Health-Related Quality of Life After Transcatheter vs. Surgical Aortic Valve Replacement in High-Risk Patients With Severe Aortic Stenosis Results From The PARTNER Trial (Cohort A)

David J. Cohen, M.D., M.Sc. On behalf of The PARTNER Investigators Saint Luke’s Mid-America Heart Institute University of Missouri-Kansas City Kansas City, Missouri Harvard Clinical Research Institute Harvard Medical School Boston, MA TCT 2011 | San Francisco | November 7, 2011

Disclosures

The PARTNER Trial was funded by a research grant from Edwards Lifesciences, Inc.

Background

3 • Transcatheter aortic valve replacement (TAVR) has been developed as a less invasive alternative to surgical valve replacement for high-risk patients with severe aortic stenosis • In PARTNER Cohort A, TAVR was found to be non-inferior to surgical AVR for the primary endpoint of 1-year mortality among patients at high surgical risk • There were differences in procedure-related complications and valve performance at 1 year – with some endpoints favoring TAVR and others favoring surgical AVR • The overall impact of these alternative treatments on health related quality of life from the patient’s perspective has not yet been reported

4

Study Objectives

1.

Compare health-related quality of life outcomes among patients with severe aortic stenosis and high surgical risk treated with either TAVR or surgical AVR 2.

Determine whether the QOL benefits of TAVR vs. AVR vary over time 3.

Examine whether the QOL benefits of TAVR vs. AVR differ according to access site or other patient characteristics

PARTNER Study Design

N = 699

Yes Symptomatic Severe Aortic Stenosis High-Risk ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened Total = 1,057 patients

2 Parallel Trials: Individually Powered

Inoperable ASSESSMENT: Transfemoral Access No ASSESSMENT: Transfemoral Access Transfemoral (TF) Transapical (TA) Yes

N = 358

No 1:1 Randomization

N = 244 N = 248

1:1 Randomization

N = 104 N = 103

TF TAVR AVR TA TAVR

VS VS

Primary Endpoint: All-Cause Mortality at 1 yr (Non-inferiority) AVR 1:1 Randomization Not In Study

N = 179

TF TAVR

N = 179

Standard Therapy

VS

Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority)

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Methods: Quality of Life

Instrument

Kansas City Cardiomyopathy Questionnaire (KCCQ)

Description/Role

• Heart failure-specific QOL • Domains: symptoms, physical limitations, quality of life, social limitations • Scores: 0-100 (higher = better)

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Methods: Quality of Life

Instrument

Kansas City Cardiomyopathy Questionnaire (KCCQ) SF-12

Description/Role

• Heart failure-specific QOL • Domains: symptoms, physical limitations, quality of life, social limitations • Scores: 0-100 (higher = better) • General physical and mental health • Scores standardized such that mean = 50, standard deviation = 10 (higher = better)

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Methods: Quality of Life

Instrument

Kansas City Cardiomyopathy Questionnaire (KCCQ) SF-12 EQ-5D (EuroQOL)

Description/Role

• Heart failure-specific QOL • Domains: symptoms, physical limitations, quality of life, social limitations • Scores: 0-100 (higher = better) • General physical and mental health • Scores standardized such that mean = 50, standard deviation = 10 (higher = better) • Generic instrument for assessment of utilities and QALYs • Scores: 0-1 (0 = death; 1 = perfect health) Assessments performed by self-administered questionnaires at baseline and at 1, 6, and 12 months

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KCCQ: Development and Validation

• 23 items that measure 5 clinically relevant domains of health status

from the patient’s perspective

– Symptoms – Quality of life – Self-efficacy Physical limitation Social limitation • Extensive validation and reliability testing • Individual scales combined into a global summary scale (KCCQ Overall Summary) –

Independently predictive of mortality with HF and cost among patients

Green CP, et al.

JACC

. 2000;35:1245-55.

Soto G, et al.

Circulation

. 2004;110:546-51.

KCCQ: Interpretation

10 Change in KCCQ-Overall Summary Score Large Medium Small Deterioration • • 546 outpts with HF KCCQ assessed at baseline and 5 weeks • Extent of deterioration or improvement assessed by physician based on sx and exam and correlated with KCCQ-Overall Summary No Change

Clinically Important Change

•

Small = 5 points

Small Medium Large •

Moderate = 10 points

Improvement •

Large = 20 points

Am Heart J

. 2005;150:707-15.

Analytic Approach

Analytic Population

• All patients with baseline QOL assessment, analyzed by assigned treatment (ITT)

Primary QOL Endpoint

• KCCQ Overall Summary Score • All other QOL scales considered secondary endpoints 11

Statistical Methods

• Scores at each time point compared within treatment group using paired t-tests • Scores between groups compared using random effect growth curve models, adjusted for baseline, age, sex, and access site (TA vs. TF) • Analytic plan specified that separate analyses would be performed for the TA and TF groups in case of a significant interaction between treatment effect and access site 12

Baseline Characteristics

13 Age (yrs) Male gender STS risk score Prior MI Prior CABG Cerebrovascular Dz COPD (O 2 dependent) Frailty

TAVR

(n = 328)

84  7 57.6% 11.8  3.4

27.4% 42.7% 26.8% 9.1% 15.4%

AVR

(n = 300)

84  6 56.7% 11.5  3.2

27.7% 45.0% 24.7% 7.3% 17.1% P = NS for all comparisons

Results

• There were highly significant interactions between treatment effect and access site for the primary endpoint (P = 0.001) and multiple secondary endpoints (P < 0.01) – mainly at the 1 month and 6 month time points • Therefore, all QOL analyses were performed separately for TF and TA subgroups 14

KCCQ Overall Summary (Primary Endpoint)

TF Subgroup

15

30 20 10 0 -10 -20 -30

D

= 9.9

P < 0.001

1 month

D

= -0.5

P = NS 6 months

D

= -1.2

P = NS 12 months

P-values are for mean treatment effect of TAVR vs. AVR

KCCQ Subscales

TF Subgroup 30

Physical Limitations

20 10 0 10 0 -10 -20

16

-30 -10 -20

D

= 10.9

P = 0.001

-30 1 month 30

Quality of Life

20

D

= 9.8

P < 0.001

1 month

D

= -0.5

P = NS 6 months

D

= 0.3

P = NS 6 months

D

= 2.3

P = NS 12 months

D

= -1.9

P = NS 12 months 20 10 0 -10 -20 -30 30

Symptom Score

20 10 0 -10 -20

D

= 6.6

P = 0.006

D

= -2.1

P = NS -30 1 month 30

Social Limitations

6 months

D

= 10.6

P = 0.006

1 month

D

= -2.9

P = NS 6 months

D

= -1.1

P = NS 12 months

D

= -2.9

P = NS 12 months

Generic QOL and Utilities

TF Subgroup

17

10.0

SF-12 Physical

7.5

5.0

2.5

0.0

-2.5

-5.0

-7.5

-10.0

D

= 2.0

P = 0.04

1 month

D

= -0.9

P = NS 6 months

D

= -0.4

P = NS 12 months 0.20

EQ-5D Utilities

0.15

0.10

0.05

0.00

-0.05

-0.10

-0.15

-0.20

D

= 0.061

P = 0.008

1 month

D

= 0.012

P = NS 6 months 10.0

SF-12 Mental

7.5

5.0

2.5

0.0

-2.5

-5.0

-7.5

-10.0

D

= 5.4

P < 0.001

1 month

D

= 0.028

P = NS 12 months

D

= 1.2

P = NS 6 months

D

= 0.4

P = NS 12 months

KCCQ Overall Summary (Primary Endpoint)

TA Subgroup

18

0 -10 -20 -30 30 20 10

D

= -5.8

P = NS 1 month

D

= -7.9

P = 0.04

6 months

D

= 0.8

P = NS 12 months

P-values are for mean treatment effect of TAVR vs. AVR

KCCQ Subscales

TA Subgroup 30

Physical Limitations

20 10 0 10 0 -10 -20

19

-30 -10 -20 -30

D

= -5.8

P = NS 1 month 30

Quality of Life

20

D

= -4.7

P = NS 1 month

D

= -9.6

P = 0.04

6 months

D

= -8.4

P = 0.06

6 months

D

= -4.1

P = NS 12 months

D

= 4.8

P = NS 12 months 20 10 0 -10 -20 -30 30

Symptom Score

20 10 0 -10 -20 -30

D

= -5.1

P = NS 1 month 30

Social Limitations D

= -13.2

P < 0.001

6 months

D

= -5.8

P = NS 1 month

D

= -3.8

P = NS 6 months

D

= -2.3

P = NS 12 months

D

= 6.1

P = NS 12 months

Generic QOL and Utilities

TA Subgroup

20

0.0

-2.5

-5.0

-7.5

-10.0

10.0

SF-12 Physical

7.5

5.0

2.5

D

= 0.3

P = NS

D

= -3.3

P = 0.05

1 month 6 months

D

= 0.2

P = NS 12 months 0.20

EQ-5D Utilities

0.15

0.10

0.05

0.00

-0.05

-0.10

-0.15

-0.20

D

= -0.057

P = NS 1 month

D

= -0.065

P = 0.05

6 months 5.0

2.5

0.0

-2.5

-5.0

-7.5

-10.0

10.0

SF-12 Mental

7.5

D

= -4.3

P = 0.02

1 month

D

= -0.051

P = NS 12 months

D

= -2.5

P = NS 6 months

D

= -2.5

P = NS 12 months

KCCQ-Summary: Substantial Improvement*

TF Subgroup

P = 0.008

P = NS P = NS 21 * Improvement ≥ 20 points vs. baseline among patients with available QOL data

KCCQ-Summary: Substantial Improvement*

TA Subgroup

P = NS at all timepoints 22 * Improvement ≥ 20 points vs. baseline among patients with available QOL data

Sensitivity Analyses

Results similar when:

• Analysis restricted to patients who underwent attempted valve treatment (“As treated” cohort; n = 607) • “Worst case” values (at the 90th percentile) were imputed to all patients with missing data • Outcomes analyzed categorically according to either significant improvement (≥ 10-point change from baseline) or a multilevel ordinal outcome 23

Summary-1

• Among patients with severe AS who were at high risk for standard valve replacement, both surgical and transcatheter AVR resulted in substantial improvement in disease-specific and generic HRQOL over 1 year follow-up –

KCCQ Summary Scale ~ 25-30 points (MCID = 5)

–

SF-12 Physical ~ 6 points (MCID = 2)

–

SF-12 Mental ~ 5 points (MCID = 2)

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Summary-2

• Although the extent of improvement at 1 year was similar with TAVR and AVR, there were important differences in the rate and extent of recovery at the earlier time points • For patients eligible for the TF approach, TAVR resulted in substantial QOL benefits compared with AVR at 1 month with similar QOL at later time points • For patients eligible only for the TA approach, there was no benefit of TAVR over AVR at any time point, and QOL tended to be better with AVR both at 1 and 6 months 25

Conclusions

• Taken together with previous data, these findings demonstrate that for patients suitable for a TF approach, TAVR provides meaningful clinical benefits compared with surgical AVR from the patient’s perspective • The lack of benefit (and suggestion of worse QOL) among patients ineligible for the TF approach suggests that the TA approach may not be preferable to surgical AVR in such patients • Whether further experience and refinements in the TA approach can overcome these limitations should be the subject of future investigation 26