RDN ACI Sharp...SNS effects are mostly bad for CV health • Arise from T10-L1, Follow the renal...
Transcript of RDN ACI Sharp...SNS effects are mostly bad for CV health • Arise from T10-L1, Follow the renal...
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.