n = 205.750 patients, follow-up 3.8 years
• Risk of cardiovascular events (adjusted)
• HR 1.47, 95% CI 1.33-1.62

Daugherty SL, Circulation 2012

• n = 205.750 patients, follow-up 3.8 years
• Risk of cardiovascular events (adjusted)
• HR 1.47, 95% CI 1.33-1.62
• 1 in 50 patients with incident hypertension started on

treatment, developed resistant hypertension

Daugherty SL, Circulation 2012

Smith et al. AJH 2004

Normotensiv

Increased SNS activity in hypertension

Afferent and efferent sympathetic nerve fibers

Afferent

Renal ischemia Adenosine 

Efferent

Renin secretion Sodium retention Proteinuria Vasoconstriction Atherosclerosis LVH Ischemia Heart Failure Gluconeogenesis ↑ Insulin resistance Mahfoud F et al, DMW 2010

Sympathetic nerves in the adventitia of renal arteries

Media Adventitia Vessel lumen Renal nerves

• A. renalis, Sprague Dawley rat, tyrosin hydroxylase antibody staining

red: tyrosine hydroxylase, green: α-smooth muscle actin, blue: DAPI Unpublished data by Mahfoud F et al

Catheter-based renal denervation

’

Inclusion and exclusion criteria

Key inclusion criteria

• Office blood pressure ≥160 mmHg (≥150 mmHg for

diabetics) despite ≥3 anti-hypertensive medications

• eGFR (MDRD) ≥45 mL/min/1.73m2

Key exclusion criteria

• known secondary cause of hypertension
• Type I diabetes mellitus
• renovascular abnormalities: significant renal artery

stenosis, prior renal stenting or angioplasty, dual renal arteries

Symplicity HTN-2 Investigators. The Lancet. 2010.

Patient’s characteristics

N=106 Age 58 ± 12 Gender (% female) 50% Type 2 diabetes 28% eGFR (MDRD, ml/min/1.73m2) 86 ± 20

Symplicity HTN-2 Investigators. The Lancet. 2010.

Patient’s characteristics

N=106 Age 58 ± 12 Gender (% female) 50% Type 2 diabetes 28% eGFR (MDRD, ml/min/1.73m2) 86 ± 20 Systolic BP (mmHg) 178 ± 16 Diastolic BP (mmHg) 98 ± 17 # Anti-HTN Meds 5.3 ± 1.8

Symplicity HTN-2 Investigators. The Lancet. 2010.

Study design

Primary Endpoint:

– Change in Office SBP from baseline to 6 months

52 Treatment Group Control Group Primary Endpoint 6M 12 - 36M Anatomical Screening Randomized Baseline 2 week observation SBP≥160

Following collection of the primary endpoint at 6-months, control patients permitted to cross-over

106 54 6M

Symplicity HTN-2 Investigators. Lancet. 2010.

Primary endpoint: 6-months office BP

∆ from Baseline to 6 Months (mmHg) 33/11 mmHg difference between RDN and Control (p<0.0001)

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• 50
• 40
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10 RDN (n=49) Control (n=51)

Systolic Diastolic Systolic Diastolic

Symplicity HTN-2 Investigators. Lancet. 2010.

BP changes (mmHg)

p<0.01 for all changes compared to baseline

Blood pressure reduction sustains over 3 years

Schlaich MS, TCT 2012

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• 25
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1 mo (n=143) 3 mo (n=148) 6 mo (n=144) 12 mo (n=132) 24 mo (n=105) 30 mo (n=44) 36 mo (n=34)

SBP mmHg DBP mmHg

Blood pressure control after 36 months

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Baseline 1 mo 12 mo 24 mo 36 mo ≥ 180 mmHg 160-179 mmHg 140-159 mmHg < 140 mmHg % Patients

(N=150) (N=143) (N=132) (N=105) (N=34)

Schlaich MS, TCT 2012

BP Change

24-hour blood pressure in Symplicity

Home BP Change (mmHg)

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• 16
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2 RDN (n=20) Control (n=25)

Systolic Diastolic Systolic Diastolic Symplicity HTN-2 Investigators.The Lancet. 2010.

p=0.006 p=0.014 p=0.51 p=0.75

Analysis on technically sufficient (>70% of readings) paired baseline and 6-month

ABPM – patient characteristics

Mahfoud F, unpublished data

N=80 Age (years) 58 ± 12 Gender (% female) 35% Type 2 diabetes 44% eGFR (MDRD, ml/min/1.73m2) 72 ± 13

ABPM – patient characteristics

N=80 Age (years) 58 ± 12 Gender (% female) 35% Type 2 diabetes 44% eGFR (MDRD, ml/min/1.73m2) 72 ± 13 Antihypertensive drugs (#) 5.4 ± 1.5 SBP (mmHg) 169 ± 22 DBP (mmHg) 92 ± 15 HR (bpm) 69 ± 12

Mahfoud F, unpublished data

ABPM – patient characteristics

N=80 Mean SBP (mmHg) 151 ± 17 Mean DBP (mmHg) 85 ± 14

Mahfoud F, unpublished data

ABPM – patient characteristics

N=80 Mean SBP (mmHg) 151 ± 17 Mean DBP (mmHg) 85 ± 14 Mean SBP day (mmHg) 154 ± 18 Mean DBP day (mmHg) 88 ± 14 Mean SBP night (mmHg) 142 ± 22 Mean DBP night (mmHg) 79 ± 15

Mahfoud F, unpublished data

Real world experience – office BP reduction

Changes in office BP (mmHg)

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3 M FU 6 M FU

SBP DBP SBP DBP

p<0.001 p<0.001 p<0.001 p<0.001

Mahfoud F, unpublished data

Changes in mean 24-hour BP

BP changes (mmHg) p=0.019 p=0.025 p=0.018 p=0.022

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3 M FU 6 M FU

SBP DBP SBP DBP

Mahfoud F, unpublished data

BP changes (mmHg) p=0.019 p=0.025 p=0.018 p=0.022

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3 M FU 6 M FU

SBP DBP SBP DBP

Changes in mean 24-hour BP

Mahfoud F, unpublished data

Changes in daytime and nighttime BP

BP changes (mmHg)

p=0.025

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• 12
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3 M FU 6 M FU 3 M FU 6 M FU

SBP DBP SBP SBP SBP DBP DBP DBP

p=0.001 p=0.001 p=0.001 p=0.002 p=0.004 p=0.004 p=0.002

daytime

Mahfoud F, unpublished data

Changes in daytime and nighttime BP

BP changes (mmHg)

p=0.025

• 9
• 12
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3 M FU 6 M FU 3 M FU 6 M FU

SBP DBP SBP SBP SBP DBP DBP DBP

p=0.001 p=0.001 p=0.001 p=0.002 p=0.004 p=0.004 p=0.002

daytime nighttime

Mahfoud F, unpublished data

Reductions in maximum and minimum SBP

BP changes (mmHg)

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3 M FU 6 M FU 3 M FU 6 M FU

Max. SBP Max. SBP Min. SBP Min. SBP

p=0.009 p=0.003 p=0.013 p=0.011

Mahfoud F, unpublished data

24-hour BP changes are comparable to spironolactone treatment – ASPIRANT study

Václavík J, et a. Hypertension. 2011;57:1069-75.

Step 4 Aged over 55 years or black person of African or Caribbean family origin of any age Aged under 55 years Calcium Channel Blocker ACE or ARB ACE/ARB + CCB ACE/ARB + CCB + Diuretic Resistant hypertension ACE/ARB + CCB+ Diuretic Consider spironolactone, alpha- or beta-blocker Seek expert advice Step 1 Step 2 Step 3

NICE Guidance on Renal Denervation

Mean ABP reductions in the subgroup of patients treated with spironolactone (n=26)

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3 M FU 6 M FU

SBP DBP DBP SBP

p=0.011 p=0.022 p=0.014 p=0.019

Mahfoud F, unpublished data

120 140 160 180 200 220 240 25 50 75 100 % of maximum workload Systolic blood pressure (mmHg) Baseline 3 months after RD p<0.0001 p<0.0001 p<0.0001 p<0.0001 p<0.001 Ukena C, Mahfoud F et al, JACC 2011

No chronotropic incompetence after RDN

25 50 75 100 % of maximum work rate Rest Recovery 20 40 60 80 100 120 140

p=0.028 p=0.006 p=0.121 p=0.074 p=0.141 p=0.001

Baseline 3 months after RD

Heart rate (bpm)

Ukena C, Mahfoud F et al, JACC 2011

Brandt MC, et al. JACC 2012

EnligHTN catheter

Papademetriou V, Hotline Session AHA 2012

Office BP reduction in EnligHTN-1

P<0.001

Papademetriou V, Hotline Session AHA 2012

ABPM changes in EnligHTN-1

Papademetriou V, Hotline Session AHA 2012

ReCor Paradise

• Up to three 50-seconds

emissions per artery

• Up to 5 minutes total

heating time

• Average of 23 minutes

between first emission and last emission

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• 50 mm Hg
• 40 mm Hg
• 30 mm Hg
• 20 mm Hg
• 10 mm Hg

0 mm Hg 2 weeks (n = 15) 1 month (n = 15) 2 months (n = 15) 3 months (n = 15) 6 months (n = 11) 12 months (n = 3) Systolic Diastolic

Error bars represent 95% Confidence Interval

Office blood pressure reduction in REDUCE

Response

Predictors of response (SBP >10 mmHg)

• SBP >175 mmHg at baseline

Symplicity HTN-2 Investigators. Lancet. 2010. Mahfoud F, Hypertension 2012 R=-0.46, p<0.001

1. G 2. G 3. G

• 1. group: <160 mmHg
• 2. group: 160-175 mmHg
• 3. group: >175 mmHg

Response

Predictors of response (SBP >10 mmHg)

• SBP >175 mmHg at baseline

No predictors of non-response available

• Non-response rate app. 20%

Symplicity HTN-2 Investigators. Lancet. 2010. Symplicity HTN1 Investigators; Hypertension. 2011;57:911-917.

Mahfoud F et al., unpublished data

Predictors of response

• 44 minutes mean procedure time

Treatment delivered without complication 98% (337/344) – 5 access site complications – 1 contrast medium reaction RF treatment related vascular complications – 3 progressions of a pre-existing renal artery stenosis (30-50%80%), possibly related to catheter manipulation, successfully stented

Mahfoud F, unpublished data

Safety profile – data from Homburg/Saar

Vonend O et al, Lancet 2012

Diabetes Renal function Myocardial function OSA

Efferent Afferent

Mahfoud F, Circulation 2011 Schlaich M, J Hypertens 2011 Hering D, Mahfoud F, JASN 2012 Mahfoud F, Hypertension 2012 Brandt MC, Mahfoud F, JACC 2012 Ukena C, Mahfoud F, Int J Card 2012 Linz D, Mahfoud F, Hypertension 2012 Linz D, Mahfoud F, Hypertension 2012 Linz D, Hypertension 2012 Witkowski A, Hypertension 2011

Pleiotropic effects of renal denervation

Quo vadis... Arrhythmias

Insulin resistance and diabetes

Chronic kidney disease

Obstructive sleep apnea

Hypertension

• Dr. Felix Mahfoud, MD

Klinik für Innere Medizin III Universitätsklinikum des Saarlandes Homburg/Saar, Germany

• Tel. +49 6841-16-21346
• Fax. +49 6841-16-13211

felix.mahfoud@uks.eu

Thank you!