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

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

3. Background
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
Compare health-related quality of life outcomes among patients with severe aortic stenosis and high surgical risk treated with either TAVR or surgical AVR
Determine whether the QOL benefits of TAVR vs. AVR vary over time
Examine whether the QOL benefits of TAVR vs. AVR differ according to access site or other patient characteristics

5. PARTNER Study Design High-Risk Inoperable N = 699 N = 358
Symptomatic Severe Aortic Stenosis
ASSESSMENT: High-Risk AVR Candidate
3,105 Total Patients Screened
N = 179
N = 358
Inoperable
Standard
Therapy
ASSESSMENT: Transfemoral Access
Not In Study
TF TAVR
Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority)
Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority)
1:1 Randomization VS
Yes No
Total = 1,057 patients
High-Risk
N = 699
2 Parallel Trials: Individually Powered
ASSESSMENT: Transfemoral Access
Transapical (TA)
Transfemoral (TF)
1:1 Randomization
Yes No
TF TAVR
AVR
Primary Endpoint: All-Cause Mortality at 1 yr (Non-inferiority)
TA TAVR VS
N = 248
N = 104
N = 103
N = 244

6. Methods: Quality of Life
Instrument
Description/Role
Kansas City Cardiomyopathy Questionnaire (KCCQ)
Heart failure-specific QOL
Domains: symptoms, physical limitations, quality of life, social limitations
Scores: (higher = better)
WNA The total number of pairs is 179×179 =
If the analysis had been based on survival only, then 71.7% (22964/32041) of the possible pairs could be compared. Such an analysis would be equivalent to the Gehan-Wilcoxon test.
The addition of the rehospitalization component allows for an additional 16.6% (5324/32041) percent of the pairs to be compared. It is this increased comparison that gives the Finkelstein-Schoenfeld method increased power over the log-rank or Gehan-Wilcoxon test.
There are three situations where a pair could not be compared on survival
Both patients are censored.
One patient died and the other was censored, with the days to death greater than the days to censoring.
Both patients died, with the days to death equal.
If the patients cannot be compared on survival, then the time to first rehospitalization is compared. The same principles apply. 6

7. Methods: Quality of Life
Instrument
Description/Role
Kansas City Cardiomyopathy Questionnaire (KCCQ)
Heart failure-specific QOL
Domains: symptoms, physical limitations, quality of life, social limitations
Scores: (higher = better)
SF-12
General physical and mental health
Scores standardized such that mean = 50, standard deviation = 10 (higher = better)
WNA The total number of pairs is 179×179 =
If the analysis had been based on survival only, then 71.7% (22964/32041) of the possible pairs could be compared. Such an analysis would be equivalent to the Gehan-Wilcoxon test.
The addition of the rehospitalization component allows for an additional 16.6% (5324/32041) percent of the pairs to be compared. It is this increased comparison that gives the Finkelstein-Schoenfeld method increased power over the log-rank or Gehan-Wilcoxon test.
There are three situations where a pair could not be compared on survival
Both patients are censored.
One patient died and the other was censored, with the days to death greater than the days to censoring.
Both patients died, with the days to death equal.
If the patients cannot be compared on survival, then the time to first rehospitalization is compared. The same principles apply. 7

8. Methods: Quality of Life
Instrument
Description/Role
Kansas City Cardiomyopathy Questionnaire (KCCQ)
Heart failure-specific QOL
Domains: symptoms, physical limitations, quality of life, social limitations
Scores: (higher = better)
SF-12
General physical and mental health
Scores standardized such that mean = 50, standard deviation = 10 (higher = better)
EQ-5D (EuroQOL)
Generic instrument for assessment of utilities and QALYs
Scores: 0-1 (0 = death; 1 = perfect health)
WNA The total number of pairs is 179×179 =
If the analysis had been based on survival only, then 71.7% (22964/32041) of the possible pairs could be compared. Such an analysis would be equivalent to the Gehan-Wilcoxon test.
The addition of the rehospitalization component allows for an additional 16.6% (5324/32041) percent of the pairs to be compared. It is this increased comparison that gives the Finkelstein-Schoenfeld method increased power over the log-rank or Gehan-Wilcoxon test.
There are three situations where a pair could not be compared on survival
Both patients are censored.
One patient died and the other was censored, with the days to death greater than the days to censoring.
Both patients died, with the days to death equal.
If the patients cannot be compared on survival, then the time to first rehospitalization is compared. The same principles apply.
Assessments performed by self-administered
questionnaires at baseline and at 1, 6, and 12 months 8

9. KCCQ: Development and Validation
23 items that measure 5 clinically relevant domains of health status from the patient’s perspective
Symptoms Physical limitation
Quality of life Social limitation
Self-efficacy
Extensive validation and reliability testing
Individual scales combined into a global summary scale (KCCQ Overall Summary)
Independently predictive of mortality and cost among patients with HF
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Green CP, et al. JACC. 2000;35:
Soto G, et al. Circulation. 2004;110: 9 9

10. KCCQ: Interpretation 546 outpts with HF
Change in KCCQ-Overall Summary Score
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
Clinically Important Change
Small = 5 points
Moderate = 10 points
Large = 20 points
Large
Medium
Small
Small
Medium
Large
No Change
Deterioration
Improvement
Am Heart J. 2005;150:

11. Analytic Approach Analytic Population Primary QOL Endpoint
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

12. 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

13. Baseline Characteristics
TAVR (n = 328)
AVR (n = 300)
Age (yrs)
84  7
84  6
Male gender
57.6%
56.7%
STS risk score
11.8  3.4
11.5  3.2
Prior MI
27.4%
27.7%
Prior CABG
42.7%
45.0%
Cerebrovascular Dz
26.8%
24.7%
COPD (O2 dependent)
9.1%
7.3%
Frailty
15.4%
17.1%
P = NS for all comparisons

14. QOL Compliance ITT Population
* Among pts eligible for QOL assessment

15. 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

16. KCCQ Overall Summary (Primary Endpoint) TF Subgroup
D = -0.5 P = NS
D = -1.2 P = NS
P-values are for mean treatment effect of TAVR vs. AVR

17. KCCQ Subscales TF Subgroup
Physical Limitations
Symptom Score
D = 10.9 P = 0.001
D = -0.5 P = NS
D = 2.3 P = NS
D = 6.6 P = 0.006
D = -2.1 P = NS
D = -1.1 P = NS
Quality of Life
Social Limitations
D = 9.8 P < 0.001
D = 0.3 P = NS
D = -1.9 P = NS
D = 10.6 P = 0.006
D = -2.9 P = NS

18. Generic QOL and Utilities TF Subgroup
SF-12 Physical
SF-12 Mental
D = 2.0 P = 0.04
D = -0.9 P = NS
D = -0.4 P = NS
D = 5.4 P < 0.001
D = 1.2 P = NS
D = 0.4 P = NS
EQ-5D Utilities
D = P = 0.008
D = P = NS
D = P = NS

19. KCCQ Overall Summary (Primary Endpoint) TA Subgroup
D = -5.8 P = NS
D = -7.9 P = 0.04
D = 0.8 P = NS
P-values are for mean treatment effect of TAVR vs. AVR

20. KCCQ Subscales TA Subgroup
Physical Limitations
Symptom Score
D = -5.8 P = NS
D = -9.6 P = 0.04
D = -4.1 P = NS
D = -5.1 P = NS
D = P < 0.001
D = -2.3 P = NS
Quality of Life
Social Limitations
D = -4.7 P = NS
D = -8.4 P = 0.06
D = 4.8 P = NS
D = -5.8 P = NS
D = -3.8 P = NS
D = 6.1 P = NS

21. Generic QOL and Utilities TA Subgroup
SF-12 Physical
SF-12 Mental
D = 0.3 P = NS
D = -3.3 P = 0.05
D = 0.2 P = NS
D = -4.3 P = 0.02
D = -2.5 P = NS
EQ-5D Utilities
D =
P = NS
D =
P = 0.05
D = P = NS

22. Overall Clinical Status TF Subgroup
P = NS
KCCQ Categories
1 month
6 months
1 year
*P-values from ordinal logistic regression

23. Overall Clinical Status TA Subgroup
P = NS
P = NS
P = NS
KCCQ Categories
1 month
6 months
1 year
*P-values from ordinal logistic regression

24. KCCQ-Summary: Substantial Improvement* TF Subgroup
P = NS
P = NS
P = 0.008
* Improvement ≥ 20 points vs. baseline among patients with available QOL data

25. KCCQ-Summary: Substantial Improvement* TA Subgroup
P = NS at all timepoints
* Improvement ≥ 20 points vs. baseline among patients with available QOL data

26. 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

27. 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 ~ points (MCID = 5)
SF-12 Physical ~ 6 points (MCID = 2)
SF-12 Mental ~ 5 points (MCID = 2)

28. 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

29. 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