Ipertensione Arteriosa Resistente - fclassevents.comiscrizioni.fclassevents.com/nefrologia2014/presentazioni/3/02... · Ipertensione Arteriosa Resistente La Denervazione Renale Pro

Ipertensione Arteriosa Resistente

La Denervazione Renale Pro

Achille Gaspardone

AGGIORNAMENTI IN NEFROLOGIA, IPERTENSIONE ARTERIOSA E DIABETE

XI Edizione Centro Convegni La Biodola,

Isola d’Elba, Livorno 3-5 Ottobre, 2014

Could renal denervation become a

valid therapeutical opportunity?

Requirements for a «Valid Therapeutical Opportunity»

Procedure • The disease to treat should be frequent and life-long • The disease to treat should be «important» • The disease to treat should be costly enough

(commercially valuable)

• The interventionalist should have direct access to the patient

• The procedure should be performed without high tech infrastructure and easy enough

• The procedure should be safe, effective and possibly durable

The Importance of Being Hypertensive: Prevalence

• One third of adult population in EU/USA has hypertension; the prevalence is expected to increase due to aging population (1.6 Bill in 2025)

• Two third of HTN patients are either untreated or have blood pressure above the recommended goal

• One third to one half of HTN patients are troubled by medications side-effects or daily pill overload

Lloyd-Jones et al. Circulation 2009; 119: 480-6. Calhoun et al. Hypertension 2008; 51: 1403-19

Calhoun et al. Hypertension 2008; 51: 1403-19.

The Importance of Being Hypertensive: Risk

• Hypertension is associated with an increased risk of: stroke, myocardial infarction, renal insufficiency, congestive heart failure, peripheral artery disease and death!

• 20 mmHg increase in blood pressure double cardiovascular mortality!

• According to the WHO, hypertension is the most frequent cause of death worldwide!

Franco et al. Hypertension 2005; 46: 280-6

Renal nerve anatomy allows a catheter-based approach:

An Easy Procedure

1. Cath Lab 2. Interven.st 3. Generator 4. Catheter

Renal Sympathetic Nerve Ablation for Uncontrolled Hypertension

New Engl J Med Case Study1

• 59-year-old patient, resistant hypertension, had renal sympathetic nerve activity modulated by catheter-based radiofrequency (RF) ablation

1.Schlaich MP, et al. New Engl J Med. 2009;361:932-934. 2.DiBona GF, et al. Physiol Rev. 1997;77:75-197.

Changes in Underlying Physiology Consistent With RDN

New Engl J Med Case Study

Staged Clinical Evaluation

First-in-Man

Series of Pilot studies

Symplicity HTN-2 EU/AU Randomized Clinical Trial

(106)

Symplicity HTN-1 (153)

USA

Symplicity HTN-3 US Randomized Clinical Trial

(535)

Worldwide Other Areas of Research:

Insulin Resistance, HF/Cardiorenal, Sleep Apnea, More

GSR Global Semplicity Registry

(~5000)

• p <0.01 for ∆ from baseline for all time points, Number of patients represents data available at time of data-lock

Systolic

Diastolic

Transcatheter Cardiovascular Therapeutics Annual Meeting 2013

Symplicity HTN-1: Significant, Sustained Blood Pressure Reductions to at Least 3 Years

-22

-27 -29

-32

-10 -14 -14

-14

-40

-30

-20

-10

0

10

6mo (n=144)

1 year (n=132)

2 years (n=105)

3 years (n=34)

Cha

nge

in B

P (m

mH

g)

Symplicity HTN-1: Responder Rate Does Not Decrease Over Time – This Clinical Benefit of RDN is Sustained

1mo (n=143)

3mo (n=148)

6mo (n=144)

9mo (n=96)

12mo (n=132)

18mo (n=108)

24mo (n=105)

36mo (n=34)*

69% 74% 71% 71%

80% 82% 82%

96% 94%

0%10%20%30%40%50%60%70%80%90%

100%

30mo (n=44)

Schlaich, M, TCT 2012 Transcatheter Cardiovascular Therapeutics Annual Meeting 2013

Esler MD et al, EHJ 2014

Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006129IE 3/14

Studi non controllati: la RDN riduce la pressione arteriosa

Fonti pubblicate: 1.Lancet 2009 2.Lancet 2010 3.TCT 2013 4.Journal of Human Hypertension 2013 5.Circulation 2013 6.Clin Res Cardiol 2013 7.J Am Soc Nephrol 2012 8.Eur Heart J 2013 9.TCT 2013 10.Eurointervention 2013 11.EuroIntervention 2013

Medtronic

EnligHTN/St Jude

Vessix/Boston Sci.

Maya/Covidien

Recor

Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014

The Cold Shower. Ouch!!!

SYMPLICITY HTN-3 Trial Design

• Office SBP ≥160 mm Hg

• Full doses ≥3 meds

• No med changes in past 2 weeks

• No planned med changes for 6 M

Home BP & HTN med

confirmation

• Office SBP ≥160 mm Hg

• 24-h ABPM SBP ≥135 mm Hg

• Documented med adherence

Screening Visit 1 Screening Visit 2

Renal angiogram;

Eligible subjects

randomized

Home BP & HTN med

confirmation

Home BP & HTN med

confirmation

Primary endpoint

2 weeks

2 weeks

Sham Procedure

Renal Denervation

1 M

1 M 3 M

3 M 6 M

6 M 12-60 M

• Patients, BP assessors, and study personnel all blinded to treatment status

• No changes in medications for 6 M

2 weeks


Primary Efficacy Endpoint & Powered Secondary Efficacy Endpoint


Superiority margin -5 mmHg Superiority margin -2 mmHg

Selected Findings of the SYMPLICITY HTN-2 and HTN-3 Studies


Why Did Symplicity HTN-3 Fail?

Why Did Symplicity HTN-3 Fail?

Potential «Flaws»

1. Study protocol, patient population, data analysis 2. Procedure related factors

Semplicity HTN-3: Design Flaws • It appears difficult to demonstrate any significant incremental

blood pressure-lowering effect of any intervention in patients already on more than five antihypertensive drugs at maximal dose.

• 40% of patients were taking direct-acting vasodilators (twice as high as in previous studies).

• Patients may have not been stabilized appropriately before randomization (only 2 weeks instead of the necessary 8 weeks)

• 40% of patients (in both groups) had therapy changes during the study despite protocol limitation.

• The patient population may differ from Caucasians recruited in previous trials, mainly performed in centres of excellence in Europe and Australia. Low renin hypertension, commonly seen in Afro-Americans, typically does not respond well to ACE-I and beta-blockers, while diuretics and vasodilators are particularly effective. In the SYMPLICITY HTN-3 study, a quarter of the recruited patients were black.


HTN-3: diversa risposta del gruppo di controllo nella popolazione afro-americana

Results: Prespecified Subgroup Analyses

*

* P value for superiority with margin of 5 mm Hg Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014


HTN-3: esperienza nella procedura a) Numero di operatori 5 volte maggiore

rispetto a HTN-1 b) Maggiore eterogeneità dell’esperienza

degli operatori rispetto a HTN-1 e HTN-2 c) I proctoring sono stati diversi e non

paragonabili

HTN-1 HTN-3

Numero di operatori 20 112

Numero di procedure per operatore 6,0 3,3

Numero di procedure per centro 8,6 4,7

M. Joner (CVPath Inc.) quoted by Mahfoud F et al JACC 2014

Distribution and Density of Renal Sympathetic Nerves

1. The maximum average number of nerves was observed in the proximal and middle segments of the renal artery and the least number in the distal segments. 2. The mean distance from the lumen to nerve was highest in the proximal and lowest in the distal segments. 3. The circumferential distribution was greatest in the ventral region and least in the dorsal regions. 4. The density of efferent fibers was far higher than afferent fibers. 5. Accessory renal arteries are surrounded by sympathetic nerves. 6. No differences in nerve anatomy in hypertensive subjects compared with nonhypertensive subjects were observed.

Sakakura K et al, J Am Coll Cardiol. 2014;64(7):635-643.

Superior Posterior Inferior Anterior

Kandzari D, EuroPCR 2014

4 quadrant ablation pattern

Notching following RDN

Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014, appendix

% o

f pat

ient

s 97%

≥

Mean number of notches 1.41±1.7

4 quadrant ablation pattern

mm

Hg

*

* *


Symplicity HTN-3: Procedural Variability

Superior Posterior Inferior Anterior

Strategie Ablative nella Fibrillazione Atriale

by courtesy of F. Lamberti, U.O.C. di Cardiologia – S. Eugenio Hospital, Rome - Italy

RDN Technologies Available and in Development

Technology Device Name (Manifacturer) Key Characteristics

Radiofrequency Symplicity Flex (Medtronic, Inc) Single-electrode catheter

Spyral (Medtronic, inc) Spiral-electrode catheter

EnlighHTN (St.Jude Medical, Inc) Multielectrode Catheter

OneShot (Covidien, Manfield, MA) Irrigated, spiral-electrode catheter

Vessix V2 (Boston Scientific Corp.) Multielectrode catheter with bipolar energy deliver

ThermoCool (Biosense Webster, Inc) Irrigated, multielectrode catheter

Iberis (Terumo) Single-electrode, radial artery access system

Verve Medical System Multielectrode, retrouretic access system

Ultrasound Paradise (ReCor Medical) Nonfocused endovascular ultrasound energy system

TIVUS (Cardiosonic) Nonfocused endovascular ultrasound energy system

Kona System (Kona Medical) Externally applied, low-intensity ultrasound

Sound 360 (Sound Innovations, Inc) Endovascular ultrasound energy system

Cryoablation Not yad named (friedrich-Schiller Universuty Standard cryoablation catheter

Brachitherapy CyberHeart Catheter based, beta-radiation Brachiterapy

Pharmacological Not yad named (Universuty of Athens) 0.1 mg vincristine delivered from six holed proprietary balloon catheter

Bullfrog (Mercator MedSystems, Inc) Guanethidine microinjecyion into the adventitia

Peregrine (Ablative Solutions) Ethanol Microinjection into the adventitia

ApexNano system (Apexnano Ther) Magnetic Nanoparticles impregnated with Botox

Boston Scientific Vessix Renal Denervation System

RDN (EnlighHTN)

3D-sympathetic RDN increases procedural efficacy in non-responders

F.Versaci, et al. Int J Cardiol, May 2014

0

50

100

150

200

250

Basal 1 week 1 M 3 M 3 day 1 M 3 M 6 M 9 M

SBPDBP

After 1° RDN (MDT Symplicity)

After REDO- RDN (EnlighHTN)

Redo of RDN: a case of effective treatment with a second generation of device in a patient with recurrent resistant hypertension after primary treatment success.

BP

(mm

Hg)

F.Versaci, et al. Int J Cardiol, May 2014

Famous (Initial) Interventional Failures in Cardiology

Coronary Stent!

STRESS: Stent REstenosis Study trial

P<0.001 P<0.001

P<0.02

NS

Bakris GL, ESC 2014

Note: BP changes are vs patient baseline not RDN-Control

mm

Hg

P<0.001

SYMPLICITY HTN-3: 12 month data

322 pts RDN (91%) 93 pts CROSS over (97%) 48 pts No CROSS OVER (77%) 171 pts initial SHAM group

New Multielectrode Catheter

Should we continue to perform Renal Denervation in Humans ?

The answer is YES provided that: 1. Right (and safe) multielectrode catheters are used 2. Indication based on evidence of “refractory”

hypertension in well defined subgroups of patients 3. The procedure performed by expert operators 4. Long follow-up required (to rule out re-innervation

issue)

.

Liberally adapted from V. Campese, Isola d’Elba 3 October 2014 (few minutes ago)

"Those who cannot change their minds cannot change anything."

George Bernard Shaw

Quoted few minutes ago by V. Campese, Isola d’Elba 3 October 2014

58% 48%

P=0.04

%

N.B. In Symplicity HTN-1 response to RDN was arbitrarily defined BP reduction > 10 mmHg 6 months after RDN. Using this definition in Symplicity HTN-3, 58 (RDN) vs 48% (SHAM) of patients met the 10 mmHg BP reduction at 6-month follow-up.

Mahfoud F, JACC 2014


HTN-3: problematica della limitazione delle modifiche alla terapia nella popolazione con ipertensione non controllata

• Il protocollo prescriveva dosaggi massimi e nessuna modifica alla terapia

• ~40% dei pazienti (n = 211) durante lo studio hanno avuto bisogno di modifiche alla loro terapia –69% delle prime modifiche alla terapia erano necessarie dal punto di vista medico

N = 137 N = 71

Pazi

enti

con

mod

ifich

e

tera

peut

iche

(%

)


≥ ≥ ≥ ≥ ≥ ≥ ≥ ≥ ≥

mm

Hg

Propensity scores using baseline characteristics as covariates were used to match sham control and denervation patients

P value for trend = 0.01 P value change in SBP for RDN vs SHAM

Sarà una vittoria per l’eternità?

:

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Ipertensione Arteriosa Resistente - fclassevents.comiscrizioni.fclassevents.com/nefrologia2014/presentazioni/3/02... · Ipertensione Arteriosa Resistente La Denervazione Renale Pro