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) Prevalence ranges from 3-15% Calhoun DA. Circulation 2008

• 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

Increased SNS activity in hypertension Normotensiv Smith et al. AJH 2004

Afferent and efferent sympathetic nerve fibers Efferent Afferent Vasoconstriction Gluconeogenesis ↑ Atherosclerosis Insulin resistance Renal ischemia Renin secretion Adenosine  LVH Sodium retention Ischemia Proteinuria Heart Failure Mahfoud F et al, DMW 2010

Sympathetic nerves in the adventitia of renal arteries A. renalis, Sprague Dawley rat, tyrosin hydroxylase antibody staining red: tyrosine hydroxylase, green: α -smooth muscle actin, blue: DAPI Renal nerves Media Adventitia Vessel lumen Unpublished data by Mahfoud F et al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/1.73m 2 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 58 ± 12 Age Gender (% female) 50% Type 2 diabetes 28% 86 ± 20 eGFR (MDRD, ml/min/1.73m 2 ) Symplicity HTN-2 Investigators. The Lancet. 2010.

Patient’s characteristics N=106 58 ± 12 Age Gender (% female) 50% Type 2 diabetes 28% 86 ± 20 eGFR (MDRD, ml/min/1.73m 2 ) 178 ± 16 Systolic BP (mmHg) 98 ± 17 Diastolic BP (mmHg) 5.3 ± 1.8 # Anti-HTN Meds Symplicity HTN-2 Investigators. The Lancet. 2010.

Study design Primary Endpoint: – Change in Office SBP from baseline to 6 months 54 Following Anatomical Screening 6M Control Group collection of the Baseline 2 week observation Randomized primary endpoint at 6-months, control patients SBP≥160 Primary 106 Endpoint permitted to cross-over Treatment Group 6M 12 - 36M 52 Symplicity HTN-2 Investigators. Lancet. 2010.

Primary endpoint: 6-months office BP RDN (n=49) Control (n=51) 10 1 ∆ from 0 0 Baseline to -10 Systolic Diastolic 6 Months -12 (mmHg) -20 Diastolic -30 -32 -40 Systolic 33/11 mmHg -50 difference between RDN and Control (p<0.0001) Symplicity HTN-2 Investigators. Lancet. 2010.

Blood pressure reduction sustains over 3 years 0 -5 BP changes (mmHg) -10 p<0.01 for all -9 -10 -10 -15 changes compared -14 -14 -20 to baseline -16 -19 -17 -25 -21 -22 -30 -27 SBP mmHg -35 -29 DBP mmHg -31 -40 -34 -45 1 mo 3 mo 6 mo 12 mo 24 mo 30 mo 36 mo (n=143) (n=148) (n=144) (n=132) (n=105) (n=44) (n=34) Schlaich MS, TCT 2012

Blood pressure control after 36 months 100% 90% 80% 70% % Patients 60% ≥ 180 mmHg 160-179 mmHg 50% 140-159 mmHg 40% < 140 mmHg 30% 20% 10% 0% Baseline 1 mo 12 mo 24 mo 36 mo (N=150) (N=143) (N=132) (N=105) (N=34) Schlaich MS, TCT 2012

24-hour blood pressure in Symplicity RDN (n=20) Control (n=25) 2 0 -2 Home BP -1 BP Change -4 -3 Diastolic (mmHg) Change -6 Systolic p=0.75 -8 -7 p=0.51 -10 -12 -11 Diastolic -14 p=0.014 -16 Systolic -18 p=0.006 Analysis on technically sufficient (>70% of readings) paired baseline and 6-month Symplicity HTN-2 Investigators.The Lancet. 2010.

ABPM – patient characteristics N=80 58 ± 12 Age (years) Gender (% female) 35% Type 2 diabetes 44% 72 ± 13 eGFR (MDRD, ml/min/1.73m 2 ) Mahfoud F, unpublished data

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

ABPM – patient characteristics N=80 151 ± 17 Mean SBP (mmHg) 85 ± 14 Mean DBP (mmHg) Mahfoud F, unpublished data

ABPM – patient characteristics N=80 151 ± 17 Mean SBP (mmHg) 85 ± 14 Mean DBP (mmHg) 154 ± 18 Mean SBP day (mmHg) 88 ± 14 Mean DBP day (mmHg) 142 ± 22 Mean SBP night (mmHg) 79 ± 15 Mean DBP night (mmHg) Mahfoud F, unpublished data

Real world experience – office BP reduction 3 M FU 6 M FU 0 Changes in office BP (mmHg) -5 DBP DBP -7 -10 -9 p<0.001 p<0.001 -15 SBP -20 -21 SBP -25 p<0.001 -26 -30 p<0.001 Mahfoud F, unpublished data

Changes in mean 24-hour BP 3 M FU 6 M FU 0 -2 BP changes (mmHg) DBP -4 -4 -6 DBP p=0.025 -8 -7 SBP p=0.022 -10 -9 SBP -12 p=0.019 -12 -14 p=0.018 -16 Mahfoud F, unpublished data

Changes in mean 24-hour BP 3 M FU 6 M FU 0 -2 BP changes (mmHg) DBP -4 -4 -6 DBP p=0.025 -8 -7 SBP p=0.022 -10 -9 SBP -12 p=0.019 -12 -14 p=0.018 -16 Mahfoud F, unpublished data

Changes in daytime and nighttime BP daytime 3 M FU 6 M FU 3 M FU 6 M FU 0 -2 BP changes (mmHg) -4 DBP DBP DBP SBP -6 -5 -5 -5 DBP -6 p=0.001 p=0.004 p=0.002 -8 -7 SBP p=0.002 SBP p=0.001 -10 -9 -10 SBP -12 p=0.025 p=0.004 -12 -14 p=0.001 -16 Mahfoud F, unpublished data

Changes in daytime and nighttime BP daytime nighttime 3 M FU 6 M FU 3 M FU 6 M FU 0 -2 BP changes (mmHg) -4 DBP DBP DBP SBP -6 -5 -5 -5 DBP -6 p=0.001 p=0.004 p=0.002 -8 -7 SBP p=0.002 SBP p=0.001 -10 -9 -10 SBP -12 p=0.025 p=0.004 -12 -14 p=0.001 -16 Mahfoud F, unpublished data

Reductions in maximum and minimum SBP 3 M FU 6 M FU 3 M FU 6 M FU 0 -2 Min. BP changes (mmHg) Min. SBP -4 SBP -4 -6 -5 p=0.013 -8 p=0.011 -10 Max. -12 SBP Max. -14 -13 SBP -16 p=0.009 -15 -18 p=0.003 Mahfoud F, unpublished data

24-hour BP changes are comparable to spironolactone treatment – ASPIRANT study Václavík J, et a. Hypertension. 2011;57:1069-75.

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

Mean ABP reductions in the subgroup of patients treated with spironolactone (n=26) 3 M FU 6 M FU 0 DBP -2 DBP -4 SBP SBP -4 -6 p=0.022 -8 -7 -8 -10 p=0.019 p=0.011 -12 -12 -14 p=0.014 -16 Mahfoud F, unpublished data

p<0.0001 240 Baseline 3 months after RD Systolic blood pressure (mmHg) p<0.001 220 p<0.0001 200 p<0.0001 p<0.0001 180 160 140 120 0 0 25 50 75 100 % of maximum workload Ukena C, Mahfoud F et al, JACC 2011

No chronotropic incompetence after RDN 140 p=0.141 Baseline 120 p=0.074 3 months after RD p=0.001 p=0.121 100 p=0.006 Heart rate (bpm) p=0.028 80 60 40 20 0 Rest 25 50 75 100 Recovery % of maximum work rate 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

Office blood pressure reduction in REDUCE 0 mm Hg -10 mm Hg -11 -12 -13 -13 -14 -17 -20 mm Hg -23 Systolic -25 -26 -27 Diastolic -30 mm Hg -28 -32 -40 mm Hg -50 mm Hg 2 weeks 1 month 2 months 3 months 6 months 12 months (n = 15) (n = 15) (n = 15) (n = 15) (n = 11) (n = 3) Error bars represent 95% Confidence Interval

Response Predictors of response (SBP >10 mmHg)  SBP >175 mmHg at baseline R=-0.46, 1. group: <160 mmHg p<0.001 2. group: 160-175 mmHg 3. group: >175 mmHg 1. G 2. 3. G G Symplicity HTN-2 Investigators. Lancet. 2010. Mahfoud F, Hypertension 2012

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.

Predictors of response Mahfoud F et al., unpublished data