Device therapy for hypertension - RCP London

Device therapy for hypertension current status and horizon scanning

Dr Vikas Kapil MA MRCP PhD

Consultant in Clinical Pharmacology

& Cardiovascular Medicine

Disclosures

Research Funding: British Heart Foundation

National Institute for Healthcare Research

Barts Charity

Honoraria: nil

Speaker bureaux: nil

Share holdings: nil

Outline

Renal sympathetectomy (renal denervation)

Carotid baroreflex strategies

Baroreflex Activation Therapy (BAT)

Carotid baroreflex amplification

Central arterio-venous anastomosis

Emerging clinical and pre-clinical stage technologies and strategies

Approaches: targeting the autonomic NS

Schlaich et al., Hypertension 2004; 43: 169-

Afferent Renal Sympathetics

The kidney is a source of central sympathetic drive in hypertension, heart failure, chronic kidney disease, and

ESRD

Efferent Sympathetic Activation

Patients cannot develop and/or maintain elevated BP without renal involvement

HR Contractility

RBF/GFR Renin

Na+/Volume

Vasoconstriction

Approaches: renal sympathectomy



Ott & Schmeider, Curr Hypertes Rep 2015; 17: 65-


Ott & Schmeider, Curr Hypertes Rep 2015; 17: 65-


Kindermann et al., J Clin Hypertens 2017: 1-


Kindermann et al., J Clin Hypertens 2017: 1-


Sharp et al., Clin Res Cardiol 2016; 105: 544-


Sharp et al., Clin Res Cardiol 2016; 105: 544-


Desch et al., Hypertension 2015; 54: 1202-

Randomised, sham controlled, blinded study

RF RSD vs renal angiography

Mild resistant HTN: 24h BP: S 135-149 and/or D 90-94 mmHg

3 medications (inc diuretic)

Screened: 1006

Eligible: 156

Randomised 71

ITT: 67

PP: 63


Desch et al., Hypertension 2015; 54: 1202-

Williams et al., Lancet 2015; 386: 2059-


Templin et al., Eur Heart J 2013; 34: 2141-

Vasospasm Oedema Dissection Thrombus


Baseline 6 months post-RDN

Left renal artery

Right renal artery

Persu et al., J Hypertens 2014; 32: 2102-


Bhatt et al., N Engl J Med 2014; 370: 15-


Criticisms of and pitfalls in Symplicity HTN-3:

Medicine stability

changes within 2 weeks of study entry allowed

40% of both groups had medication changes within randomisation period

baseline differences in use of spironolactone/vasodilators between groups

Procedural

new technique with inadequate proctoring

inadequate burns [number/location] to achieve renal sympathectomy


NHS England. 2016


Externally focussed US RSD Kona Medical


Externally focussed US RSD Kona Medical


WAVE IV

Randomised, sham-controlled, blinded trial

Focussed, diagnostic US vs focussed, [therapeutic] high intensity US energy

n=132

Primary efficacy end point: change in OBP at 6m

Secondary efficacy end point: change in 24h ABP at 6m

clinicaltrials.gov/NCT02029885


Schmeider, TCT 2016

Category Sham Treatment

number 39 42

Male/Female 25/14 30/12

Age, years 62.0 (11.1) 60.3 (11.2)

Ethnicity (W/B/Asian/Other) 30/2/4/3 32/3/3/4

BMI, kg/m² 29.8 (4.2) 29.9 (4.5)

Office SBP, mmHg 184.8 (18.2) 181.1 (19.7)

Office BP, mmHg 100.3 (16.2) 99.5 (16.5)

24h SBP, mmHg 155.5 (11.8) 155.7 (14.3)

24h DBP, mmHg 87.2 (13.1) 86.8 (11.4)

Heart rate, bpm 70.6 (15.8) 68.4 (12.1)

Meds, number 5.0 (1.5) 4.3 (1.4)


Schmeider, TCT 2016

Office BP (mmHg)

N=39 N=29

-10

-15

-20

-25

0

-5

12 weeks 24 weeks

mm

Hg

p = .208

p = .091

RDN Sham


Schmeider, TCT 2016

Office BP (mmHg)

N=39 N=29

-10

-15

-20

-25

0

-5

12 weeks 24 weeks

mm

Hg

p = .208

p = .091 -15

-10

-5

0

RDN 24-hour (N=26)

RDN day (N=26)

RDN night (N=26)

Sham 24-hour (N=21)

Sham day (N=21)

Sham night (N=21)

24-hour day night

Amb. BP (mmHg)

mm

Hg

P= .62 P= .58 P= .45

RDN Sham


Decision to stop trial in July 2016 on grounds of futility after interim analysis

No safety concerns identified

n=81 completed primary end point analysis

Schmeider, TCT 2016


Is this the end of renal sympathectomy?


Issues to be solved

What is the true effect of RSD, taking out medication/adherence effects?

Can we identify patients who will respond?

Can we identify if we have achieved renal denervation?

Do we need to know which technologies are better?


Azizi et al., Lancet 2015; 385: 1957-

DenerHTN protocol Resistant HTN on >2 drugs + supine BP>140/90 All changed to: Ramipril 10mg [Irbesartan 300mg] Amlodipine 10mg [5mg if oedema] Indapamide MR 1.5mg Randomised if ABP>135/85 to: stepped care or stepped care + RSD Force added on monthly [m2-5] basis if home BP not to target: Spironolactone 25mg Bisoprolol 10mg Prasozin SR 5mg Rilmenidine 1mg Primary endpoint: Δ day amb SBP


Azizi et al., Circulation 2016; 134: 847-

DenerHTN protocol Resistant HTN on >2 drugs + supine BP>140/90 All changed to: Ramipril 10mg [Irbesartan 300mg] Amlodipine 10mg [5mg if oedema] Indapamide MR 1.5mg Randomised if ABP>135/85 to: stepped care or stepped care + RSD Force added on monthly [m2-5] basis if home BP not to target: Spironolactone 25mg Bisoprolol 10mg Prasozin SR 5mg Rilmenidine 1mg Primary endpoint: Δ day amb SBP

50% of patients non adherent [partial or complete] Not difference in either group No difference in magnitude of effect of RSD in sub groups



RADIANCE-HTN: SOLO and TRIO cohorts

Sham, randomised, blinded study (n=292)

Solo: Patients with uncontrolled HTN on 0-2 medications

Washout for 4 weeks

daytime ABP 135-170/85-110 mmHg

Trio: Patients with uncontrolled HTN on 3 or more medications

Switched to single-pill, triple, fixed dose medication for 4 weeks

Sevikar HCT: amlodipine, olmesartan, hydrochlorothiazide

Primary end-point: daytime ABP 2 months post procedure


Issues to be solved






Mahfoud et al., Eur Heart J 2017; 38: 93-


de Jong et al., Hypertension 2016; 68: 707-


Issues to be solved






ATTENUATION OF SPLANCHNIC AUTOTRANSFUSION FOLLOWING NON-

INVASIVE ULTRASOUND RENAL DENERVATION: A NOVEL MARKER OF

PROCEDURAL SUCCESS

Manish Saxena, Tariq Shour, Mussadiq Shah, Christopher Wolff, David J Collier,

Vikas Kapil, Armida Balawon, Jane Pheby, Anne Zak, Peter Julu, Benjamin

O’Brien, Roland E. Schmieder, Melvin D Lobo

ESH 2017 Oral presentation


Issues to be solved






Kandzari et al., Eur Heart J 2015; 36: 219-


Mahfoud et al., J Am Coll Cardiol; 2015: 1766-


Pekarskiy et al., J Hypertens 2017; 35: 369-



RADIOSOUND study

Resistant HTN on stable meds for 4 weeks

OBP >160 mmHg

US main braches

vs

RF main branches

vs

RF main and accessory branches

n=120

Primary end point: daytime ABP at 3m



How do we design robust clinical studies that give meaningful results when

interventional sham procedures give such a large reduction in BP?

Approaches: baroreflex modulation

Normal baroreflex. Showing input from the carotid sinus to nucleus tractus solitarii (NTS) via the glossopharyngeal nerves with additional cortical influences. Also represented is the output from the nucleus tractus solitarii to the heart and blood vessels via various sympathetic and parasympathetic nerve fibres. Intact baroreflex function leads to appropriate cholinergic and adrenergic influence on heart rate and blood pressure. PNS indicates parasympathetic nervous system; SNS, sympathetic nervous system;

Ach, acetylcholine; NE, norepinephrine; HR, heart rate; and BP, blood pressure.

Approaches: baroreflex modulation

Approaches: baroreflex amplification

Carotid Baroreflex Amplification [MobiusHD]


Carotid Baroreflex Amplification [MobiusHD]


CALM FIM Europe & US studies [n=50 total]

Neuro-interventional radiologists experienced in carotid stent placement [>100]

US Duplex and CT or MR angiography to determine suitability

DAPT required pre and post procedure

OBP > 160 mmHg

3 medications (inc diuretic)


Spiering, TCT 2016


Spiering, TCT 2016


CALM START

randomised, sham-controlled, end-point blinded study

n=110

ON meds: resistant HTN (3 meds inc diuretic) for 4 weeks

24h daytime ASBP 135-170 mmHg

OFF meds: 24h daytime ASBP 135-170 mmHg after medication washout

Primary outcome: difference in change in 3m ASBP

Approaches: baroreflex activation


Heusser et al., Hypertension 2010; 55: 619-

Rheos (1st Generation)

http://www.cvrx.com/wp/wp-content/uploads/2011/12/DoseResponse3.jpg


Hoppe et al., J Am Soc Hypertens 2012; 6: 270-

Rheos (1st Generation) Next-generation Barostim neo

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1 2 3 4 5 6Pe

rce

nt

Fre

e f

rom

Co

mp

lic

ati

on

Months from Implant

1st Generation Rheos

2nd Generation neo


Hoppe et al., J Am Soc Hypertens 2012; 6: 270-

Next-generation Barostim neo


Floyd et al., Int J Cardiol 2016; 220: 517-

BAT for extreme BP variability

First in man use

49y old man of work for 2y because

of symptomatic extremes of BP

Systemic sclerosis related autonomic

neuropathy

intact baroreflex on physiological

stimulation

BAT implanted locally in Galway


BAT in UK

First in UK use for BP variability UK BAT 001

reduced frequency of blackouts and hospital admissions

no longer on oral medications for HTN

on transdermal clonidine

First in UK use for refractory hypertension UK BAT 002

2007-2011; 6 admissions with HTN urgencies/emergencies

total in-patient time: 9 months

On 7 medications orally negative tablet feed study

home BP 240/110

No response RF RSD; no response CB excision; unsuitable conduit AVA

Improved OBP 180/100 on no anti HTN meds


NICE IPG 533 Cot 2015

“Current evidence on the safety and efficacy of implanting a baroreceptor stimulation device for resistant hypertension is inadequate. Therefore, this procedure should only be used in the context of research.”


BAT in rest of world

Large studies in resistant hypertension recruiting in:

France French BAT study

Finland Nordic BAT study

Company has pulled out of funding further studies in HTN in Europe

has CE mark

going for heart failure indication

Future for BAT in UK unclear…

Approaches: conduit AV anastomosis

Placement between

Iliac Artery & Vein



Prospective, Randomized, Controlled, Blinded-Endpoint

OBP >140 and daytime ABP S >135 and/or D >85 mmHg

3 meds inc diuretic, maintained for 6m

Primary endpoints:

Change in mean 24-hour ABPM SBP at six months as compared to baseline

Change in mean office SBP at six months as compared to baseline

Secondary endpoints:

Change in mean 24-hour ABPM DBP at six months as compared to baseline

Change in mean office DBP at six months as compared to baseline

Incidence of complications associated with delivery and/or use of the ROX

Coupler


ROX Coupler (n = 44)

Control (n = 39)

Age (years) 59 ± 9 58 ± 9

Sex (female) 11 (25%) 14 (36%)

Race (white) 40 (91%) 31 (79%)

Body-mass index (kg/m2) 30 ± 4 30 ± 5

eGFR (ml/min) MDRD Calculation 76 ± 20 77 ± 18

Previous renal denervation 10 (23%) 7 (18%)

Coronary artery disease 7 (16%) 10 (26%)

Type 2 diabetes mellitus 9 (20%) 5 (13%)

Prior cerebrovascular events 5 (11%) 8 (21%)

Baseline office systolic BP (mm Hg) 175 ± 18 171 ± 22

Baseline office diastolic BP (mm Hg) 100 ± 13 100 ± 18

Baseline 24-Hr ABPM systolic BP (mm Hg) 157 ± 15 156 ± 14

Baseline 24-Hr ABPM diastolic BP (mm Hg) 93 ± 11 93 ± 13

Lobo et al., Lancet 2015; 385: 9978-


Lobo et al., Lancet 2015; 385: 9978-


Lobo, ESC 2016


Lobo, ESC 2016


Lobo, ESC 2016

Approaches: central AV anastomosis

ROX in the rest of world

Sham controlled US IDE study started March 2017 [n=500]

24h ABP at 6m

ROX registry study ongoing

Other technologies

Approaches: short AV pacing

The main mechanism of BP reduction is by short AV delay pacing, which reduces LV filling and thus

reduces LV pressure generation (Starling Mechanism).

LV Pressure-Volume

Decreased Filling

Atrial pacing versus AV sequential pacing with short AV interval (40ms). Acute Porcine Model

Neuzil, ESC 2016


Neuzil, ESC 2016


FiM BackBeat Study

Patients with indication for dual chamber (AV) pacemaker

On >1 medication for HTN for 2m

OBP >150 for 1 week on repeated measures (all >140) mmHg

Neuzil, ESC 2016


Neuzil, ESC 2016


Approaches: vagal nerve stimulation

Pre-clinical data only

Hampered by tendency to cause bradycardia, bradypnoea

Novel cuffed electrode may overcome these issues

Approaches: vagal nerve stimulation

Approaches: median nerve stimulation

Median Nerve Stimulation [Valencia]

positive FiM (n=96) [abstract]

Approaches: median nerve stimulation

Approaches: carotid body modulation

Carotid Body Excision/Ablation


Narkiewicz et al., JACC Basic Trans Science 2016; 1: 313-


Narkiewicz et al., JACC Basic Trans Science 2016; 1: 313-

Responders had higher levels of peripheral chemoreceptor activity prior to

resection

higher hypoxic ventilatory drive

faster ventilatory frequency [short nitrogen breathing protocol]

Possible to identify responders

Possibly amenable to endovascular approach

Approaches: chemical RSD with ethanol

Fischell et al., JACC Cardiovasc Interv 2016; 9: 589-

Blood pressure reduction at 6 Months

Fischell et al., JACC Cardiovasc Interv 2016; 9: 589-

Approaches: chemical RSD with novel Na+/K+ ATPase inhibitor

Kipshidze et al., J Inv Cardiol 2017; 29: 1-

Approaches: pizoelectric gastric stimulation

medautonomic.com

Approaches: pizoelectric gastric stimulation

medautonomic.com

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Device therapy for hypertension - RCP London

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