Renal Denervation (RDN) in Korea

In-Ho Chae, MD, PhD

Seoul National University College of Medicine

SNU Bundang Hospital, Cardiovascular Cente

Disclosure

Speaker name: IN-HO CHAE

.................................................................................

I have the following potential conflicts of interest to report:

Consulting

Employment in industry

Stockholder of a healthcare company

Owner of a healthcare company

Other(s)

I do not have any potential conflict of interest

Symplicity HTN-1

Initial Cohort – Reported in the Lancet, 2009:

-First-in-man, non-randomized

-Cohort of 45 patients with resistant HTN (SBP ≥160 mmHg on ≥3 anti-HTN drugs,

including a diuretic; eGFR ≥ 45 mL/min)

- 12-month data\

Expanded Cohort – This Report (Symplicity HTN-1):

-Expanded cohort of patients (n=153)

-24-month follow-up

Lancet. 2009;373:1275-1281

Sievert et al. European Society of Cardiology. 2010. Symplicity HTN-1

Significant, Sustained Blood Pressure Reductions to at Least 3 Years

Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

p <0.01 for from baseline for all time points

-22 -26 -33 -33-10 -13 -15 -19

-40

-30

-20

-10

0

10

6M(n=144)

1Y(n=130)

2Y(n=59)

3Y(n=24)

Ch

an

ge

in

Blo

od

Pre

ss

ure

(m

mH

g)

Systolic Diastolic

Symplicity HTN-1

Lancet. 2010. published electronically on November 17, 2010

Symplicity HTN-2 Investigators. The Lancet. 2010.

• Purpose: To demonstrate the effectiveness of catheter-based renal

denervation for reducing blood pressure in patients with uncontrolled

hypertension in a prospective, randomized, controlled, clinical trial

• Patients: 106 patients randomized 1:1 to treatment with renal denervation

vs. control

• Clinical Sites: 24 centers in Europe, Australia, & New Zealand (67% were

designated hypertension centers of excellence)

Symplicity HTN-2

∆ from

Baseline

to

6 Months

(mmHg)

Primary Endpoint:

• 84% of RDN patients had ≥10 mmHg reduction

in SBP

• 10% of RDN patients had no reduction in SBP

Systolic

Diastolic

Systolic Diastolic

Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.)

-28

-10

-50

-40

-30

-20

-10

0

10RDN (n= 49)

∆ from

Baseline

to

12 Months

(mmHg)

Systolic

Diastolic

Primary Endpoint

(6M post Randomization)

Latest Follow-up

(12M post Randomization)

Latest Follow-up:

•Control crossover (n = 35): -24/-8 mmHg

(Analysis on patients with SBP ≥ 160 mmHg at 6

M)

p <0.01 for

from baseline

p <0.01 for

difference

between RDN

and Control

Symplicity HTN-2: RDN Superior to Medical Management, Reductions Sustained to 12M

Symplicity HTN-2

Symplicity HTN-3

• Inclusion criteria• Average office SBP >160mmHg (ABPM >135mmHg)• On stable medication regimen of full tolerated doses of 3 or more

antihypertensive medications, with one being a diuretic:– No changes for a minimum of 2 weeks prior to screening

– No planned medication changes for 6 months

• Age 18-80• eGFR >45 mL/min

• Randomization – initial design• N = 530 randomized (at 90 US sites)• Randomization

– 2:1 ratio Treatment or Sham Control

– Stratified by study center & by race

• Single blind– Specific staff & subject until 6 months

Symplicity HTN-3 Investigators. NEJM APR 10, 2014

Symplicity HTN-3 : Primary efficacy end point

Symplicity HTN-3 Investigators. NEJM APR 10, 2014

RDN Control P value

Baseline SBP 179.7 180.2 0.765

6 mo SBP 165.6 168.4 0.260

Change-14.1

P < 0.001-11.7

P < 0.0010.2551

Symplicity HTN-3: Conclusions

In a prospective, multicenter, randomized, blinded, sham

controlled trial of patients with uncontrolled resistant

hypertension, RDN was safe but not associated with

significant additional reductions in office or ambulatory

blood pressure.

These findings contradict most published data on renal

denervation.

RDN in KOREA

10

GSR Korea: Purpose

• Designed to assess the safety and effectiveness

of the Symplicity™ renal denervation system in

Korean patients with severe resistant

hypertension

Global SYMPLICITY Registry: Real-World Clinical Outcomes

6mo 3yr2yr1yr

Follow-up schedule

3mo

~ 200 Global Sites

Minimum 10% randomly assigned to 100% monitoring

30% monitoring to date

4yr 5yr

Consecutive patients treated in real world population

~ 5000 patients

GREAT Registry

N=1000

Korea Registry*

N=102

South Africa Registry*

N=400Canada and

Mexico*

Rest of GSR

N~3500

Worldwide evaluation of the safety and efficacy of treatment with the

Symplicity™ renal denervation system in real world uncontrolled

hypertensive patients

Inclusion/Exclusion Criteria

Key Inclusion Criteria• ≥ 18 years• Systolic BP≥160 mm Hg, ≥150 mm Hg in type II diabetes• Stable drug regimen of 3 or more medications

Key Exclusion Criteria• Renal artery anatomy that is ineligible for treatment

– Hemodynamically or significant renal artery abnormality– Renal diameter <4 mm or <20 mm treatable length

• eGFR <45 mL/min/1.73m2

• Type 1 diabetes mellitus

Baseline Patient Characteristics

GSR-Korea (N=102)

Demographics Age (years) 55 ± 14

Gender (% male) 70%

BMI (kg/m2 28 ± 4.8

Co-Morbidities Diabetes Mellitus II (%) 46%

History of Cardiac Disease (%) 43%

eGFR (ml/min/1.73 m2) 91± 26.6

Serum Creatinine (mg/dl) 0.9 ± 0.3

Baseline Patient Characteristics

GSR-Korea (N=102)

Blood Pressure Baseline BP (mm Hg) 170/97 ± 15/14

Number of classes anti-HTN meds (mean) 3.78 ± 0.94

Diuretic (%) 86%

Aldosterone blocker (%) 11%

ACE (%) 10%

ARB (%) 88%

Beta-Blocker (%) 80%

Calcium Channel Blocker (%) 75%

Alpha adrenergic Blocker(%) 14%

Vasodilator (%) 6%

Centrally-acting sympatholytics (%) 0%

Procedure Detail & SafetyGSR-Korea

Procedure Details:

99% procedures completed

• Average number renal arteries: 2.03

• Mean length of renal artery: 45±13 mm

• Mean diam. of rt. artery: 6.1±1.2 mm

• Mean diam. of lt. artery: 6.0±1.2 mm

• 55 minute mean Symplicity procedure time*

• Mean contrast used: 142±78 cc

*Symplicity catheter insertion to Symplicity catheter removal

Procedure Safety:

4.5% incidence of spasm

No major complications

No vascular complications

No serious adverse events related to

delivery of RF energy to the renal

artery

Change in Office Blood Pressure GSR-Korea

-23-20

-27

-11 -11

-14

-40

-30

-20

-10

0

3 months (n=97) 6 months (n=97) 12 months (n=54)

Δ SBP

Δ DBP

P<.001 for all values

compared to baseline

Change in B

P (

mm

Hg)

Responder Rate over timeGSR-Korea

76%69%

83%

60%52%

61%

0%

20%

40%

60%

80%

100%

3 months(n=99)

6 months(n=97)

12 months(n=54)

↓SBP ≥ 10 mm Hg ↓SBP ≥ 20 mm Hg

% R

esponder

GSR-Korea Safety through 6 months*

• No vascular complications requiring intervention

• No new renal artery stenosis

• Stroke (1)

• Atrial fibrillation in hospital (1)

• Hospitalization for hypertensive emergency (1)

• New onset of end-stage renal disease at 3 months follow-up (1)

– Nephrotoxic overdose

*Data collected on all patients who reached either 3 or 6 month follow up

Symplicity HTN-3 : selected subgroup analysis -> genetic difference ?

Symplicity HTN-3 Investigators. NEJM APR 10, 2014

RDN for Korean patients?

Asian patients have a lower BMI and other different characteristics than Caucasian populations.

Previous studies on RDN have primarily included Caucasian patients. Responses to RDN in Korean patients is limited.

It is unclear whether the pathophysiology of resistant hypertension could be different in Asian patients and whether any differences might affect the role of sympathetic tone and consequently RDN results.

Outcomes of Korean population5000 consecutive “real-world” patients treated with Symplicity™ for uncontrolled

hypertension and/or conditions associated with sympathetic nervous system activation

GREAT Registry

N=1000

Korea Registry1

N=102

South Africa Registry1

N=400

Canada &

Mexico1

Rest of GSR

N≈3500

• To evaluate 6- and 12-month outcomes after RDN in patients from the Korea substudy treated in the Global SYMPLICITY Registry (GSR) and to compare them to Caucasian patients.

BK Kim, et al. J Hum Hypertens. 2016;30:315-21

Baseline patient characteristics% or mean ± SD

GSR Korea(N=93)

GSR Caucasian(N=169)

P-value

Office systolic blood pressure, mm Hg 168.3 ± 13.9 176.1 ± 15.6 < 0.001

Office diastolic blood pressure, mm Hg 95.5 ± 12.8 94.5 ± 14.5 0.403

Age, years 55.9 ± 13.4 61.8 ± 10.8 < 0.001

Male gender 72.0 62.7 0.127

Body mass index, kg/m2 27.5 ± 4.3 31.2 ± 5.1 < 0.001

Obesity (≥ 30 kg/m2) 10.8 38.5 < 0.001

Diabetes mellitus type 2 46.2 36.3 0.117

eGFR, ml/min/1.73 m2 88.9 ± 25.3 80.9 ± 18.2 0.011

Renal insufficiency (eGFR <60 ml/min/1.73 m2) 5.4 13.6 0.039

History of atrial fibrillation 5.4 11.3 0.112

History of sleep apnea 2.2 21.9 < 0.001

Heart rate (beats per minute) 72.3 ± 11.5 69.0 ± 14.2 0.016

Heart failure 2.2 3.0 > 0.999

Antihypertensive medication at baseline

% (n)GSR Korea

(N=93)GSR Caucasian

(N=169)P-value

No. of anti-hypertensive medication classes

3.7 ± 0.9 4.7 ± 1.2 < 0.001

ACE inhibitors 8.6 (8) 38.5 (65) < 0.001

Angiotensin receptor blockers 88.2 (82) 69.2 (117) < 0.001

Calcium channel blockers 84.9 (79) 78.1 (132) 0.18

Diuretics 83.9 (78) 78.1 (132) 0.26

Aldosterone antagonists 8.6 (8) 18.3 (31) 0.03

Direct renin inhibitors 0.0 (0) 12.4 (21) < 0.001

Beta blockers 79.6 (74) 79.9 (135) 0.95

Alpha-adrenergic blocker 11.8 (11) 37.3 (63) < 0.001

Direct-acting vasodilators 4.3 (4) 16.6 (28) 0.004

Office BP changes at 6 & 12 months

BK Kim, et al. J Hum Hypertens. 2016;30:315-21

Office systolic BP reduction >10 & 20mmHg

BK Kim, et al. J Hum Hypertens. 2016;30:315-21

Determinants for office systolic BP change

A higher baseline office systolic BP was associated with a larger reduction in systolic BP at both 6 [Estimate=-0.53, p<0.001] and 12 months [-0.73, p<0.001].

Notable as previous analyses have consistently shown an association between a higher baseline office systolic BP and a greater reduction in systolic BP after RDN.

Korea patients also had a larger reduction in systolic BP at 12 months independent of baseline office systolic BP.

6 Months Estimate 95% CI p-value

Korean (vs. Caucasian) -2.4 (-7.14, 2.29) 0.315

12 Months Estimate 95% CI p-value

Korean (vs. Caucasian) -11.8 (-16.85, -6.73) <0.001

conclusions

RDN in the GSR Korea substudy provided a significant reduction in office systolic BP at 6 and 12 months compared to baseline.

As compared to the GSR Caucasian subset, the reduction in systolic BP in GSR Korea was similar at 6 months but higher at 12 months depsite fewer medications and a lower systolic BP in baseline.

In multivariate analysis, Korean patients remained more likely to have a larger reduction in 12-month systolic BP.

Renal Denervation (RDN) in Korea

In-Ho Chae, MD, PhD

Seoul National University College of Medicine

SNU Bundang Hospital, Cardiovascular Cente