Ultrasound Renal Denervation for Hypertension Resistant to a Triple Medication Pill: - PowerPoint Presentation

Slide1

Ultrasound Renal Denervation for Hypertension Resistant to a Triple Medication Pill:The RandomizedSham ControlledRADIANCE-HTN TRIO Trial

Six-Month Outcomes of a Randomized Trial ofRenal Denervation Versus a Sham Procedure:Blinded Medication Titration forResistant Hypertension in the RADIANCE-TRIO Trial

Ajay Kirtane, MD, SM

Columbia University Irving Medical Center

NewYork-Presbyterian Hospital

On Behalf of Michel Azizi and the RADIANCE-HTN TRIO Investigators

@

ajaykirtane

Slide2

DisclosuresDr Kirtane reports Institutional funding to Columbia University and/or Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Amgen, CSI, Siemens, Philips, ReCor Medical, Neurotronic, Biotronik

, Chiesi. In addition to research grants, institutional funding includes fees paid to Columbia University and/or Cardiovascular Research Foundation for consulting and/or speaking engagements in which Dr. Kirtane controlled the content. Personal: Consulting from IMDS; Travel Expenses/Meals from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, Siemens, Philips, ReCor Medical, Chiesi, OpSens, Zoll, and Regeneron.The PARADISE System is Limited by US Federal Law to Investigational Use Only in the United States

Slide3

RADIANCE TRIO BackgroundRADIANCE-HTN TRIO demonstrated that endovascular ultrasound renal denervation reduced 2-month SBP to a greater extent than a sham procedure in patients with HTN resistant to a stable and standardized triple combination antihypertensive pill administered daily

Slide4

RADIANCE-HTN TRIO Primary Endpoint: Change in Daytime ASBP at 2M

RDN(N=69)Sham(N=67)

IQR:

-16.4 to 0.0

IQR:

-10.3 to 1.8

Median Between Group

Difference

-4.5 mmHg

(95% CI, -8.5 to -0.3)

P=0.022

RDN

(N=63)

Sham

(N=67)

Median Between Group

Difference

-5.8 mmHg

(95% CI, -9.7 to -1.6)P=0.005

IQR:-17.1 to -1.4IQR:-10.3 to 1.8

Intent-To-Treat Population

Complete ABPM Population

Azizi M et al. Lancet. 2021;397:2476

Medication adherence by urine LCMSMS

Slide5

RADIANCE TRIO 6M Analysis ObjectivesWe assessed the institution and effects of a standardized stepped-care medication escalation protocol if Home BP remained uncontrolled from 2 to 6 months after randomizationBlinded comparison between patients randomized to endovascular ultrasound RDN vs. sham procedure

Slide6

RADIANCE-HTN TRIO Design: Blinded, Sham-Controlled, Powered to Demonstrate BP Lowering Effectiveness at 2MKey Entry Criteria:

Office BP ≥140/90 on 3+ anti-HTN medsDaytime ABP ≥135/85 on a fixed-dose, 3-drug combination pill Age 18-75 yearsNo secondary hypertension aside from OSANo CV or cerebrovascular events within the prior 3MNo Type I or uncontrolled Type II diabetes

eGFR ≥40

mL/min/m

2

Eligible renal artery anatomy

No Med Changes Unless

Escape BP Criteria Exceeded

Patients Blinded at Randomization

Outpatient Assessors Blinded

Fixed Dose, 3-Drug Combination Pill Stabilization

(4 weeks)

Baseline Daytime ABP

≥135/85

Office BP Screening

CTA / MRA,

Renal Duplex, Renal Angiography

6-Month Follow-up

(ABP, home BP, office BP, Duplex Driven CTA/MRA)

12-Month Follow-up

(ABP, home BP, office BP, CTA/MRA)

24, 36, 48, & 60 Month Follow-up (Office BP)

Renal Denervation

Sham Procedure

R

Blinded

Medication Titration Protocol

Unblinded

“Standard of Care” Meds

Primary Efficacy Endpoint @ 2 Months

∆ Daytime Ambulatory Systolic BP

Slide7

69 Were assigned to RDN (ITT)

67 Were assigned to Sham procedure (ITT)

67 RDN Subjects at 2M

67 Sham Subjects at 2M

2 Excluded* (1 Died, 1 Lost to Follow-up)

136 Underwent Randomization

66 RDN Subjects at 6M

1 Excluded (Lost to Follow-up)

3 Excluded (Lost to Follow-up)

65 RDN Subjects with ABPM

(6M Analysis Population)

63 Subjects with Office BP

59 Subjects with Home BP

64 Sham Subjects at 6M

64 Sham Subjects with ABPM

(6M Analysis Population)

Patient Flow

64 Subjects with Office BP

61 Subjects with Home BP

Slide8

Patient Characteristics at Screening (Inclusion)

RDN(N=65)Sham

(N=64)

Age (years)

51.9 ± 7.5

53.0 ± 9.1

Female sex

12/65 (18%)

13/64 (20%)

White

41/65 (63%)

49/64 (77%)

Black

14/65 (22%)

11/64 (17%)

BMI - kg/m

2

32.8 ± 5.7

32.7 ± 5.5

eGFR - mL/min/1.73m2 *86.8 ± 25.482.5 ± 18.7  eGFR<60 mL/min/1.73m2 *

7/63 (11%)

6/62 (10%)Diabetes – Type 2

19/65 (29%)

17/64 (27%)

Sleep apnea

19/65 (29%)

10/64 (16%)

Prior Hospitalization for hypertensive crisis

14/65 (22%)

11/64 (17%)

Prior cardiovascular / cerebrovascular event

8/65 (12%)

9/64 (14%)

Screening Blood Pressure

Office SBP (mmHg)

161.7 ± 15.9

163.3 ± 16.2

Office DBP (mmHg)

104.9 ± 11.5

102.8 ± 12.2

Screening # of Anti-hypertensive Medications

4.0 ± 1.0

3.9 ± 1.1

* Two subjects in RDN and 2 subjects in Sham are missing race data. The four subjects with missing race data are not included in eGFR MDRD calculations. Site reported eGFR for these 4 subjects were all greater than 60mL/min/1.73 m

2

at baseline.

Classes of Anti-HTN Medications at Screening

Slide9

Baseline Blood Pressures and Medications: After 4 weeks of Triple Medication Combination Daily Pill

RDN(N=65)Sham

(N=64)

Ambulatory BP

Daytime SBP (mmHg)

150.1 ± 12.2

151.3 ± 12.7

Daytime DBP (mmHg)

93.9 ± 7.8

94.6 ± 9.0

Nighttime SBP (mmHg)

134.6 ± 18.2

136.4 ± 18.1

Nighttime DBP (mmHg)

81.7 ± 10.7

81.3 ± 11.6

24-h SBP (mmHg)

144.1 ± 13.7

145.5 ± 13.8

24-h DBP (mmHg)

89.2 ± 8.3

89.4 ± 9.3

Home BP

SBP (mmHg)

152.7 ± 16.3

153.2 ± 16.6

DBP (mmHg)

96.7 ± 11.0

96.3 ± 10.5

Office BP

SBP (mmHg)

155.0 ± 17.1

154.8 ± 16.8

DBP (mmHg)

101.6 ± 11.5

99.2 ± 10.9

Amlodipine 10mg

(Amlodipine 5mg)

HCTZ 25mg

Valsartan 160mg

(Olmesartan 40mg)

Classes of Anti-HTN Medications at Baseline

Beta-blocker maintained for compelling indication (CHD, HF)

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Blinded Medication Titration Protocol During Months 2-5

2, 3, 4, & 5 Month Visits BP Control Achieved (1-week Home BP <135/85 mmHg)?Add Medications

6-Month Follow-Up:

Medication Burden, Ambulatory, Home and Office BP

Yes

No

No Change

Escalation Step

Recommended drugs

1

Spironolactone: 25 mg

2

Bisoprolol: 10 mg

3

Clonidine: 0.1-0.2 mg

Rilmenidine: 1-2 mg

Moxonidine 0.2-0.4 mg

4

Slow release Prazosin 5-10 mg

Doxazosin 4-8 mg

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RDN

(n=65)Sham

(n=64)

P-Value

# Anti-HTN Meds at 6 months

3.8 ± 1.0

4.1 ± 1.1

0.078

Change in Anti-HTN Meds from Baseline

0.7 ± 1.0

1.1 ± 1.1

0.045

Medication Class

CCB

98.5% (64/65)

98.4% (63/64)

1.000

RAS blockers

96.9% (63/65)

100% (64/64)

0.496

Diuretic

95.4% (62/65)

95.3% (61/64)

1.000

Aldosterone antagonist

40.0% (26/65)

60.9% (39/64)

0.017

Beta blocker

33.8% (22/65)

39.1% (25/64)

0.538

Centrally acting

drug

4.6% (3/65)

9.4% (6/64)

0.324

Alpha receptor blocker or vasodilator

6.2% (4/65)

6.3% (4/64)

1.000

Anti-Hypertensive Medications at 6 Months

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Medication Adherence through 6 months

Comparison Between GroupsBaselineP=0.47

2 Months

P=0.86

6 Months

P=0.41

Slide13

Clinical Assessments / BP Measurements at Follow-up Visits

Home BPOffice BP, Med Adherence Testing*2 measurements in AM prior to anti-HTN medications2 measurements in PM

Measured prior to anti-HTN medications

Ambulatory BP Monitoring*

7 Consecutive Days Prior to Office Visit

Office Visit

(Strongly Recommended 8-10AM)

24 hours

Placed in Office

*Med Adherence (urine) and Ambulatory BP done at Baseline, 2M, and 6M Visits

Anti-HTN Pills

(Directly observed)

https://

www.bhf.org.uk

/

informationsupport

/heart-matters-magazine/medical/tests/

https://blood-pressure-

monitoring.org

/omron-m10-it/https://www.microlife.com/professional-products/watchbp-o3/watchbp-o3-ambulatory

Slide14

Mean Office SBP Change

(mmHg)Mean Home SBP Change (mmHg)Aldo. Antagonist UseMonth

P=0.012

P=0.047

P=0.017

Home and Office SBP and Aldosterone Antagonist Use through 6M

*

By Linear Mixed Models Adjusting for Baseline BP and # Medications

Mean Home SBP difference

(95% CI)

*

(mmHg)

P-value

-4.28 [-8.06, -0.49]

0.027

Mean O

ffice SBP difference

(95% CI)*

(mmHg)P-value

-2.95 [-7.89, 1.99]

0.240

Aldosterone Antagonists

at Screening:

RDN: 37%

Sham: 31%

Slide15

ABPM Profiles at Baseline, 2 Months, and 6 Months (ABPM measured after medication administration)

RDN (N=65)

Sham (N=64)

* Three subjects in the RDN arm did not have ABPM data at 2 months.

†

Baseline-adjusted ANCOVA on the ranks

 

RDN (N=65)

Sham (N=64)

6M Mean between-group difference

adjusted for

baseline

BP

(95% CI)

P-value

†

 

Randomization

2 months*

6 months

6M Mean Difference

Randomization

2 months

6 months

6M Mean Difference

Daytime Ambulatory SBP (mmHg)

150.1 ± 12.2

140.5 ± 16.8

138.3 ± 15.1

-11.8 ± 14.2

151.3 ± 12.7

145.1 ± 18.3

139.0 ± 14.3

-12.3 ± 14.2

-0.0

(-4.6, 4.5)

0.65

Daytime Ambulatory DBP (mmHg)

93.9 ± 7.8

88.3 ± 12.1

86.0 ± 10.2

-7.9 ± 9.1

94.6 ± 9.0

89.6 ± 11.6

86.1 ± 10.2

-8.4 ± 9.7

0.3

(-2.8, 3.4)

0.79

Slide16

Individual Patient Responses: Change in Daytime Ambulatory SBP

at 2 Months By Aldosterone Antagonist UseRDN(N=65)SHAM

(N=64)

Orange bars indicate patients on Aldosterone antagonist

Aldosterone Antagonist use at 2M

P=0.16

RDN

Sham

Slide17

Individual Patient Responses: Change in Daytime Ambulatory SBP

at 6 Months By Aldosterone Antagonist UseRDN(N=65)SHAM

(N=64)

Aldosterone Antagonist use at 6M

P=0.017

RDN

Sham

Orange bars indicate patients on Aldosterone antagonist

Slide18

Individual Patient Responses: Change in Daytime Ambulatory SBP

at 6 Months By Aldosterone Antagonist UseRDN(N=65)SHAM(N=64)

Aldosterone Antagonist use at 6M

P=0.017

RDN

Sham

Orange bars indicate patients on Aldosterone antagonist

Slide19

Patients Achieving BP control at 2M and 6M(Blinded physicians titrating medications from 2-6 months to Home BP)

P=0.396

P=0.160

P=0.061

P=0.520

ABPM placed after directly observed medication administration

Home BP measured

7 days prior to FU visit

Office BP measured

on day of urine testing / FU

Lighter shaded columns are 2M rates

Slide20

eGFR at 6 Months (Matched data at baseline and 6 months)

The PARADISE System is Limited by US Federal Law to Investigational Use Only in the United States.

Baseline-Adjusted

Between

Group Difference

P=0.39

Baseline

Baseline

6 months

6 months

Slide21

Safety Events Through 6 Months (Complete Cohort)

Safety EventsRDN(N=69)

Sham

(N=67)

Major Adverse Events

 

Death within 30 days

1 (1%)

1

0

Vascular complication requiring intervention within 30 days

1 (1%)

3

0

Doubling of serum creatinine within 30 days

1 (1%)

2

0

End stage renal disease, the need for permanent renal replacement therapy within 30 days

00

Embolic event resulting in end-organ damage within 30 days

0

0

Renal artery complication requiring intervention within 30 days

0

0

Hypertensive crisis within 30 days

0

0

New renal artery stenosis of more than 70% within 6 months

0

0

Other Prespecified Safety Events Through 6 Months

Procedure-related pain lasting for > 2 days

12 (17%)

10 (15%)

Any coronary revascularization

2 (3%)

1 (1%)

Acute myocardial infarction (STEMI/non-STEMI)

1 (1%)

1 (1%)

Doubling of serum creatinine (>30 days)

1 (1%)

2

0

Hypertensive crisis (>30 days)

0

1 (1%)

Stroke, transient ischemic attack, cerebrovascular accident

0

1 (1%)

Death (>30 days)

0

0

End stage renal disease, the need for permanent renal replacement therapy (>30 days)

0

0

Embolic event resulting in end-organ damage (>30 days)

0

0

Renal artery or other vascular complication requiring intervention (>30 days)

0

0

Acute renal injury

0

0

Hypotensive emergency

0

0

Hospitalization for heart failure

0

0

New onset renal stenosis of greater than 50%

0

0

Need for renal artery angioplasty or stenting

0

0

New onset orthostatic hypotension

0

0

1

Sudden death unrelated to device or procedure 21 days post-procedure

2

Transient acute renal injury associated with spironolactone use and resolved upon discontinuation occurred 25 and 134 days post-procedure in the same patient

3

Groin site pseudoaneurysm post-procedure resolved with thrombin injection

Slide22

Conclusions: RADIANCE-TRIO 6M AnalysisAfter demonstrating that RDN (vs. a sham procedure) reduces BP at 2 months in patients with hypertension resistant to a stable and uniform regimen of combination triple therapy, at 6 months of blinded follow-up:Further BP reductions were observed in both study arms with the addition of a standardized stepped care antihypertensive regimen

BP reductions after RDN were achieved with a smaller increase in additional medications prescribed and less use of aldosterone antagonists compared with shamDespite this smaller increase in prescribed medications compared with sham, RDN achieved lower home SBP but similar ambulatory SBP (the latter measured following directly observed therapy)There were no differences in safety outcomes between groupsThese results demonstrate the additional effects of pharmacologic intervention with maintenance of a BP-lowering effect of endovascular ultrasound RDN at 6 months, mirroring the results of the RADIANCE SOLO trial

Slide23

RADIANCE-TRIO at 6M: Clinical PerspectiveLifestyle modification and pharmacotherapy are effective and standard of care for the treatment of hypertensionDespite best efforts to institute these interventions, patients may not be able to tolerate them or may not adhere to them, resulting in persistently elevated BP / resistant HTN, which increases CVD risk over time

In this light, RDN can offer an additional (but not a replacement) option to further lower BP, especially for patients whose BP is uncontrolled despite genuine attempts to institute conventional therapies

Slide24

Thank you to all the RADIANCE-HTN TRIO Study Centers!

Europe (N=25)United States (N=28)St. Barts Health NHS Trust – M. Saxena

Deborah Heart & Lung Center – K. Sanghvi

Hôpital Saint-André - CHU Bordeaux

–

P. Gosse

Ochsner Heart and Vascular Institute – J.P. Reilly

Royal Bournemouth Hospital

–

T. Levy

Vanderbilt University Medical Center – P. Fong

Hôpital

Européen

Georges-Pompidou – M. Azizi

Stamford Hospital – D.

Hsi

Cliniques Universitaires Saint-Luc

–

A. Persu

NYU Langone Medical Center – S. BangaloreUniversity Clinic Dusseldorf – L.C. RumpMedical University of South Carolina – T. TodoranClinique Pasteur / GCVI – Toulouse – A. Pathak

Emory University – C. Devireddy

Erasmus MC Rotterdam

– J. Daemen

Cedars-Sinai Medical Center – F. Rader

Hôpital de la Croix Rousse, Lyon

–

P.

Lantelme

University of Utah Medical Center – J. Abraham

Royal Devon and Exeter NHS Foundation Trust – A.S.P. Sharp

University of Alabama

–

D. Calhoun

Institute of Cardiology, Warsaw - A. Witkowski

Columbia University Medical Center – A.J. Kirtane

Sana

Kliniken

Lübeck GmbH - J. Weil

Massachusetts General Hospital – J.

Garasic

University Clinic of Saarland, Homburg – F.

Mahfoud

The Cardiac and Vascular Institute, Gainesville – M.

Khuddus

The Essex Cardiothoracic Centre – J. Sayer

Minneapolis Heart Institute Foundation – Y. Wang

Leipzig Heart Center – P.

Lurz

Drexel University – J. Goldman

Medical University of Gdansk – D.

Hering

The Heart Hospital Baylor Plano – S. Potluri

Conquest Hospital, East Sussex NHS Trust – R. Gerber

The Brigham and Women's Hospital – N.D.L. Fisher

University Clinic Erlangen – R.E. Schmieder

University of North Carolina – R. Stouffer

Maastricht University Hospital – A. Kroon

University Hospitals Cleveland Medical Center – D. Zidar

Hammersmith Hospital, Imperial College NHS Trust – J. Davies

Renown Institute for Heart & Vascular Health – M.J. Bloch

Katholisches

Klinikum

Mainz – S.

Genth

-Zotz

University of

Pennsylvania –

D. Cohen

University Medical Center Utrecht – P.

Blankestijn

Franciscan Health Indianapolis - A.R.

Chugh

CHRU Lille - P.

Delsart

Sutter Medical Center, Sacramento – P. Huang

Nottingham University Hospitals NHS Trust – S. Jadhav

Southern Illinois University School of Medicine – J. Flack

Freiburg University – C. von

zur

Mühlen

Bridgeport Hospital - R. Fishman

Baptist Health Lexington - M. Jones

Munson Medical Center - T. Adams

Cleveland Clinic - C.

Bajzer