MEDICAL DEVICE DEVELOPMENT TOOL (MDDT) QUALIFICATION

DECISION SUMMARY FOR

KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE (KCCQ)

BACKGROUND

MDDT NAME: KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE (KCCQ)

SUBMISSION NUMBER: MDDT020

DATE OF SUBMISSION: JANUARY 19, 2016

CONTACT: JOHN SPERTUS, MD, MPH

SAINT LUKE’S MID AMERICA HEART INSTITUTE
4401 WORNALL ROAD
KANSAS CITY, MO 64111
EMAIL: [email protected]

TOOL DESCRIPTION AND PRINCIPLE OF OPERATION

The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item self-administered
questionnaire developed to independently measure the patient’s perception of their health status,
which includes heart failure symptoms, impact on physical and social function, and how their
heart failure impacts their quality of life (QOL) within a 2-week recall period.

The KCCQ tool quantifies the following six (6) distinct domains and two (2) summary scores:

 KCCQ Symptom Domain quantifies the frequency and burden of clinical symptoms in
heart failure, including fatigue, shortness of breath, paroxysmal nocturnal dyspnea and
patients’ edema/swelling. An overall symptom score is generally used in analyses; subscale
scores for both frequency and severity are also available.

 KCCQ Physical Function Domain measures the limitations patients experience, due to
their heart failure symptoms, in performing routine activities. Activities are common,
gender-neutral, and generalizable across cultures, while also capturing a range of exertional
requirements.

 KCCQ Quality of Life Domain is designed to reflect patients’ assessment of their quality
of life, given the current status of their heart failure.

 KCCQ Social Limitation Domain quantifies the extent to which heart failure symptoms
impair patients’ ability to interact in a number of gender-neutral social activities.

MDDT Qualification Decision Summary (MDDT020) 1

 KCCQ Self-efficacy Domain quantifies patients’ perceptions of how to prevent heart
failure exacerbations and manage complications when they arise. This scale is not included
in the summary scores.

 KCCQ Symptom Stability Domain measures recent changes in patients’ symptoms; their
shortness of breath, fatigue or swelling. It is compares patients frequency of heart failure
symptoms at the time of completing the KCCQ with their frequency 2 weeks ago. As a
measure of change, it is most interpretable as a baseline assessment of the stability of
patients’ symptoms at the start of a study and shortly thereafter, as a measure of the acute
response to treatment. This domain is not included in the summary scores.

 Clinical Summary Score includes total symptom and physical function scores to
correspond with NYHA Classification.

 Overall Summary Score includes the total symptom, physical function, social limitations
and quality of life scores.

Note: KCCQ Qualification includes only the Symptom, Physical Limitation, Social Limitation,
Quality of Life (QOL) domains and the Overall Summary Score.

KCCQ responses are provided along a rating scale continuum with equal spacing from worst to
best. On average, the 23-item version takes 4-6 minutes to complete. The concepts quantified in
the KCCQ are designed to be relevant and appreciable by all heart failure patients specified in
the qualified context of use. The Flesch Reading Ease is 76 and the Flesch-Kincaid Grade level
is 6.7. The tool can be used to evaluate the effectiveness of a heart failure medical device studied
in a clinical study.

QUALIFIED CONTEXT OF USE

The paper self -administered version of the 23-item KCCQ questionnaire is used for quantifying
patients’ health status, including the symptoms (frequency and burden), physical and social
limitations, and quality of life impact due to the heart failure syndrome. The instrument can be
used in feasibility and pivotal studies of patients with symptomatic heart failure (e.g. AHA/ACC
Stages of Heart Failure C and D, or NYHA II-IV).

The KCCQ instrument may be used by medical device companies and sponsor-investigators for
evaluation of safety and effectiveness for heart failure medical devices to support regulatory
submissions. The KCCQ instrument, specifically the Symptom Domain Score, Physical
Limitation Domain Score, Social Limitation Domain Score, Quality of Life Domain Score and
Overall Summary Score, can be used as a component of a composite primary endpoint or
secondary endpoint in a feasibility or pivotal clinical trial evaluating heart failure medical
devices. The instrument can be used in superiority and non-inferiority trials evaluating out
patients or in-patients with heart failure syndrome. For in-patient studies, post-discharge
outcomes could be helpful to define the health status benefits of treatment.

SUMMARY OF EVIDENCE TO SUPPORT QUALIFICATION

Published literature on previous clinical studies as well as unpublished concept elucidation and

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 cognitive interview study reports were submitted as evidence to support the qualification of the
MDDT for the qualified context of use. Proprietary data including interview logs, secondary
analyses of clinical study data and a missing data analysis were also submitted to support the
validity of the MDDT. The scientific evidence provided in the qualification package
demonstrates the validity and reliability of the MDDT to quantify a patient’s perception of their
overall health status, including heart failure symptoms, social and physical limitations, and QOL.
The evidence to support the KCCQ validity submitted is as follows:

Validity Evidence Based on Content

The concepts of interest that the KCCQ measures is supported by evidence based on qualitative
concept elucidation studies and cognitive debriefing exercises in heart failure patients that
assessed item generation, data collection methods, the instrument administration model, recall
period, response options, instrument format, instructions, patient understanding, scoring, as well
as respondent and administrator burden. Additional studies were conducted by other
investigators who performed further validation to support the KCCQ concepts.1,2

Validity Evidence Based on the Construct

Validation studies presented by Green, Porter, Bresnahan, and Spertus (2000) and Spertus,
Peterson, and Conard (2005) were cited to provide evidence of correlation between the KCCQ
domains and other heart failure constructs, such as the 6 minute walk test, NYHA class, and
Short Form 36 (SF-36). A summary of the construct validity assessments of the KCCQ qualified
domains are presented in Table 1. 3,4

Table 1. Summary of Construct Validity Assessments of the KCCQ3,4

Domain Reference Measure Statistics Validity Type, Analysis
1) 6 minute walk test, 1) r = 0.48** Convergent validity,
Physical 2) NYHA class, 2) r = -0.65** r=Spearman correlation
Function 3) SF-36 physical 3) r = 0.84** coefficient
4) MLHFQ physical 4) r = 0.65**
Mean score difference: Convergent Validity
NYHA class
Symptom F=51.3** ANOVA
(I, II, III, IV)
Linear trend: F=142.2**
Convergent validity
Social 1) NYHA class 1) r = 0.62 **
Correlation
Limitation 2) SF-36 social scale 2) r = -0.57 **
Convergent validity
Quality of 1) SF-36 general health 1) r = 0.45 **
Correlation
life 2) NYHA 2) r = -0.64 **
1) Mean score difference: Convergent and
KCCQ 1) NYHA class F=41.9** discriminant validity
Overall 2) Survival or Linear trend: F=156.8** ANOVA, 2-sample t-test
Summary hospitalization 2) Mean score difference:
34.1 vs. 52.1**
r=Spearman correlation coefficient; F=F statistics; p<0.01; **p≤0.001; ***p≤0.0001;
MLHFQ=Minnesota Living with Heart Failure Questionnaire; KCCQ = Kansas City
Cardiomyopathy Questionnaire; SF-36 = Short from-36; NYHA = New York Heart Association.

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Reliability
Green et al. (2000) was cited to provide evidence of the KCCQ reliability. Both test-retest
reliability and internal consistency reliability tests were presented in the validation study. A
summary of the test-retest results presented in the publication is shown in Table 2.

Table 2. Test-Retest Reliability of the Qualified KCCQ Domains among Stable Patients3

Baseline 6-Week Difference

KCCQ Domain P-value ICC
Mean ± SD Mean ± SD Mean ± SD
Physical limitation 63.4 ± 26.3 64.4 ± 25.9 1.1 ± 16.4 0.25 0.80
Symptoms 69.1 ± 23.8 69.9 ± 24.1 0.8 ± 15.1 0.33 0.80
Social limitation 56.5 ± 30.5 58.9 ± 29.7 2.4 ± 19.2 0.03 0.79
Quality of life 58.6 ± 27.5 59.4 ± 26.3 0.9 ± 17.2 0.37 0.79
Overall Summary Score 62.1 ± 24.0 63.4 ± 23.8 1.3 ± 11.8 0.04 0.88
ICC=Interclass correlation coefficient

The internal reliability assessed by Green et al. (2000) of the qualified domains was > 0.70.
The Cronbach’s alpha for each qualified domain is listed below in Table 3.

Table 3. Internal Consistency of Qualified KCCQ Domains3

Domain Cronbach’s alpha
Physical Limitation 0.90
Total Symptom Score 0.88
Social Limitation 0.86
Quality of Life 0.78
Overall Summary Score 0.95

Responsiveness
Two observational studies of different patient cohorts provided evidence that the KCCQ was
responsive to changes in heart failure status over time (Green et al., 2000 and Spertus et al.,
2005). The evidence indicated that the KCCQ is equally sensitive to gains and losses in the
measurement of concepts of interests for the population specified in the qualified context of use
when compared to other, similar measures.

Extent of Prediction
Prognostic association between KCCQ Overall Summary Score and hospitalization or death was
described in the cited literature included in the qualification package.5-7 Controlling for other
indicators and measures of heart failure, low KCCQ Overall Summary Scores were consistently
associated with poor prognosis after 1 year. The populations studied consisted of patients with
heart failure after acute myocardial infarction, patients undergoing transcatheter aortic valve
replacement (TAVR) and patients with an ischemic heart failure etiology.

DISCUSSION OF THE EVIDENCE STRENGTH TO SUPPORT QUALIFICATION

The KCCQ has an extensive history of use in clinical trials evaluating heart failure medical
devices to inform regulatory decisions. This experience was considered during the review in

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addition to the data submitted in the Qualification Package and was used as evidence to support
the Agency’s decision to qualify the KCCQ as a MDDT. The developer also submitted evidence
that includes peer-reviewed publications and unpublished and proprietary data, which
demonstrated that the KCCQ tool was valid and reliable for the qualified context of use. Along
with other evidence, the correspondence between KCCQ scores and other measures of heart
failure, including hospitalization and survival were good indicators of the accuracy of the
scores.3-7 The overall score of the KCCQ was shown to predict hospitalization and mortality, as
well as differential risk based on cut scores. Similarly, there were a number of examples of the
match between KCCQ scores and NYHA classifications and between change scores and
physician ratings of change. The multiple sources and types of evidence provide confidence in
the accuracy of the scores. Evidence of the reliability was provided as both test-retest reliability
and internal consistency. All of the reported reliabilities support the precision of the scores. The
KCCQ captures the important aspects of treatment effectiveness from the patient’s perspective in
a reliable and reproducible manner.

ASSESSMENT OF ADVANTAGES/DISADVANTAGES OF QUALIFICATION

Assessments of Advantages of Using the MDDT:

The main advantage of using the MDDT is that it provides a robust approach to measuring the
impact of heart failure on symptoms, function of patients and quality of life. The MDDT has
already been used in numerous heart failure device clinical trials reviewed by CDRH. Therefore,
CDRH has experience in evaluating and interpreting the KCCQ results in clinical trials. The
MDDT has the potential to impact multiple device development programs in the area of heart
failure as the Agency considers the patient’s perspective in rendering regulatory decisions. As
discussed in the “Strength of Evidence” section, the MDDT has been extensively studied for
validity and predictive ability; therefore it has a high likelihood of an advantage for use in
clinical investigations of heart failure devices.

Assessments of Disadvantages of Using the MDDT:

The following disadvantages of using the MDDT were identified: 1) the inability to measure all
important outcomes in heart failure patients; 2) potential susceptibility of a placebo device effect;
3) potential impact of missing data; and 4) potential bias due to care provider participation in the
KCCQ administration. When specific patient populations are used, such as the heart failure
populations described in the context of use, the inability to measure all important outcomes in
heart failure patients can be mitigated. The study design, such as the use of randomized trials,
can assist in addressing placebo device effect or minimizing the impact of missing data.
Additionally, limiting use of the MDDT as a secondary endpoint or a component of a composite
endpoint can further mitigate concern of a placebo device effect, as the data will be considered
along with other primary endpoint data.

Risk mitigation has been performed to address the disadvantages listed above. These mitigations
included specifying the patient population in the context of use, evaluating a missing data
analysis performed by the developer to assess the handling of missing data and its impact on
scoring, and recommending that non-care providers (e.g., administration staff) distribute the
instrument to the patient to minimize unintentional bias.

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Additional Factors for Assessing Advantages and Disadvantages of Using the MDDT:
There is minimal uncertainty associated with the MDDT with respect to the specified context of
use based on its extensive validation and documented history of use in clinical trials. The MDDT
can be used to facilitate development and regulatory evaluation of heart failure technologies.

CONCLUSIONS
The submitted materials and correspondence to clinical outcomes in numerous pivotal heart
failure medical device trials in the past provide sufficient evidence to support the validity and
reliability of the KCCQ for the qualified context of use.

REFERENCES
1. Gwalteny C, Slagel A, Martin M, Ariely R, Brede Y, “Hearing the voice of the heart
falilure patient: Key experienced identified in qualitative interviews,” British Journal of
Cardiology, 19:e1-7 (2012).

2. Pierson RF, Traina S, Braan L, Bushnell SM, McCarrier K, Martin ML, “ The Most
Frequently Reported Symptoms of Heart Failure, their Impacts on Daily Life, and Why
these Matter with Respect to Clinical Outcomes,” 21st Annual Conference International
Society for Quality of Life Research, Poster 1017 (2014).

3. Green CP, Porter CB, Bresnahan DR, Spertus JA, “Development and evaluation of the
Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart
failure,” J Am Coll Cardiol, 35:1245-5 (2000).

4. Spertus J, Peterson E, Conard MW, et al., “Monitoring clinical changes in patients with
heart failure: a comparison of methods,” Am Heart J, 150:707-15 (2005).

5. Heidenreich PA, Spertus JA, Jones PG, et al., “Health status identifies heart failure
outpatients at risk for hospitalization or death,” J Am Coll Cardiol, 47(4):752-756 (2006).

6. Soto GE, Jones P, Weintraub WS, Krumholz HM, Spertus JA. Prognostic Value
of Health Status in Patients With Heart Failure After Acute Myocardial Infarction.
Circulation, 110(5):546-551 (2004).

7. Arnold SV, Spertus JA, Vemulapalli S, et al., “Association of Patient-Reported Health

Status With Long-Term Mortality After Transcatheter Aortic Valve Replacement: Report
From the STS/ACC TVT Registry,” Circulation Cardiovascular Interventions, 8(12)
(2015).

CONTACT INFORMATION FOR ACCESS TO TOOL

FOR ACCESS TO THE KCCQ, PLEASE CONTACT:
JOHN SPERTUS, MD, MPH
SAINT LUKE’S MID AMERICA HEART INSTITUTE
4401 WORNALL ROAD
KANSAS CITY, MO 64111
EMAIL: [email protected]

MDDT Qualification Decision Summary (MDDT020) 6