Renal Denervation

Prof Andrew SP Sharp MBChB, MD, FRCP Consultant Cardiologist and Honorary Associate ProfessorRoyal Devon and Exeter Hospital and University of Exeter

Conflicts of Interest

• Consultant/Speaker’s Fees: Medtronic, Recor Medical

High Blood Pressure

Half of all HT patients are uncontrolled

69.7

5.53.1 4.1 2.2 2.5 0.5

3.70.5

8.2

0.00 1.00 2.00 4.35 13.04 26.09 39.13 52.18 78.27 104.36

Peop

le (%

)

Number of Weeks Willing to Trade

Hutchins et al. Circ Cardiovasc Qual Outcomes. 2015;8:00-00.

8% of adults (100 million hypertensives?) would rather die two years early than take drugs

forever

Case Study from Exeter• 42 yr old diabetic male• Elevated BMI (35)• Observed to take: – Indapamide 2.5– Ramipril 10– Amlodipine 10– Spironolactone 25

• BP:–Office: 188/98– DABP 188/94, NABP 177/88

ABP before RDN

Post procedure ABP at 1 year

Ambulatory BP response

• Fall of Day ABP of 42/14

• Fall of Night ABP of 38/11

• Drugs at time of 1 year ABP were:

– Indapamide 2.5, Ramipril 10, Amlod 10, Eplerenone 25

(switched due to S/E)

• Five year follow-up – BP controlled on three agents

ECG before RDN

ECG at 1 year – regression of LVH and strain pattern

What this case tells us:

• There is no doubt that blood pressure has fallen

• Dramatically

SNS effects are mostly bad for CV health

• Arise from T10-L1, Follow the renal artery to the kidney

Vessel Lumen

Media

Adventitia

Renal Nerves

Renal Nerves as a Therapeutic Target

We have known that the process of sympathectomy reduces blood pressure for

a long-time

Dr. Reginald H. Smithwick

Sympathectomy: An Early Surgical Precedent

1952

How will the kidney function without sympathetic control?

Transplanted kidneys:• Lack innervation • Effectively maintain fluid and electrolyte balance

Supports that sympathetic component of control represents “overdrive” system, rather than foundation of basic renal function

Blaufox et al. N Engl J Med. 1969;280(2):62–66.

Symplicity HTN-1 (severe HT on drugs)

Symplicity HTN-2 – severe HT on drugs

Lancet 2010;376:1903–09

• Mean baseline BP 178/97 � 18/16 vs 178/98 � 16/17

• Mean no. of drugs: 5.2 � 1.5 vs 5.3 � 1.8

Then came Symplicity HTN-3…

N Engl J Med 2014;370:1393-401.

N Engl J Med 2014;370:1393-401

HTN 3 BP results

So what happened in HTN-3?

• Option 1 – RF ablation did not work

So what happened in HTN-3?

• Alternative explanations are:– The RDN BP lowering effect is much less powerful than that observed

in open label studies– The study design masked the measured clinical benefit– The study procedure was not conducted properly

The crucial issue of renal nerve anatomy and catheter design

We thought that most of the nerves were within range of a 3mm burn depth

Reality – the nerves extend further out

Can we do better with new methodological approaches to denervation with the existing technology?

Nerves more frequently make a close approach in the distal segment

• Histological analyses suggest that a more distal approach could increase the frequency of successful ablations

• Distal ablation strategies can be executed with both existing RDN catheters

• Human Main Renal Artery• 5.18 + 0.71mm Dia.

• Human Branch Renal Artery• 4.05+0.90mm Dia. Superior• 3.81+0.80mm Dia. Inferior

Melder R. EuroPCR 2014; Virmani R., Mahfoud F. Sakakura et al. JACC 2014

Distribution of renal nerves around renal artery

Reality

Are there any signals within HTN-3 to support this?

Ablation attempts and change in BP in HTN-3

pattern of increasing reduction in office (P value for trend 0.10), am-bulatory (P value for trend 0.24), and home blood pressures (P valuefor trend0.58) (Figure3). These analyses revealed thatonly 19 treatedpatients received four-quadrant ablations in both renal arteries.

DiscussionAmidst enthusiasm for a promising breakthrough therapy in treat-ment-resistant hypertension, the failure of SYMPLICITY HTN-3 todemonstrate a significant improvement in blood pressure comparedwith a sham procedure led to the examination of factors that mighthave contributed to the unexpected results. These post hoc analyseswere conducted following completionof the primary analyses for theSYMPLICITY HTN-3 trial. The implementation of blinding and a

sham control were expected to narrow but not eliminate the differ-ence between experimental and control groups; what was observedwas a less than expected RDN treatment effect and a morepronounced response in the sham group. Our initial multivariableanalysis serves to guide further exploration of factors that mayhave affected the overall study efficacy result, since the result wassimilar between treatment groups, yet factors predicting changes inSBP differed between subgroups. Recognizing the limitations ofadditional exploratory testing in the context of an overall negativeresult, this preliminary analysis also provides the basis to identifyand prioritize various factors for further study.

Variable adherence to and frequent revisions of antihypertensivetherapy are well documented among hypertensive patients.14 – 18

However, in this trial, an analysis eliminating those with medication

Figure2 The impactof numberof ablationattemptsondifference in6-month change inoffice systolic bloodpressure (A), 24-h ambulatory systolicblood pressure (B), and heart rate (C) between treated and matched sham patients. Baseline characteristics of the sham patients were propensityscoredmatched with the RDNpatients. The SBP changemeasures for the RDN andmatched sham patients, 95% confidence intervals, and P-valuesfor the difference in change between the groups are shown.

D.E. Kandzari et al.224

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OFFICE 24 hr ambulatory SBP

MORE ABLATIONS = MORE BP REDUCTION

What proportion of patients had the recommended (required?) four

quadrant ablation in the HTN-3 trials?

5%

Four-quadrant ablations in HTN-3

changes did not affect the primary outcomeor pre-specified second-ary outcome.14 Nevertheless, a substantial decrease in blood pres-sure among sham patients suggests a change in patient behaviour(despite self-reported documentation of medication adherence),or changes in prescribed antihypertensive medications during thecourse of trial participation. To the latter issue, although nearly allpatients were prescribed maximal medical therapy at least 6 weeksprior to randomization, many patients (39%) underwent medicationchanges between the randomization and the 6-month endpointassessment. These changes typically represented both alterations indose and class of prescribed medications, a finding that challenges thepremise that patients were actually receiving maximally tolerateddoses at enrolment. Several randomized placebo-controlled pharma-ceutical trials19–21 have shownmuch smaller reductions in ambulatoryblood pressure than that observed in this trial, which also suggests thatthe observed sham response might be related to the maximum toler-ated dose requirement and changing medication adherence patterns.The fact that there were eight clinical contact points with enrolledpatients between the initial screening visit and the 6-month follow-upis clearly not representative of usual clinical practice and may alsohave impacted medication adherence. Moreover, the sham interven-tion and related hospitalization are not encountered in placebo-controlled pharmaceutical trials and may have had more impact thananticipated. This observation identifies the challenge for future RDNtrials that, in spite of protocol mandate, patients with treatment-resistant hypertension can be maintained on a stable medicationregimen to avoid confounding the assessment of device effectiveness.In fact, it is unclear whether a 2-week screening period for stabilizationof antihypertensive medications is adequate for drugs that are not atmaximal tolerated dose or whether the mandate for maintenance ofa complex medical regimen under close supervision actually increasedmedication changes during the study.

Whether a differential blood pressure response following RDNexists relative to classes of antihypertensive therapy has been ofparticular interest, and in fact, outcomes among patients takingaldosterone antagonists represented a pre-specified analysis. Thegreater decline in blood pressure with RDN among patients alreadytaking aldosterone antagonists seems initially counterintuitive andmaybepartially related toahigherbaselineSBP for patients prescribedanaldosteroneantagonist anddifferences incertainbaselinecharacter-istics (younger age and history of significantly more hypertensivecrises).Alternatively, itmaybethatdenervationcontributesanadditiveeffect to pre-existing neurohormonal blockade demonstrated withaldosterone antagonists22 and therefore results in the more exagger-ated blood pressure response in this subgroup. However, it may beby chance alone that baseline aldosterone antagonist use appears asa predictor of blood pressure reduction.

Unlike previous SYMPLICITY trials, SYMPLICITY HTN-3 enrolleda substantial number of African-American patients who representa significant proportion of hypertensive patients in the USA. TheAfrican-American sham patients demonstrated an unusually largedecrease in SBP compared with non-African-American controls.Although a genetic basis has been postulated for differential responseto hypertension and heart failure therapies among African Amer-icans,23–25 the marked reduction in blood pressure in the shamgroup could be related to a change in medical adherence and/or typeof therapy; notably, a higher proportion of African Americans wereprescribed vasodilator therapy. The exact reasons for blood pressuredifferences observed between African-American and non-African-American control patients are unclear and highlight the importanceofconsistent and standardizedBPcare in subsequentdenervation trials.

Anespecially challenging aspectofRDNtherapy is thatnopracticaland immediate measure of procedural success exists. Based onearly experience, catheter-based RDN was expected to result in an

Figure 3 Systolic blood pressure change at 6 months according to the ablation pattern. Change in office, ambulatory, and home systolic bloodpressure at 6 months are shown based on delivery of ablations in four quadrants of the renal artery for both kidneys, one kidney, or neitherkidney. A four-quadrant ablation is defined as one superior, one inferior, and two anterior/posterior ablations delivered.

Predictors of blood pressure response in the SYMPLICITY HTN-3 trial 225

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Lesion

Inferior Anterior Superior Posterior

Procedural VariabilityCorrelation with # of ablations

Correlation with 4-quadrant ablation pattern

Cross-section of artery

4 quadrant ablation pattern

HTN-3: Two arms

Ineffective denervation

‘RDN’ arm

Ineffective denervation

‘Sham’ arm

Medication Changes During Trial

~40% (n = 211) of trial subjects required medication changes between baseline and primary efficacy endpoint assessment:

– 69% of first medication changes were medically necessary

– 121 patients had a med change due to an adverse event

– 80 patients had a med change due to a drug side-effect

– ~69% were changes in drugs at maximally-tolerated dose

38%40%

0

5

10

15

20

25

30

35

40

45

RDN Control

N = 139 N = 72Pat

ient

s W

ith M

edic

atio

n C

hang

es (%

) • Medication changes were permitted between procedure and primary endpoint assessment in cases of ‘hypertensive urgency’

• What proportion of patients with hypertension under your care meet such a criteria during 6 month follow-up?

Drug changes during the trial

Medication changes

UK Renal Denervation Affiliation - results

UK Renal Denervation Affiliation

• Investigator-led Initiative• 18 of 21 UK centers with

RDN experience• All performed 5+ RDN

cases at time of conception

• All cases performed for treatment-resistant hypertension

UK Renal Denervation Affiliation

Sharp et al, CRC, 2016

Dener-HTN study• Stepped HTN

care• 6 point

difference in ABP with RDN

• Used to power RADIANCE studies

Azizi, Lancet, 2015

Townsend et al, Lancet. Published online ahead of print August 28, 2017

§ Office BP

§ Drug naïve or

medications

discontinued

VISIT 1

3M4

RANDOMIZED, SHAM-CONTROLLED TRIAL IN MILD-MOD HYPERTENSION OFF ALL DRUGS

VISIT 2 R

RENAL DENERVATION

SHAM CONTROL

124-36M

3M4 124-36M

Drug titration5

if OSBP≥140

Screen failure if OSBP ≥180

Follow-up every

2 weeks3

Follow-up every

2 weeks3

§ Office BP (baseline)

SBP ≥150 to <180DBP ≥90

§ 24-hr ABPM

SBP ≥140 to <170 § Drug testing

1-2 weeks2

SCREENING TREATMENT

3-4 weeks2

2-week safety check1

6M4

6M4

Unblinding and optional crossover

to RDN

§ ABPM

§ Office BP

§ Drug testing

SPYRAL HTN – OFF MED

SPYRAL HTN – OFF MEDBlood Pressure Change from Baseline to 3 Months: 24-Hr ABPM

-5.5(-9.1, -2.0)P=0.003

-4.8(-7.0, -2.6)P<0.001

-0.5(-3.9, 2.9)

P=0.76

-0.4(-2.2, 1.4)

P=0.65

-14

-12

-10

-8

-6

-4

-2

0

BP C

hang

e fro

m b

aseli

ne to

3 m

onth

s (m

mHg

)

Chart Title

RDN

Δ -4.4 mmHg(-7.2, -1.6)

P=0.002

n=35 n=35

Systolic Diastolic

Δ -5.0 mmHg(-9.9, -0.2)

P=0.04

Baseline BP (mmHg) 154 152 100 99n=36 n=36

-10.0(-15.1, -4.9)

P<0.001

-5.3(-7.8, -2.7)P<0.001

-2.3(-6.1, 1.6)

P=0.24

-0.3(-2.9, 2.2)

P=0.81

-14

-12

-10

-8

-6

-4

-2

0

BP C

hang

e fro

m b

aseli

ne to

3 m

onth

s (m

mHg

)

Chart Title

RDN

Systolic Diastolicn=37 n=37

Baseline BP (mmHg) 162 161 100 101n=41 n=41

Δ -4.9 mmHg(-8.5, -1.4)

P=0.008

Δ -7.7 mmHg(-14.0, -1.5)

P=0.02

SPYRAL HTN – OFF MEDBlood Pressure Change from Baseline to 3 Months: 24-Hr ABPM

RADIANCE SOLO

Key Entry Criteria• Hypertension controlled on 1-2 anti-HTN meds or

uncontrolled on 0-2 meds

• Off-medication daytime ABP ≥135/85 and

<170/105 mmHg

• Age 18-75 years

• No prior cardiovascular or cerebrovascular events

• Blinded, sham-controlled and

randomized 1:1 (N=146)

• Powered to detect 6 mmHg

difference in ambulatory SBP

between treatment arms with

80% power

NoAntihypertensive

Medicationsunless escape

BP criteria exceeded

Antihypertensive Medication Washout - 4 weeks

Daytime ABP ≥135/85 and <170/105 mmHg

Office BP Baseline

Primary Efficacy Endpoint @ 2 Months∆ Daytime Ambulatory Systolic BP

CTA / MRA, Renal Duplex, Renal Angiography

6 Month Follow-up (office BP, ABP, Duplex Driven CTA/MRA)

12 Month Follow-up(office BP, ABP, CTA/MRA)

24 & 36 Month Follow-up (office BP)

Renal Denervation Sham Procedure

146 Randomized

RADIANCE-HTN SOLO – Study Design

Primary Efficacy Endpoint (ITT):Change in Daytime Ambulatory Systolic BP

at 2 Months

Between Group DifferenceAdjusted for Baseline BP

-6.3 mm Hg (95% CI, -9.4 to -3.1)

P<0.001

RenalDenervation

(N=74)

ShamProcedure

(N=72)

95% CI:-10.6 to -6.3

95% CI:-4.5 to 0.2

Azizi et al. Lancet. 2018

Individual Patient Response at 2 Months:Change in Daytime Ambulatory Systolic BP

at 2 Months

Renal Denervation (N=74)

Sham Procedure (N=72)

% Patients with ≥ 5 mm Hg Decrease

Renal Denervation: 66%Sham Procedure: 33%

P<0.001

66%

33%

Azizi et al. Lancet. 2018

SPYRAL ON

1According to schedulingClinicaltrials.gov NCT02439775Kandzari D, et al. Am Heart J. 2016;171:82-91.

1-2weeks1

§ Drug testing§ Office BP

SBP≥150 to <180DBP ≥90

§ Witnessed drug intake§ 24-hr ABPM

SBP ≥140 to <170

2-4 weeksVISIT 1 VISIT 2

Inclusion criteria:§Office SBP ≥150 to <180 § Stable on 1, 2, or 3 antihypertensive drugs for 6 weeks

§ Office SBPSBP≥150 to <180DBP ≥90

Screen failure if OSBP ≥180

§ Thiazide diuretic§ Calcium channel blocker

§ ACE/ARB§ Beta blocker

SCREENING

3M

Renal Denervation

+ Medications

Sham Control + Medications

12-36M

3M1 12-36M

ENROLLMENT

1M

6M

6M1

1M

§ Office BP § Drug testing§ Office BP § Witnessed drug intake§ 24-hr ABPM2

§ Office BP § Witnessed drug

intake§ 24-hr ABPM2

RUnblinding and

optional crossover to RDN

RANDOMIZED, SHAM-CONTROLLED TRIAL in mild-mod hypertension on 1, 2 or 3 drugs

SPYRAL HTN – ON MED

SPYRAL HTN – ON MEDBlood Pressure Change from Baseline to 6 Months

-9.0(-12.7, -5.3)

P<0.001

-6.0(-8.5, -3.5)P<0.001

-9.4(-13.5, -5.3)

P<0.001

-5.2(-7.7, -2.7)P<0.001

-1.6(-5.2, 2.0)

P=0.37

-1.9(-4.7, 0.9)

P=0.17-2.6

(-6.7, 1.6)P=0.22

-1.7(-4.2, 0.9)

P=0.19

-14

-12

-10

-8

-6

-4

-2

0

BP C

hang

e fro

m b

aseli

ne to

3 m

onth

s (m

mHg

)

Chart Title

RDN

Δ -4.1 mmHg(-7.8, -0.4)

P=0.03

n=36 n=36 n=38 n=40 n=38 n=40

Δ -3.5 mmHg(-7.0, -0.0)

P=0.048

24-hr SBP 24-hr DBP Office SBP Office DBP

Δ -7.4 mmHg(-12.5, -2.3)

P=0.005

Δ -7.7 mmHg(-14.0, -1.5)

P=0.02

Baseline BP (mmHg) 152 151 97 98 165 163 100 102n=36 n=36

Kandzari D, et al., Lancet 2018.

SPYRAL HTN – ON MED24-Hr ABPM – Progressive Change Over Time

-4.3

-8.8

-0.7-1.8

-12

-10

-8

-6

-4

-2

0

2

Chan

ge in

24-

hour

SBP

(m

mHg

) -4.2

-6.1

-0.8-1.8

-12

-10

-8

-6

-4

-2

0

2

Chan

ge in

24-

hour

DBP

(m

mHg

)

Systolic Diastolic

RDN Sham Control

Baseline

3 Months

6 Months

Baseline

3 Months

6 Months

ANCOVA adjusted analysis Kandzari D, et al., Lancet 2018.

SPYRAL HTN – ON MED

Medication Adherence

Kandzari D, et al., Lancet 2018.

‘Non-responders’

Renal Denervation (N=74)

Sham Procedure (N=72)

% Patients with ≥ 5 mm Hg Decrease

Renal Denervation: 66%Sham Procedure: 33%

P<0.001

66%

33%

Medtronic GLOBAL registry

Radiosound

Fengler et al, Circulation, 2018

N=120; 40/40/40

So how important is a 10mmHg drop in SBP?

Ettehad D, Lancet 2016

123 studies with 613,815 participants

Relative risk reduction for a 10 mmHg fall in office blood pressure

What next?

• More data on safety, efficacy and durability from sham-controlled RCTs and rigorous registries

Thank you.