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Quality of Life in Early-Stage HCM: �A Secondary Analysis of the VANISH Trial

Casey Ireland, MD

Brigham and Women’s Hospital

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Group 2

(EXPLORATORY)

Age 10-25 years

Baseline

History

Family History

Genotype

PE

ECG

Echo

Biomarkers

CMR

CPET

PedsQL

Evaluation at 12 and 24 months

History

PE

ECG

Echo

Biomarkers

PedsQL

CPET and

CMR at 24M

R

a

n

d

o

m

i

z

e

1° Composite Outcome

Z-score of change from baseline across domains:

Myocardial injury
Hemodynamic stress
Collagen metabolism
Functional capacity
Myocardial fibrosis
Cardiac morphology
Cardiac function

2° Endpoints

Safety
Clinical outcomes
Individual components of primary composite outcome
Quality of Life and Physical Activity
Alternative assessments of cardiac function
Interactions with age, genotype, baseline characteristics

STRATIFY

Valsartan

n ~75

Group 1

Pre-pubertal or Post-pubertal*

AND

NYHA Class I or Class II

AND

LVWT < or ≥ 14 mm

AND

Group 1 or Group 2

Placebo

n ~75

Group 1

(PRIMARY)

8-30 years old, NYHA I-II, no obstruction

Active Run In

Titration over 2 week intervals to

Goal Dose:

Adults: 320 mg/d

Children ≥35 kg: 160 mg/d

Children <35 kg: 80 mg/d

*Post-pubertal:

Males ≥17 years; Females ≥16 years

ClinicalTrials.gov NCT01912534

Ho CY, et al. Am Heart J. 2017

BASELINE CHARACTERISTICS (n=178)

Mean Age 23 years

< age 18yrs 43%

Female 39%

Mean LVWT 17 mm, z-score 8

Phase II Randomized, Placebo-controlled, Double-Blind Clinical Trial of Valsartan for Attenuating Disease Evolution in Early Sarcomeric HCM

24 months treatment

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Primary endpoint and prespecified subgroup analysis

Placebo

better

Valsartan

better

Ho CY, et al, Nature Medicine, 2021

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Secondary QOL analysis

Do QoL scores vary between subclinical and early-stage HCM?

Are there baseline correlates of QoL in patients with early-stage HCM?

Does valsartan impact QoL in early-stage HCM?

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PedsQL structure

23 question Likert scale survey, reverse-scored and transformed to 0-100 scale (higher better)
We used 4 versions by age:

Child: 8-12
Teen: 13-18
YA: 19-25
Adult: >26

Composite

Physical

Psychosocial

Emotional

Social

Work/School

Parent + child options

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In the past month, how often have you had a problem … (always, often, sometimes, never)

Physical Function:

- Walking >1 block

- Running

- Sports/exercise

- Lifting something heavy

- Bathing independently

- Household chores

- Low energy

- Having aches/pains

Emotional Function:

- Feeling afraid/scared

- Feeling sad/blue

- Feeling angry

- Trouble sleeping

- Worrying about what will happen to you

Social Function:

- Getting along with peers

- Peers not wanting to be a friend

- Getting teased by peers

- Not able to do things peers can do

- Keeping up playing with peers

Work/School Function:

- Paying attention

- Forgetting things

- Keeping up with assignments

- Missing time because not feeling well

- Missing time for medical care

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QOL in early-stage HCM is diminished compared to subclinical HCM

Domain	Difference	MCID
Composite	5.6	4.50
Physical	5.6	6.92
Psychosocial	5.5	5.49

84.6 v 90.2

p=0.005

86.6 v 92.2

p=0.019

83.6 v 89.1

p=0.012

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Baseline correlates of QOL

	Composite QOL		Physical QOL		Psychosocial QOL
	Estimate (95% CI)	p-value	Estimate (95% CI)	p-value	Estimate (95% CI)	p-value
Age, per 10 years	-0.3 (-2.0, 1.3)	0.69	-3.5 (-5.4, -1.5)	<0.001	1.3 (-0.5, 3.1)	0.14
Pre-pubertal (vs post)	-0.3 (-3.7, 4.3)	0.88	3.5 (-8.4, 1.3)	0.15	-2.4 (-2.0, 6.7)	0.29
Female sex (vs male)	-0.3 (-3.7, 3.0)	0.85	-3.4 (-7.5, 0.7)	0.10	1.3 (-2.4, 5.0)	0.49
White race (vs non-white)	13.9 (4.6, 23.2)	0.004	20.3 (8.9, 31.7)	<0.001	10.6 (0.1, 21.0)	0.048
Non-Hispanic ethnicity (vs Hispanic)	6.0 (2.1, 9.8)	0.003	8.3 (3.6, 13.1)	<0.001	4.7 (0.4, 9.1)	0.032
Thick filament mutation (vs thin filament)	-3.8 (-8.8, 1.2)	0.13	-4.6 (-10.8, 1.5)	0.14	-3.3 (-8.9, 2.2)	0.24
Composite primary outcome z score, per 0.6	1.3 (-0.4, 2.9)	0.13	3.7 (1.8, 5.6)	<0.001	0.0 (-1.8, 1.8)	0.98
Log NT-proBNP, per SD	-0.7 (-2.2, 0.9)	0.41	-2.1 (-4.0, -0.1)	0.038	0.0 (-1.7, 1.8)	0.98
LV mass index, per 25 g/m²	-0.9 (-2.5, 0.8)	0.30	-1.2 (-3.2, 0.9)	0.25	-0.7 (-2.5, 1.1)	0.45
LA volume index, per 15 mL/m²	-1.6 (-3.2, 0.0)	0.047	-3.4 (-5.3, -1.5)	<0.001	-0.6 (-2.3, 1.2)	0.51
LV end diastolic volume index, per 17 mL/m²	1.0 (-0.7, 2.6)	0.26	1.6 (-0.4, 3.7)	0.12	0.7 (-1.2, 2.5)	0.49
LV end systolic volume index, per 8 mL/m²	-0.3 (-1.8, 1.3)	0.75	-0.1 (-2.0, 1.8)	0.92	-0.3 (-2.0, 1.4)	0.75
Maximum LV wall thickness (BSA-adjusted z-score), per 5	-0.3 (-2.1, 1.4)	0.71	-2.7 (-4.8, -0.5)	0.014	0.9 (-1.0, 2.8)	0.36
E' velocity, per 3.2 cm/s	0.9 (-0.7, 2.6)	0.26	3.9 (1.9, 5.8)	<0.001	-0.6 (-2.4, 1.2)	0.52
S' velocity, per 1.5 cm/s	1.3 (-0.4, 2.9)	0.14	3.6 (1.6, 5.7)	<0.001	0.0 (-1.9, 1.9)	0.98
Peak VO₂, per 9 ml/(kg min)	2.2 (0.6, 3.8)	0.007	5.1 (3.2, 7.0)	<0.001	0.7 (-1.1, 2.5)	0.44
Percent predicted peak VO₂, per 16 %	2.5 (0.9, 4.0)	0.003	3.6 (1.7, 5.5)	<0.001	1.9 (0.1, 3.6)	0.040
VE/VCO₂ slope, per 5	-1.8 (-3.5, 0.0)	0.044	-3.3 (-5.4, -1.2)	0.003	-1.0 (-3.0, 0.9)	0.31

Estimate is represented as the beta-value in regression analysis. Positive effect size indicates increasing QOL; negative indicates decreasing QOL.

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Valsartan improves physical QOL

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Summary

PedsQL allows evaluation of QOL domains across pediatric and adult age groups.
Patients with early-stage HCM have a good baseline QOL, although reduced compared to those with only subclinical disease.
QOL can vary with race and ethnicity, but larger and more diverse cohorts are needed to understand full impact.
Valsartan improves physical QOL in early-stage HCM.

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Participating Sites

Executive Committee

Eugene Braunwald, MD

Calum A. MacRae, MD, PhD

John J.V. McMurray, MD

E. John Orav, PhD

Scott D. Solomon, MD

Core Lab Directors

Steve Colan, MD Echo

Renee Margossian, MD

Jose Vargas, MD CMR

Greg Lewis, MD CPET

Clinical Events Committee

Akshay Desai, MD, MPh, Chair

Neal Lakdawala, MD

Betsy Blume, MD

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Supplemental slides

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PedsQL scoring varies with age, reporter, and domain

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Table 1: Baseline characteristics by cohort and treatment group

	Early-stage HCM			Subclinical HCM
	Placebo (n=84)	Valsartan (n=82)	Full cohort (n=166)	Full cohort (n=34)
Mean age, years	23.7 (10.1)	23.1 (10.1)	23.4 (10.1)	16.4 (4.9)
Pre-pubertal, n (%)	19 (22.6)	17 (20.7)	36 (21.7)	14 (41.2)
Female, n (%)	34 (40.5)	32 (39.0)	66 (39.8)	17 (50.0)
White, n (%)	82 (97.6)	79 (96.3)	161 (97.0)	34 (100.0)
Hispanic, n (%)	21 (25)	15 (18.3)	36 (21.7)	1 (2.9)
Country of enrollment, n (%)
USA	65 (77.4)	65 (79.3)	130 (78.3)	32 (94.1)
Brazil	15 (17.9)	12 (14.6)	27 (16.3)	0 (0.0)
Denmark	4 (4.8)	5 (6.1)	9 (5.4)	2 (5.9)
BMI, kg/m²	25.6 (5.7)	24.9 (5.7)	25.2 (5.7)	22.7 (4.8)
Systolic BP, mmHg	118 (12)	118 (10)	118 (11)	114 (12)
NYHA class I, n (%)	79 (94.1)	74 (90.2)	153 (92.2)	34 (100.0)
NYHA class II, n (%)	5 (6.0)	8 (9.8)	13 (7.8)	0 (0.0)
LVEF, %	66.8 (7.1)	66.2 (5.7)	66.5 (6.5)	64.1 (4.4)
Beta blocker use, n (%)	14 (16.7)	16 (19.5)	30 (18.1)	2 (5.9)
Calcium channel blocker use, n (%)	1 (1.2)	4 (4.9)	5 (3.0)	0 (0.0)

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Table 2: Baseline quality of life, biomarker, imaging and exercise metrics

	Early-stage HCM			Overall cohort
	Placebo (n=84)	Valsartan (n=82)	p-value	Early-stage HCM (n=166)	Subclinical HCM (n=34)	p-value
Composite QOL, pts	85.0 (10.0)	84.2 (11.3)	0.62	84.6 (10.6)	90.2 (9.8)	0.005
Physical QOL, pts	86.3 (12.8)	86.9 (13.6)	0.77	86.6 (13.2)	92.2 (9.2)	0.019
Psychosocial QOL, pts	84.4 (10.9)	82.7 (12.6)	0.37	83.6 (11.8)	89.1 (11.1)	0.012
Composite primary outcome z-score	0.041 (0.548)	-0.055 (0.654)	0.31	-0.006 (0.603)	0.000 (0.313)	0.95
NT-proBNP, pg/ml (median, IQR)	88 (40, 201)	124 (46, 427)	0.06	101 (434, 294)	32 (20, 63)	0.003
LV mass index, g/m²	73 (26)	75 (24)	0.61	74 (25)	55 (10)	<0.001
LA volume index, ml/m²	39 (16)	39 (14)	0.92	39 (15)	30 (6)	0.001
LV end diastolic volume index, ml/m²	74 (16)	75 (17)	0.82	75 (17)	77 (11)	0.39
LV end systolic volume index, ml/m²	25 (9)	25 (8)	0.65	25 (8)	27 (6)	0.20
Maximum LV wall thickness, mm	15.5 (3.7)	16.5 (4.7)	0.15	16 (10)	4.2 (0.1)	<0.001
Maximum LV wall thickness, BSA-adjusted z-score	8.3 (4.2)	9.5 (5.1)	0.09	8.9 (4.7)	2.6 (0.7)	<0.001
E' velocity, cm/s	9.5 (2.6)	9.4 (3.7)	0.82	9.4 (3.2)	12.9 (2.1)	<0.001
S' velocity, cm/s	8.0 (1.4)	7.7 (1.5)	0.11	7.8 (1.5)	8.2 (0.9)	0.15
Peak VO₂, ml/(kg min)	31.9 (8.8)	31.8 (9.3)	0.92	31.9 (9.0)	38.5 (8.8)	<0.001
Percent predicted peak VO₂, %	72 (15)	71 (17)	0.51	72 (16)	78 (16)	0.046
VE/VCO₂ slope	27.0 (4.5)	27.6 (4.8)	0.37	27.3 (4.7)	27.5 (3.7)	0.84
Peak watts	181 (61)	173 (63)	0.38	177 (62)	174 (61)	0.80
RER	1.18 (0.13)	1.17 (0.10)	0.75	1.18 (0.12)	1.17 (0.11)	0.80

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Supplemental Table 1: Baseline participant characteristics by non-white vs white race

Baseline participant characteristics	Non-white (n=5)	White (n=161)	p-value
Mean age, years	26.4 (11.4)	23.3 (10.1)	0.50
Pre-pubertal, n (%)	1 (20.0)	35 (21.7)	1.00
Female, n (%)	2 (40.0)	64 (39.8)	1.00
Hispanic, n (%)	4 (80.0)	32 (19.9)	0.008
Country of enrollment, n (%)			0.40
USA	3 (60.0)	127 (78.9)
Brazil	2 (40.0)	25 (15.5)
Denmark	0 (0.0)	9 (5.6)
Thick filament mutation, n (%)	5 (100.0)	141 (87.6)	0.27
BMI	28.0 (7.1)	25.1 (5.6)	0.96
Systolic BP, mmHg	118 (7)	118 (11)	1.00
NYHA class I, n (%)	5 (100.0)	148 (91.9)	1.00
NYHA class II, n (%)	0 (0.0)	13 (8.1)	0.67
LVEF, %	65.3 (2.9)	66.5 (6.5)	1.00
Beta blocker use, n (%)	1 (20.0)	29 (18.0)	0.14
Calcium channel blocker use, n (%)	1 (20.0)	4 (2.5)	<0.001
Composite z-score	-0.956 (0.683)	0.023 (0.578)	0.002
NT-proBNP, pg/ml (median, IQR)	668 (323, 795)	92 (41, 265)	0.002
LV mass index, g/m²	108 (34)	73 (24)	<0.001
LA volume index, ml/m²	64 (30)	38 (14)	0.85
LV end diastolic volume index, ml/m²	76 (15)	75 (17)	0.81
LV end systolic volume index, ml/m²	26 (6)	25 (8)	0.003
Maximum LV wall thickness, mm	21.4 (4.3)	15.8 (4.1)	0.005
Maximum LV wall thickness, BSA-adjusted z-score	14.7 (4.1)	8.7 (4.6)	0.015
E' velocity, cm/s	6.0 (2.7)	9.5 (3.2)	0.07
S' velocity, cm/s	6.7 (1.8)	7.9 (1.4)	0.30
Peak VO₂, ml/(kg min)	27.7 (16.0)	32.0 (8.8)	0.17
VE/VCO₂ slope	30.1 (5.8)	27.2 (4.6)	0.20
Peak watts	142 (72)	178 (62)	0.39
RER	1.22 (0.11)	1.18 (0.12)	0.10
Percent predicted peak VO₂, %	60 (21)	72 (16)	0.27

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Supplemental Table 2: Baseline participant characteristics by non-Hispanic vs Hispanic ethnicity

Baseline participant characteristics	Non-Hispanic (n=36)	Hispanic (n=130)	p-value
Mean age, years	21.8 (9.3)	29.1 (11.1)	<0.001
Pre-pubertal, n (%)	29 (22.3)	7 (19.4)	0.82
Female, n (%)	52 (40.0)	14 (38.9)	1.00
White, n (%)	129 (99.2)	32 (88.9)	0.008
Country of enrollment, n (%)			<0.001
USA	121 (93.1)	9 (25.0)
Brazil	0 (0.0)	27 (75.0)
Denmark	9 (6.9)	0 (0.0)
Thick filament mutation, n (%)	110 (84.6)	36 (100.0)	0.008
BMI	25.0 (5.8)	26.0 (5.0)	0.33
Systolic BP, mmHg	119 (11)	115 (10)	0.14
NYHA class I, n (%)	124 (95.4)	29 (80.6)	0.008
NYHA class II, n (%)	6 (4.6)	7 (19.4)	0.008
LVEF, %	66.7 (6.8)	65.6 (4.8)	0.34
Beta blocker use, n (%)	18 (13.9)	12 (33.3)	0.013
Calcium channel blocker use, n (%)	3 (2.3)	2 (5.6)	0.30
Composite z-score	0.091 (0.546)	-0.360 (0.670)	<0.001
NT-proBNP, pg/ml (median, IQR)	78 (37, 208)	245 (104, 496)	<0.001
LV mass index, g/m²	73 (25)	77 (24)	0.36
LA volume index, ml/m²	36 (13)	50 (20)	<0.001
LV end diastolic volume index, ml/m²	74 (17)	78 (17)	0.14
LV end systolic volume index, ml/m²	25 (8)	26 (10)	0.41
Maximum LV wall thickness, mm	15.3 (4.0)	18.4 (4.3)	<0.001
Maximum LV wall thickness, BSA-adjusted z-score	8.2 (4.6)	11.4 (4.5)	<0.001
E' velocity, cm/s	10.0 (3.0)	7.3 (3.1)	<0.001
S' velocity, cm/s	8.0 (1.4)	7.3 (1.5)	0.007
Peak VO₂, ml/(kg min)	32.5 (9.1)	29.4 (8.4)	0.07
VE/VCO₂ slope	27.0 (4.8)	28.3 (3.8)	0.13
Peak watts	180 (65)	167 (51)	0.27
RER	1.17 (0.12)	1.21 (0.09)	0.05
Percent predicted peak VO₂, %	72 (17)	69 (14)	0.27

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Supplemental Table 3: Baseline QOL in white vs non-white race, univariate adjustment

	Composite QOL		Physical QOL		Psychosocial QOL
	Estimate (95% CI)	p-value	Estimate (95% CI)	p-value	Estimate (95% CI)	p-value
Unadjusted	13.9 (4.6, 23.2)	0.004	20.3 (8.9, 31.7)	0.001	10.6 (0.1, 21.0)	0.048
Age	13.9 (4.5, 23.2)	0.004	19.3 (8.2, 30.3)	0.001	11.0 (0.6, 21.4)	0.039
Country of origin	12.6 (3.4, 21.8)	0.008	18.0 (6.8, 29.2)	0.002	9.7 (-0.7, 20.1)	0.066
Hispanic vs non-Hispanic ethnicity	11.0 (1.5, 20.5)	0.023	16.3 (4.7, 27.9)	0.006	8.2 (-2.5, 18.9)	0.132
Thick filament mutation	13.5 (4.2, 22.8)	0.005	19.8 (8.4, 31.2)	0.001	10.2 (-0.3, 20.7)	0.056
NYHA class	14.6 (5.5, 23.7)	0.002	21.6 (10.8, 32.4)	<0.001	11.0 (0.5, 21.4)	0.04
Beta blocker use	13.9 (4.6, 23.1)	0.004	20.2 (8.9, 31.5)	0.001	10.5 (0.1, 21.0)	0.049
Log NT-proBNP	13.5 (4.0, 3.0)	0.006	18.3 (6.6, 30.0)	0.002	10.9 (0.2, 21.6)	0.045
Maximum LV wall thickness, BSA-adjusted z-score	14.2 (4.6, 3.8)	0.004	17.9 (6.3, 29.6)	0.003	12.2 (1.5, 22.9)	0.025

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Supplemental Table 4: Baseline QOL in Hispanic vs non-Hispanic ethnicity, univariate adjustment

	Composite QOL		Physical QOL		Psychosocial QOL
	Estimate (95% CI)	p-value	Estimate (95% CI)	p-value	Estimate (95% CI)	p-value
Unadjusted	-6.0 (-9.8, -2.1)	0.003	-8.3 (-13.1, -3.6)	0.001	-4.7 (-9.1, -0.4)	0.032
Unadjusted, Hispanic vs non-Hispanic in American participants*	-7.3 (-14.2, -0.4)	0.037	-3.6 (-11.6, 4.3)	0.369	-9.3 (-17.3, -1.4)	0.022
Age	-6.3 (-10.3, -2.2)	0.003	-6.4 (-11.2, -1.5)	0.011	-6.2 (-10.7, -1.8)	0.007
Country of origin	-7.3 (-14.3, -0.3)	0.041	-3.6 (-12.3, 5.0)	0.41	-9.3 (-17.1, -1.5)	0.019
White vs non-white race	-4.8 (-8.8, -0.9)	0.017	-6.6 (-11.4, -1.8)	0.007	-3.9 (-8.3, 0.6)	0.086
Thick filament mutation	-5.6 (-9.5, -1.7)	0.006	-7.9 (-12.7, -3.1)	0.002	-4.4 (-8.8, 0.0)	0.051
NYHA class	-5.0 (-8.9, -1.1)	0.013	-6.4 (-11.1, -1.7)	0.008	-4.3 (-8.7, 0.2)	0.059
Beta blocker use	-5.6 (-9.5, -1.6)	0.006	-7.6 (-12.4, -2.7)	0.002	-4.5 (-9.0, -0.1)	0.045
Log NT-proBNP	-5.7 (-9.7, -1.7)	0.005	-7.3 (-12.2, -2.4)	0.004	-4.9 (-9.4, -0.4)	0.034
Maximum LV wall thickness, BSA-adjusted z-score	-6.2 (-10.3, -2.2)	0.003	-7.2 (-12.1, -2.3)	0.004	-5.8 (-10.2, -1.3)	0.012

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Supplemental Table 5: Quality of life score changes with valsartan

Composite QOL	n	Mean difference	Confidence interval	p-value
Overall	166	2.6	(-0.4, 5.7)	0.09
Pre-pubertal	36	-1.7	(-8.1, 4.8)	0.61
Post-pubertal	130	3.8	(0.3, 7.3)	0.031
Male	100	3.6	(-0.1, 7.3)	0.06
Female	66	0.7	(-4.7, 6.1)	0.80
LV wall thickness < median	83	4.4	(-0.7, 9.6)	0.09
LV wall thickness > median	83	0.8	(-2.7, 4.2)	0.66
Thin filament variant	20	1.5	(-7.9, 11.0)	0.73
Thick filament variant	146	2.7	(-0.6, 6.0)	0.11
MYH7 variant	59	2.3	(-3.1, 7.7)	0.40
MYBPC3 variant	82	2.8	(-1.6, 7.2)	0.21
Physical QOL	n	Mean difference	Confidence interval	p-value
Overall	166	4.1	(0.9, 7.3)	0.012
Pre-pubertal	36	3.1	(-3.9, 10.0)	0.38
Post-pubertal	130	4.3	(0.8, 7.9)	0.018
Male	100	4.3	(0.5, 8.1)	0.028
Female	66	3.6	(-2.1, 9.3)	0.21
LV wall thickness < median	83	6.3	(1.6, 11.0)	0.009
LV wall thickness > median	83	2.0	(-2.4, 6.3)	0.38
Thin filament variant	20	-4.3	(-13.7, 5.1)	0.35
Thick filament variant	146	5.0	(1.5, 8.4)	0.005
MYH7 variant	59	5.9	(0.1, 11.7)	0.046
MYBPC3 variant	82	3.6	(-0.8, 8.0)	0.11
Psychosocial QOL	n	Mean difference	Confidence interval	p-value
Overall	166	1.7	(-2.0, 5.3)	0.37
Pre-pubertal	36	-4.2	(-11.6, 3.2)	0.26
Post-pubertal	130	3.4	(-0.8, 7.6)	0.12
Male	100	2.9	(-1.4, 7.3)	0.19
Female	66	-0.7	(-7.2, 5.8)	0.83
LV wall thickness < median	83	3.2	(-3.0, 9.4)	0.31
LV wall thickness > median	83	0.0	(-4.0, 4.1)	0.98
Thin filament variant	20	4.9	(-8.3, 18.2)	0.44
Thick filament variant	146	1.3	(-2.6, 5.2)	0.51
MYH7 variant	59	0.4	(-5.7, 6.5)	0.89
MYBPC3 variant	82	2.2	(-3.1, 7.5)	0.41

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VANISH: A Phase II Randomized, Placebo-controlled, Double-Blind Clinical Trial of Valsartan for Attenuating Disease Evolution in Early Sarcomeric HCM