Randomized Trial of Patient-Reported Outcome Measurement in Heart Failure Clinic
Phase: NA
Conditions: Heart Failure
Sponsor: Stanford University

 
Randomized Trial of Patient-Reported Outcome Measurement in Heart Failure Clinic 
(PRO-HF Trial) 
 
Version 5 
 
June 30, 2023 
 
 
 
 
 

 
 
2 
CLINICAL TRIAL SUMMARY  
Title 
Randomized Trial of Patient-Reported Outcome Measurement in 
Heart Failure Clinic  
Study Objectives 
Primary objective is to evaluate the impact of routine assessment 
of patient-reported heath status among outpatients with heart 
failure on heart failure health status one year later. 
 
Secondary objectives include evaluating the following:  
 
- Changes in heart failure therapy patterns 
 
- Changes in healthcare utilization (testing, clinic visits, acute care 
visits)  
 
- Patient experience 
 
- Concordance between clinician and patient perception of patient 
health status 
 
Study Design 
This randomized clinical trial evaluates the routine assessment of 
patient-reported heath status, using the Kansas City 
Cardiomyopathy Questionnaire-12 (KCCQ-12) among adult 
outpatients with heart failure. Any patients being seen in the heart 
failure clinics are eligible for enrollment. Patients will be enrolled 
via secure email or telephone call. They will be randomized in a 1:1 
fashion to KCCQ-12 assessment or usual care with permuted block 
randomization stratified by clinician. Participants randomized to 
KCCQ-12 assessment will complete the KCCQ-12 at every heart 
failure clinic visit. Their results will be available to clinicians to 
assist with clinical management. Heath status surveys will not be 
integrated into clinical care for patients in the usual care arm.  
 
In a subset of the total study, we will compare clinician perception 
of patient health status and patient experience across the two 
arms. 
Number of 
Participants 
Minimum of 1,200 participants will be randomized;  600 patients in 
sub-study 
Trial Location 
Stanford Hospital & Clinics adult heart failure clinic 
Inclusion Criteria 
Adult heart failure clinic visit 
Exclusion Criteria 
None 
Intervention 
Participants randomized to KCCQ assessment will complete a 
KCCQ-12 survey with each heart failure clinic visit. These 
responses will be shared with their heart failure clinician. Treating 
clinicians will continue to make all diagnostic and treatment 
decisions at their discretions. 

 
 
3 
Primary Endpoint 
KCCQ-12 score at least 1 year post-randomization 
Secondary 
Endpoints 
Treatment patterns at 12 months: 
• Rates of guideline-directed therapy use 
• Dose of guideline-directed medical therapy 
• Advanced heart failure therapy evaluation 
• Cardiovascular testing 
 
Healthcare resource use at 12 months: 
• Heart failure clinic visits (in-person and televisits) 
• Heart failure telephone encounters (other than visits) 
• Emergency department visits 
• Hospitalizations (heart failure and non-heart failure)  
Other Outcomes of 
Interest in Sub-
Study 
• Clinician perception of health status 
• Patient experience 
Assessment 
Schedule 
• Baseline KCCQ-12 at time of first clinic visit 
• Repeat KCCQ-12 within 12-15 months post-randomization 
 
Sub-study: 
• Patient experience survey 
• Clinician evaluation of patient health status 
 
Study Duration 
Patients will be enrolled for 12 months. Expected follow-up will be 
12-15 months post-randomization. Patients will be followed until 
their first clinic visit after one year. Patients without a follow-up visit 
within 15 months, will be contacted for final outcome ascertainment 
at that time. 
Statistical 
Considerations 
A sample size of 1,200 randomized participants has 95% power to 
detect a mean difference in KCCQ-12 of 5 between arms (72 in 
KCCQ arm versus 67 in usual care; SD ~24) and an 80% power to 
detect a mean difference in KCCQ-12 of 4 without covariate 
adjustment. 
 
 

 
 
4 
TABLE OF CONTENTS 
 
1.  
LIST OF ABBREVIATIONS AND DEFINITONS 
5 
2. 
BACKGROUND AND RATIONALE 
6 
3. 
HYPOTHESIS 
8 
4.  
STUDY OBJECTIVES 
9 
5. 
STUDY DESIGN 
10 
6. 
STUDY PROCEDURES 
13 
7. 
TREATMENT ARMS 
17 
8. 
STUDY ASSESSMENT AND SCHEDULE 
18 
9. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
19 
10. DATA HANDLING AND RECORD KEEPING 
23 
11. DATA AND SAFETY 
24 
12. PROTOCOL AMENDMENTS 
25 
13. REFERENCES 
26 
14. APPENDICES 
27 
 

 
 
5 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS  
EHR 
Electronic health record 
KCCQ-12 
Kansas City Cardiomyopathy Questionnaire-12 
PHI 
Protected health information 
PRO 
Patient-reported outcome 
STARR 
Stanford Research Repository 
 
 

 
 
6 
2. 
BACKGROUND AND RATIONALE  
Patient-reported outcome (PRO) measures are being increasingly emphasized by quality 
measurement programs and healthcare payers. The Centers for Medicare & Medicaid Services 
now include the measurement of patient-reported health status as a quality measure. While these 
measures capture patient symptoms accurately and have been shown to be highly prognostic, the 
feasibility and impact of PRO assessment among heart failure patients is unknown. There are no 
prior studies evaluating the effect of collecting this data on patient experience or quality of care. 
This study aims to fill those gaps. 
Understanding the effect of PRO assessment on patient outcomes will determine the overall utility 
of the data collection. Although PRO assessment is low-cost and low-risk for a given patient, a 
systematic collection of PRO data and reporting is costly and shifts resources away from other 
potentially important interventions. There is currently a large gap in the evidence whether routine 
assessment of heart failure PROs improves clinical care. Determining whether PRO collection 
improves health-related quality of life or increases the use of guideline-recommended therapies will 
fill this gap. This knowledge will help weigh the benefits and costs of integrating PRO collection into 
clinical practice. Finding that PRO assessment leads to a significant improvement in quality of life 
will promote broader adoption of PRO assessment in clinical care. This could lead to an important 
reduction in the morbidity and mortality of heart failure. Finally, the trial will provide critical 
preliminary data for a multicenter trial that will verify these findings in a larger, broader sample.  
 

 
 
7 
3. 
HYPOTHESIS 
Routinely assessing heart failure health status during outpatient clinic visits leads to 
differences in treatment patterns and better health status at one year. 
  
 
 

 
 
8 
4. 
STUDY OBJECTIVES 
PRIMARY AIM 
The primary aim of this study is to estimate the impact on heart failure health status in 1 
year among outpatients with heart failure who are randomized to routine KCCQ-12 
assessment vs. usual care. 
 
SECONDARY AIMS 
The secondary aims of this trial are to compare the following outcomes at 1 year in 
participants randomized to KCCQ-12 or usual care: 
• Rates of guideline-directed therapy use 
• Dose of guideline-directed medical therapy 
• Advanced heart failure therapy evaluation 
• Cardiovascular testing 
• Heart failure clinic visits (in-person and televisits) 
• Heart failure telephone encounters (other than visits) 
• Emergency department visits 
• Hospitalizations (heart failure and non-heart failure)  
 
Additional aims include comparing the following outcomes between participants 
randomized to KCCQ-12 or usual care: 
• Patient experience 
• Clinician perception of patients’ heart failure heath status 
 
 
 
 

 
 
9 
5. 
STUDY DESIGN 
This randomized trial will prospectively evaluate the effectiveness of patient-reported 
health status assessment among patients with heart failure seen in the Stanford Heart 
Failure Clinic. Any adult patients with heart failure who have a clinic visit during the 6-
month enrollment period will be potentially enrolled. Before the appointment, patients will 
be contacted via either secure email or via telephone. Patients who consent will undergo 
stratified permuted block randomization to routine KCCQ assessment or usual care with 
stratification by treating clinician. Patients randomized to KCCQ assessment will undergo 
KCCQ-12 assessment at each clinic visit. The results of these assessments will be 
available in Epic to the clinical heart failure team. Those randomized to usual care will only 
undergo KCCQ-12 assessment at baseline and again at the conclusion of the study. For 
usual care patients, the baseline KCCQ-12 will not be displayed on Epic.  
 
5.1 
Study Flow 
 
 
 

 
 
10 
5.2 
Study Population 
 
Patients with an outpatient visit in Stanford adult heart failure clinic. 
 
5.3 
Inclusion/Exclusion Criteria  
5.3.1  Inclusion 
 
• Clinic visit in Stanford adult heart failure clinic 
o In-person 
o Telehealth 
5.3.2 Exclusion 
 
Patients may be excluded at the discretion of their treating cardiologist if already enrolled 
in an alternate clinical trial. There are no other clinical exclusions. 
 

 
 
11 
6. STUDY PROCEDURES 
6.1 Clinic Training 
Before trial enrollment, all heart failure clinic staff will receive educational material regarding 
patient-reported health status and the KCCQ-12. These materials will summarize data regarding 
the survey, its interpretation, and prognostic significance. Examples of how patient-reported health 
status has impacted disease management in other health conditions will also be included. The 
information will also be presented during an interactive educational session with heart failure 
clinicians and clinic staff. 
6.1 Screening 
All patients with a clinic visit in adult heart failure are eligible for the study. Heart failure clinicians 
have agreed to enroll any of their patients. Select patients may be excluded due to enrollment in 
alternate clinical trials. 
6.2 Enrollment and Enrollment 
Patients with a heart failure clinic appointment during the 6-month enrollment period will be 
contacted regarding potential enrollment approximately one week before their visit via secure 
email. The email will include information regarding the study and consent. There will also be 
contact information for additional information. Patients who consent will be randomized to KCCQ 
assessment or usual care. Patients who decline enrollment will receive no further contact from the 
study team.  
Patients without an email response (confirming or declining participation) will be contacted via 
postal letter approximately two weeks before their clinic visit with information about the study and 
the opportunity to either enroll in the trial or decline further communication. Patients who neither 
decline or enroll will be contacted by telephone a few days before the visit. They have the ability to 
consent or decline further communication during the telephone encounter. Individuals who do not 
respond via telephone may also be contacted via text message. 
We aim to enroll at least 1,200 patients over the 6 month enrollment period. If we enroll 1,200 
patients prior to 6 months, we will still complete the 6-month enrollment period with a potential 
enrollment exceeding 1,200 patients given the minimal-risk nature of the study and ability to 
provide more precise effect estimates. If the trial fails to enroll 1,200 patients by 6 months, we will 
discuss reducing the trial enrollment versus extending enrollment with the IRB and the National 
Institute of Health (the trial sponsor). 
6.3 Randomization 
We will randomize patients using a secure online randomization module on REDCap. 
Randomization will be stratified by treating clinician with a block sizes of 2 and 4. Randomization 
occurs automatically via the online platform after a patient consents. Following randomization, the 
patient either receives the usual care KCCQ survey via REDCap or notification of an upcoming 
KCCQ survey via MyHealth for those in the KCCQ arm. 
6.4 KCCQ-12 Completion: KCCQ Assessment Arm 
6.4.1 Index Visit 

 
 
12 
For the KCCQ assessment arm, the KCCQ-12 will be collected before each heart failure clinic visit 
(in person and tele-visit). For patients who consent online, the KCCQ-12 will be available for online 
completion. For patients who do not complete the survey pre-visit, the survey can be completed 
during check-in. Patients who did not complete their assigned KCCQ-12 survey before the visit will 
be able to use their personal device or an office computer to complete the survey. 
For patients who are consented via telephone, patients will be given the option of completing the 
survey during the call or via the online site. If completed over the phone, survey responses will be 
entered directly into the online database without any additional paper records. 
 
6.4.2 Follow-up Visits 
Patients in the KCCQ-12 assessment arm will complete the questionnaire prior to each follow-up 
clinic visit. They will be automatically messaged regarding questionnaire completion via Epic 
MyHealth message. Those who do not complete the questionnaire in advance will be able to 
complete it during check-in as described above. Patients can voluntarily select to not complete the 
questionnaire at any time. 
 
6.4.3 Clinician Accessibility of KCCQ-12 Data 
The KCCQ-12 is either entered by patients onto MyHealth app that is linked to Epic or by a 
research team member during a telephone call. For patients in the KCCQ arm, the KCCQ-12 will 
be printed out for clinicians at the time of the visit. The KCCQ-12 results, in addition to prior results, 
are also available in Epic. However, clinicians will not need to access the results or use them in 
any way if they select not to. 
6.4 KCCQ-12 Completion: Usual Care 
 
6.4.1 Index Visit 
Patients in usual care will undergo baseline assessment of KCCQ-12. This data will be used to 
understand the change in KCCQ-12 between arms at follow-up. The data will be captured in the 
same way as the KCCQ arm using a secure website, REDCap. This data will not be available on 
Epic.  
Patients who have not completed the KCCQ-12 questionnaire before their clinic visit will receive an 
email to notify them to complete the questionnaire. If they have received the notification email and 
the questionnaire remains unanswered, the participant will receive a phone call from the study 
team to help them complete the KCCQ-12. 
 
6.4.2 Follow-up Visits 
Patients in the usual care are will not be assigned any KCCQ-12 surveys during the 12-month 
follow-up period after their first clinic visit. 
6.5 KCCQ-12 Assessment at Trial Completion 
This study will compare KCCQ-12 across trial arms at least one year after randomization. All 
patients with clinic visits between 12-15 months after their initial visit will be assigned the KCCQ-
12. The data will be collected similar to the manner described above. Patients will be messaged 
regarding KCCQ-12 completion one week before their clinic visit. Patients who do not complete the 

 
 
13 
KCCQ-12 will be able to complete the survey in clinic during the check-in process. Patients who do 
not complete the survey within 15 months (either due to not having a clinic visit between 12-15 
months or not completing the survey in clinic) will be contacted via telephone to complete the 
survey. Among patients without clinic visits, we will ask additional questions regarding their 
medications and other heart failure therapies. 
 
6.6 Sub-study: Clinic Experience Surveys 
Approximately 600-patient subset will also be enrolled in a sub-study. This will involve one brief 
survey, conducted either in-person, via telephone or online, regarding their overall experience 
during clinic.  
The substudy participants will be selected based on the month of enrollment. Three of the six 
enrollment months will automatically enroll patients in the substudy. After each clinic visit during the 
sub-study months, participants will receive an email notification to complete their Clinic Experience 
Survey if they have not already completed the survey in-person. They will receive a subsequent 
phone call following the email if the survey remains incomplete. 
 
6.7 Sub-study: Clinician Perception of Health Status 
A related sub-study will ask clinicians regarding their perception of patient health status. All heart 
failure clinicians will undergo informed consent and enrollment. Clinicians who are caring for the 
600-patient sample described above (section 6.6) will be asked a brief set of questions regarding 
their perception of their patient’s health status. Each treating clinician will also be consented given 
their involvement in the sub-study. 
 
6.8 Data Storage 
For the KCCQ assessment arm, the KCCQ-12 responses will be stored in REDCap, a secure 
research database. For patient responses collected via telephone, those responses will be 
transcribed directly to the database. At the end of the study, all trial data will be stored on a secure 
hospital server (Stanford Medicine Box) that is HIPAA-compliant and approved for patient-level 
data including personalized health information and personally identifiable information. Patient 
identifiable information and personalized health information, however, will not be stored. Each 
patient will be given a non-identifiable study code, and all dates will be coded based on an index 
date. 

 
 
14 
7. TREATMENT ARMS 
 
7.1  
KCCQ Assessment 
Participants randomized to KCCQ assessment will complete the KCCQ-12 each clinic visit. 
Their results will be made visible to their treating clinician in Epic. The treating clinicians 
will be able to incorporate these results in their assessment as they see fit. 
 
7.2 
Usual Care 
 
Patients in usual care will only undergo KCCQ assessment at the start of the trial and one-
year follow-up. Their results will not be made visible to their treating clinicians. Their 
treating clinicians can continue to assess their quality of life and health status via clinical 
interview, which is the current standard of care.  
 
 

 
 
15 
8. STUDY ASSESSMENTS AND SCHEDULE 
8.1 
Baseline Clinical Eligibility 
 
Any patients with a clinic visit scheduled for Stanford’s adult heart failure clinic will be 
eligible. Eligibility will be based on the clinic schedule. 
 
8.2 Surveys 
 
8.2.1 KCCQ-12 
 
The KCCQ assessment is described in detail above in Section 6.4. The KCCQ-12 is 
shown in Appendix A. 
 
8.2.2 Clinic Experience Survey 
 
The clinic experience survey will be distributed to patients in the sub-study following their 
first heart failure clinic visit post-randomization. The survey will be emailed to patients. 
Patients who do not complete the survey online will be contacted via telephone. The clinic 
experience survey is shown in Appendix B. 
 
8.2.3 Clinician Perception of Health Status 
 
The clinician perception of health status survey will be completed by the treating clinician 
for each patient in the sub-study following their first heart failure clinic visit post-
randomization. The survey will be distributed on paper but also be available online. The 
clinician perception of health status survey is shown in Appendix C. 
 
8.3 Other Baseline Clinical Data 
Baseline clinical values of the following will be extracted from the EHR using structured 
data elements: 
• Demographic characteristics (age, sex, race, ZIP) 
• Vital signs, average over prior 3 months 
o Systolic/diastolic blood pressure over previous 3 months 
o Heart rate over previous 3 months 
o Respiratory rate 
o Oxygen saturation 
• Most recent BMI 
• Comorbidities using diagnosis coding 
o Diabetes mellitus 
o Hypertension 

 
 
16 
o Hyperlipidemia 
o Chronic kidney disease 
o Cerebrovascular disease 
o Liver disease 
o Atherosclerotic cardiovascular disease 
o Peripheral vascular disease 
o Chronic lung disease 
o Major psychiatric disease 
o Cognitive dysfunction 
o Smoking status 
o Cancer 
• Prior procedures 
o Implantable cardiac defibrillator 
o Cardiac resynchronization therapy 
o Valve repair/replacement 
o Coronary artery bypass surgery 
o Percutaneous coronary intervention 
o Right heart catheterization 
• Lab Results 
o NT-Brain natriuretic peptide 
o Creatinine 
o Hemoglobin 
o Hemoglobin A1c 
o White blood count 
o Blood urea nitrogen 
• Echocardiography results 
o Left ventricular ejection fraction 
o Right ventricular systolic pressure 
o Left ventricular internal diameter during diastole 
o Right ventricular systolic function, qualitative 
o Left atrial volume 
o Average E/e’ 
o Mitral regurgitation, qualitative 
o Tricuspid regurgitation, qualitative 
o Tricuspid regurgitation peak velocity 
o Estimated right ventricular systolic pressure 
o Left ventricle posterior wall thickness 
o Left ventricle septal thickness 
• Medications (specific drug and dose) 
o Beta-blocker 
o Angiotensin-converting enzyme inhibitor 

 
 
17 
o Angiotensin receptor blocker 
o Angiotensin-receptor neprilysin inhibitor 
o Sodium-glucose co-transporter 2 inhibitor 
o Mineralocorticoid antagonist 
o Long-acting nitrates 
o Hydralazine 
o Loop diuretics 
o Other diuretics 
o Digoxin 
o Statin 
o Aspirin 
o Other antiarrhythmic agents 
o Other blood pressure medications 
o NSAIDs 
o Bronchodilators 
o Inhaled steroids 
o Oral steroids 
• Prior Stanford Cardiology Clinic (specific to the affiliated clinician’s clinic) 
o Date of last clinic visit 
o Number of clinic visits since 2018 
• Other Healthcare utilization 
o Number of total Stanford clinic visits since 2018 (tele-health and in-person) 
o Prior cardiovascular diagnostic tests  
§ Electrocardiogram 
§ Echocardiogram 
§ Stress test  
§ CT Coronary Angiogram 
§ Invasive coronary angiography) 
o Number of health system ED visits since 2018 
§ Heart failure related 
§ Non-heart failure related 
o Number of health system hospitalizations since 2018 
§ Heart failure related 
§ Non-heart failure related 
 
8.4 Endpoint Assessments 
Primary and secondary endpoints will be assessed using direct assessment (KCCQ-12 
assessment) or EHR structured data elements. The following will be assessed between 
12-18 months post-randomization: 
• KCCQ-12 
• Medications, as listed above 

 
 
18 
• Procedures, as listed above in addition to the following: 
o Left ventricular assist device 
o Cardiac transplant 
• Transplant or LVAD workup initiation 
• Hospitalizations 
o Heart-failure 
o Non-heart failure 
• ED Visits 
o Heart-failure 
o Non-heart failure 
• Clinic Visits 
o Heart failure clinic (tele-visit and in-person) 
o Non heart failure 
• Telephone Encounters 
o Heart failure clinic 
• Referrals 
o Palliative medicine 
o Psychiatry 
o Other referrals 

 
 
19 
9. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
9.1 Primary Analysis and Statistical Power 
The primary effectiveness outcome is the difference in KCCQ-12 overall summary score after one 
year of follow-up. Scores will be compared using mixed effects linear regression with adjustment 
for baseline KCCQ-12 score and a random intercept for the treating clinician. The primary analysis 
will be limited to patients with follow-up scores. Baseline covariate adjustment can substantially 
improve the precision of the statistical estimate. This has been previously shown to improve 
statistical power even in randomized trials with baseline covariate balance (as modeled below in 
the statistical power analysis).1-3 The covariate used for adjustment of the primary analysis 
(baseline KCCQ) has been selected due to the moderate association with follow-up health status.  
As a secondary analysis, we will repeat the analysis with adjustment for other baseline 
characteristics (age and left ventricular ejection fraction) that have also been previously shown to 
be associated with health status.4-6 As an additional secondary analysis,  the unadjusted KCCQ-12 
scores will be compared using a two-sample t-test.  
Prior work has suggested a 6 point increase in the KCCQ represents a small improvement and 11 
a moderate improvement, with a standard deviation of 24.7-9 However, these estimates represent a 
significant change for an individual. A smaller mean change across a population may be clinically 
meaningful. The sample size calculations are based on prior Stanford Heart Failure clinic data. 
Prior studies of populations with heart failure have found an average KCCQ score of approximately 
67. With 1,200 patients, with 20% loss to follow-up, we estimate a 97% power to detect a 
difference of 6, a 90% power of a mean difference of 5 in the KCCQ-12, and 73% power for a 
mean difference of 4 in the KCCQ-12. 
As discussed above, the statistical power should be amplified with baseline covariate adjustment. 
We assumed baseline KCCQ-12 would explain approximately 35% of the variance in the final 
KCCQ-12. With baseline adjustment, we estimate approximately 55% power for a mean difference 
of 3 in the KCCQ-12 and 81% power for a mean difference of 4. This was estimated by simulating 
trial results. 
Multiple sensitivity analyses to account for missing data will be conducted. First, potential 
assumptions around mortality will be explored. The primary analysis assumes the collection of 
KCCQ-12 data is independent of mortality over a 1-year follow-up. If KCCQ-12 assessment is 
associated with a reduction in mortality, the primary analysis will underestimate the effect of KCCQ 
assessment on health status. If KCCQ-12 assessment is associated with increased mortality, it will 
overestimate the effect of KCCQ assessment. In a secondary analysis, a KCCQ-12 score of 0 will 
be used for all patients who die during follow-up. This secondary analysis will test if the primary 
findings are consistent after placing a negative weight on mortality. Second, sensitivity analyses 
will account for living patients with missing data. This is important given loss to follow-up may be 
differential between treatment arms. This will be addressed with two different imputation 
techniques. The first will predict follow-up KCCQ-12 score using observed patient characteristics 
(including baseline KCCQ) via multiple imputation. This assumes the data is missing at random. 
The second approach conservatively assumes patients with missing data have worse outcomes by 
using the minimum observed KCCQ-12 value in the trial. These sensitivity analyses will assess the 
robustness of the findings. 
As secondary analyses, we will compare domain scores (physical limitation, social limitation, 
quality of life) and the clinical summary score across arms. For these models, we will adjust for 
baseline domain score and include random intercepts for the treating clinician.   
9.2 Primary Analysis Subgroup Analyses 

 
 
20 
We will evaluate the primary effectiveness outcome across multiple subgroups. We identified these 
subgroups as having potential heterogeneity of treatment effect based on likely differences in 
symptom reporting or treatment patterns: 
• 
Age 
• 
Sex 
• 
Left ventricular ejection fraction 
• 
Charlson comorbidity index (marker of disease comorbidity) 
• 
Baseline KCCQ-12 score  
• 
Prior heart failure/cardiomyopathy diagnosis 
• 
Baseline use of recommended therapies 
Each of the continuous covariates will be analyzed by modeling the interaction between the 
continuous covariate and the randomization allocation (KCCQ assessment) along with stratification 
at the median value. Binary characteristics (e.g. sex) will also be interacted with the randomization 
allocation.  
We will also evaluate the primary analysis among the subgroup with a history of heart 
failure/cardiomyopathy and a baseline KCCQ-12 score of <100. 
Secondary Outcomes 
Secondary outcomes will include evaluating the effect of KCCQ assessment on heart failure 
therapy use and healthcare resource utilization. Details regarding each outcomes are listed above 
in the “Study Outcomes” section. Each secondary outcome will be evaluated using multivariable 
regression with adjustment for prespecified patient characteristics: age, left ventricular ejection 
fraction, baseline therapy/utilization, and Charlson Comorbidity Index. A standard regression model 
will be selected based on the distribution of the outcome. Therapy use (a binary outcome) will be 
evaluated using multivariable logistic regression. Therapy doses (ordinal outcome) will be 
evaluated using an ordinal regression model (including no therapy as the base category). The 
number of medication changes each visit (a count outcome with a high frequency of no medication 
changes) will be evaluated using a zero-inflated negative binomial model. Hospitalizations and 
telephone encounters will also be evaluated using a zero-inflated negative binomial model. Clinic 
visits (count outcomes without a high frequency of zero events) will be evaluated using a standard 
negative binomial model. For each model, an indicator variable for allocation to the KCCQ 
assessment arm will be included. The coefficient on this variable represents the effect of PRO 
collection. Each model will be adjusted for the baseline rate (e.g. hospitalizations or telephone 
encounters in the prior year) or baseline treatment (e.g. baseline therapies and doses) to improve 
model precision. Each of the secondary outcomes will be analyzed for the subgroup with a history 
of heart failure/cardiomyopathy and a baseline KCCQ-12 score of <100. For secondary outcomes 
of treatment intensity (clinic visits, therapy rates, and testing), we will also evaluate if the 
association between baseline KCCQ-12 and the secondary outcome is significantly larger in the 
KCCQ arm than the usual care arm.   
9.3 Sub-Study Analyses 
9.3.1 Clinic Experience 
Clinic experience will be compared across the two arms of the study. Each question will receive an 
ordinal score from worst to best response. For each question, the score across trial arms will be 
compared using an mixed effects ordinal logistic regression model with a random intercept for the 

 
 
21 
treating clinician. We will perform subgroup analyses based on patient characteristics as described 
above for the primary analysis. 
9.3.2 Concordance Between Clinician and Patient Perception of Health Status     
We will compare the concordance of health status assessment between patients and their treating 
clinician across the two arms. First, we will evaluate the proportion of explained variation of KCCQ-
OSS via the clinician’s NYHA score in each arm using linear regression.  
Second, we will define concordance by linking the ordinal responses in the clinician survey to 
ordinal responses in the KCCQ-12 or the patient experience survey.  
For question 1 of the clinician survey (NYHA Class), we will approximate patient estimation of 
NYHA category using their KCCQ-OSS score: KCCQ-OSS ≥80 – NYHA Class I, ≥60 to < 80 – 
NYHA Class II,  ≥30 to <60 – NYHA Class III, and <30 – NYHA Class IV.  
Question 2 of the clinician survey (quality of life) will be linked to the quality of life domain score. 
We will classify the response “none” as equivalent to a domain score>80, “mildly” as a score of ≥60 
to <80, “moderately” as a score of ≥30 to <60 and <30 as “severely.” 
Question 3 of the clinician survey evaluates symptom frequency of edema, dyspnea, orthopnea, 
and fatigue on a 4-point ordinal scale with a 5th option of “I don’t know.” The following is the 
mapping between the KCCQ-12 responses and the clinician survey: 
Edema 
KCCQ 
Never over 
past 2 
weeks 
Less than 
once per 
week 
1-2 times 
per week 
3 or more 
times per 
week but 
not every 
day 
Every 
morning 
 
 
Clinician 
Perception 
None 
Once 
More than 
once, but 
not daily 
More than 
once, but 
not daily 
Daily 
 
 
Fatigue 
KCCQ 
Never over 
past 2 
weeks 
Less than 
once per 
week  
1-2 times 
per week 
3 or more 
times per 
week but 
not every 
day 
At least 
once per 
day 
Several 
times per 
day 
All the time 
Clinician 
Perception 
None 
Once 
More than 
once, but 
not daily 
More than 
once, but 
not daily 
Daily 
Daily 
Daily 
Shortness 
of breath 
KCCQ 
Never over 
past 2 
weeks 
Less than 
once per 
week  
1-2 times 
per week 
3 or more 
times per 
week but 
not every 
day 
At least 
once per 
day 
Several 
times per 
day 
All the time 
Clinician 
Perception 
None 
Once 
More than 
once, but 
not daily 
More than 
once, but 
not daily 
Daily 
Daily 
Daily 
Orthopnea 
KCCQ 
Never over 
past 2 
weeks 
Less than 
once per 
week 
1-2 times 
per week 
3 or more 
times per 
week but 
Every night 
 
 

 
 
22 
not every 
day 
Clinician 
Perception 
None 
Once 
More than 
once, but 
not daily 
More than 
once, but 
not daily 
Daily 
 
 
 
Questions 4 and 5 in the clinician survey will be mapped directly to questions 10 and 9 in the 
patient experience surveys. 
Questions 1-4 have ordinal responses with linked questions as described above. For these 
questions, we will classify concordance as “concordant” if the categories match, “neither 
concordant or discordant” if the response categories differ by 1, and “discordant” if the response 
categories differ by >1. For question 5, we will classify as concordant or discordant. We will 
compare concordance between arms for each of these questions using mixed effects ordinal 
logistic regression with random intercepts for the treating clinician.  

 
 
23 
10. DATA HANDLING AND RECORD KEEPING 
10.1  Electronic Data Capture (EDC) System  
 
EHR data will be extracted via the STARR registry and kept on the REDCap system. After 
data extraction, patients will be de-identified and labeled with a study ID number. Linkage 
between the medical record number and study ID will be kept separately as a locked file 
and only be available to the data analyst.  
 
10.2 Data Confidentiality and Security 
Computerized data will be accessible only by password. The Stanford University computer 
network is protected by a firewall.  Participants will be identified by study number only, to 
ensure participant anonymity. No participant identifiers will be used in the presentation of 
data. Study records that might identify participants will be kept confidential as required by 
law. Except when required by law, participants will not be identified by name, personal 
identification number (e.g. social security number, social insurance number), address, 
telephone number, or any other direct personal identifier in study records. 
 
10.3  Training 
 
All investigational site staff authorized to enter the study data will receive training on the 
EDC system. 
 
10.4 Records Retention  
 
Study records will be maintained by the site investigators for a period of six (6) years 
following the expiration of the grant or length of time as required by local regulations, 
whichever is longer. 

 
 
24 
11. DATA AND SAFETY  
 
11.1 OVERALL PLAN  
As per NHLBI requirements, there is a data and safety monitoring plan commensurate with 
the risk of the trial, The planned study is minimal risk and non-blinded given the 
intervention solely consists on an additional patient survey of health status at the time of 
clinic visits. The heart failure clinician will continue to make all treatment decisions.   
 
The data and safety monitoring plan will screen for any concerns, unanticipated problems, 
or adverse events related to KCCQ assessment. Both heart failure clinic staff and enrolled 
patients will be given contact information for the study team to report concerns related to 
assessment.  
 
The independent safety monitors will be Kelsey Flint, MD, Assistant Professor 
(Cardiovascular Medicine) at University of Colorado and Dr. Lee Chang at Swedish 
Hospital in Seattle, Washington. Dr. Flint is an advanced heart failure specialist. She is 
also a health services researcher with experience evaluating heart failure health status. Dr. 
Chang is also an advanced heart failure specialist with experience in clinical research. He 
also has detailed experience with the Stanford cardiology clinics, having completed his 
cardiology fellowship at Stanford. They will review issues raised by clinic staff or heart 
failure patients as they arise and will advise the research study team regarding the need to 
adjust the collection protocol or terminate the study prematurely. 
 
Adverse events or serious adverse events related to KCCQ assessment are very unlikely. 
Potential adverse events detected by heart failure clinic staff or patients will be reported to 
the study principal investigator on a continuous basis. Potential adverse events will also be 
reported to the Stanford University IRB committee and the NIH Program Officer. As a 
second step, the PI, IRB committees, and the independent safety monitors will review 
adverse events to evaluate if the events were caused by the intervention. 
 

 
 
25 
12. PROTOCOL AMENDMENTS 
 
12.1 Protocol Amendments 
 
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by the IRB. Notwithstanding the need for approval of formal 
protocol amendments, the investigator is expected to take any immediate action required 
for the safety of any participant included in this study, even if this action represents a 
deviation from the protocol. In such cases, the IRB will be informed. 
 
 

 
 
26 
13. REFERENCES 
1. 
Hernandez AV, Steyerberg EW, Habbema JD. Covariate adjustment in randomized 
controlled trials with dichotomous outcomes increases statistical power and reduces sample 
size requirements. J Clin Epidemiol. 2004;57(5):454-460. 
2. 
Canner PL. Covariate adjustment of treatment effects in clinical trials. Control Clin 
Trials. 1991;12(3):359-366. 
3. 
Tsiatis AA, Davidian M, Zhang M, Lu X. Covariate adjustment for two-sample treatment 
comparisons in randomized clinical trials: a principled yet flexible approach. Stat Med. 
2008;27(23):4658-4677. 
4. 
Heidenreich PA, Spertus JA, Jones PG, et al. Health status identifies heart failure 
outpatients at risk for hospitalization or death. J Am Coll Cardiol. 2006;47(4):752-756. 
5. 
Joseph SM, Novak E, Arnold SV, et al. Comparable performance of the Kansas City 
Cardiomyopathy Questionnaire in patients with heart failure with preserved and reduced 
ejection fraction. Circ Heart Fail. 2013;6(6):1139-1146. 
6. 
Pokharel Y, Khariton Y, Tang Y, et al. Association of Serial Kansas City Cardiomyopathy 
Questionnaire Assessments With Death and Hospitalization in Patients With Heart Failure 
With Preserved and Reduced Ejection Fraction: A Secondary Analysis of 2 Randomized 
Clinical Trials. JAMA Cardiol. 2017;2(12):1315-1321. 
7. 
Khariton Y, Hernandez AF, Fonarow GC, et al. Health Status Variation Across Practices 
in Outpatients With Heart Failure: Insights From the CHAMP-HF (Change the Management of 
Patients With Heart Failure) Registry. Circ Cardiovasc Qual Outcomes. 2018;11(4):e004668. 
8. 
Gallagher AM, Lucas R, Cowie MR. Assessing health-related quality of life in heart 
failure patients attending an outpatient clinic: a pragmatic approach. ESC Heart Fail. 
2019;6(1):3-9. 
9. 
Stehlik J, Rodriguez-Correa C, Spertus JA, et al. Implementation of Real-Time 
Assessment of Patient-Reported Outcomes in a Heart Failure Clinic: A Feasibility Study. J Card 
Fail. 2017;23(11):813-816. 
 
 
 

 
 
27 
Appendices 
 
Appendix A: Kansas City Cardiomyopathy Questionnaire-12 
 
 
 
 
 
Rev. 2012-04-11 
Kansas City Cardiomyopathy Questionnaire (KCCQ-12) 
 
The following questions refer to your heart failure and how it may affect your life. Please read and complete the following 
questions. There are no right or wrong answers. Please mark the answer that best applies to you. 
 
1. Heart failure affects different people in different ways. Some feel shortness of breath while others feel fatigue. Please 
indicate how much you are limited by heart failure (shortness of breath or fatigue) in your ability to do the following 
activities over the past 2 weeks. 
Activity 
Extremely 
Limited 
Quite a bit 
Limited 
Moderately 
Limited 
Slightly 
Limited 
Not at all 
Limited 
Limited for 
other reasons 
or did not do 
the activity 
a. Showering/bathing 
O 
O 
O 
O 
O 
O 
b. Walking 1 block on 
level ground 
O 
O 
O 
O 
O 
O 
c. Hurrying or jogging 
(as if to catch a bus) 
O 
O 
O 
O 
O 
O 
 
1 
2 
3 
4 
5 
6 
 
2. Over the past 2 weeks, how many times did you have swelling in your feet, ankles or legs when you woke up in the 
morning? 
Every morning 
3 or more times 
per week but 
not every day 
1-2 times per week 
Less than 
once a week 
Never over the 
past 2 weeks 
O 
O 
O 
O 
O 
 
 
 
1 
2 
3 
4 
5 
 
 
 
3. Over the past 2 weeks, on average, how many times has fatigue limited your ability to do what you wanted? 
 
All of 
the time 
Several times 
per day 
At least 
once a day 
3 or more times 
per week but 
not every day 
1-2 times 
per week 
Less than 
once a week 
Never over the 
past 2 weeks 
O 
O 
O 
O 
O 
O 
O 
 
 
1 
2 
3 
4 
5 
6 
7 
 
 
4. Over the past 2 weeks, on average, how many times has shortness of breath limited your ability to do what you 
wanted? 
All of 
the time 
Several times 
per day 
At least 
once a day 
3 or more times 
per week but 
not every day 
1-2 times 
per week 
Less than 
once a week 
Never over the 
past 2 weeks 
O 
O 
O 
O 
O 
O 
O 
 
 
1 
2 
3 
4 
5 
6 
7 
 
 
5. Over the past 2 weeks, on average, how many times have you been forced to sleep sitting up in a chair or with at 
least 3 pillows to prop you up because of shortness of breath? 
 
Every night 
3 or more times 
per week but 
not every day 
1-2 times 
per week 
Less than 
once a week 
Never over the 
past 2 weeks 
O 
O 
O 
O 
O 
 
 
1 
2 
3 
4 
5 
 

 
 
28 
 
 
 
KCCQ-12 
Page 2 of 2 
 
6. Over the past 2 weeks, how much has your heart failure limited your enjoyment of life? 
 
It has extremely 
limited my enjoyment 
of life 
It has limited my 
enjoyment of life 
quite a bit 
It has moderately 
limited my enjoyment 
of life 
It has slightly 
limited my enjoyment 
of life 
It has not limited 
my enjoyment 
of life at all 
O 
O 
O 
O 
O 
 
 
1 
2 
3 
4 
5 
 
 
7. If you had to spend the rest of your life with your heart failure the way it is right now, how would you feel about this? 
 
Not at all 
satisfied 
Mostly 
dissatisfied 
Somewhat 
satisfied 
Mostly 
satisfied 
Completely 
satisfied 
O 
O 
O 
O 
O 
 
 
1 
2 
3 
4 
5 
 
 
8. How much does your heart failure affect your lifestyle? Please indicate how your heart failure may have limited your 
participation in the following activities over the past 2 weeks. 
 
Activity 
Severely 
Limited 
Limited 
quite a bit 
Moderately 
limited 
Slightly 
limited 
Did not 
limit at all 
Does not apply 
or did not do for 
other reasons 
a. Hobbies, recreational 
activities 
O 
O 
O 
O 
O 
O 
b. Working or doing 
household chores 
O 
O 
O 
O 
O 
O 
c. Visiting family or 
friends out of your 
home 
O 
O 
O 
O 
O 
O 
 
1 
2 
3 
4 
5 
6 
 

 
 
29 
Appendix B: Clinic Experience Survey 
 
This survey is to evaluate your experience at your recent cardiology clinic visit. Using the 5-item scale below 
each question, please indicate how much you agree with the following statements by marking the answer 
that best applies to you :  
 
1.) My clinician listened to me carefully:  
O 
Completely agree 
O 
Somewhat agree 
O 
Neither agree nor 
disagree 
O  
Somewhat 
disagree 
O  
Completely 
disagree 
 
2.) My clinician understood symptoms related to my heart: 
O 
Completely agree 
O 
Somewhat agree 
O 
Neither agree nor 
disagree 
O  
Somewhat 
disagree 
O  
Completely 
disagree 
 
3.) My clinician showed respect for what I had to say:  
O 
Completely agree 
O 
Somewhat agree 
O 
Neither agree nor 
disagree 
O  
Somewhat 
disagree 
O  
Completely 
disagree 
 
4.) My clinician and I agreed on how I was doing overall: 
O 
Completely agree 
O 
Somewhat agree 
O 
Neither agree nor 
disagree 
O  
Somewhat 
disagree 
O  
Completely 
disagree 
 
5.) My clinician spent enough time with me:  
O 
Completely agree 
O 
Somewhat agree 
O 
Neither agree nor 
disagree 
O  
Somewhat 
disagree 
O  
Completely 
disagree 
 
6.) My clinician explained things in a way that was easy to understand: 
O 
Completely agree 
O 
Somewhat agree 
O 
Neither agree nor 
disagree 
O  
Somewhat 
disagree 
O  
Completely 
disagree 
 
7.) I understand the importance of taking the treatments recommended by my clinician:  
O 
Completely agree 
O 
Somewhat agree 
O 
Neither agree nor 
disagree 
O  
Somewhat 
disagree 
O  
Completely 
disagree 
 
 
 

 
 
30 
8.) My goals regarding treatment and those of my clinician are aligned: 
O 
Completely agree 
O 
Somewhat agree 
O 
Neither agree nor 
disagree 
O  
Somewhat 
disagree 
O  
Completely 
disagree 
 
9.) What has the biggest impact on your quality of life? 
O 
Heart Failure 
O 
Other 
Cardiovascular 
Problems 
O 
Other Medical 
Problems 
O  
Heart Failure 
and Other 
Medical 
Problems 
Equally 
O  
Non-medical 
Reasons 
 
O  
None of the 
Above 
 
 
10.) In terms of your overall quality of life, how do you expect your heart failure health status to change over 
the following year: 
O 
Significant 
Improvement 
O 
Mild Improvement 
O 
Remain Stable 
O 
Mild Worsening 
O 
Significant 
Worsening 
 
 
 
 

 
 
31 
Appendix C: Clinician Perception of Health Status Survey 
 
 
You saw _________________ in clinic today. We have five questions regarding your perception of their 
heart failure health status (please circle all answers). 
 
1.) What is their current New York Heart Association functional class? 
° 
NYHA Class I  
° 
NYHA Class II  
° 
NYHA Class III  
° 
NYHA Class IV  
 
2.)  How much does heart failure impact their overall quality of life? 
° 
None  
° 
Mildly  
° 
Moderately  
° 
Severely  
 
3.)  How frequently did they have the following symptoms in the last two weeks? 
 
Edema 
° 
None 
° 
Once 
° 
More than once, but 
not daily 
° 
Daily 
° 
I Don’t Know 
Orthopnea 
° 
None 
° 
Once 
° 
More than once, but 
not daily 
° 
Nightly 
° 
I Don’t Know 
Fatigue 
° 
None or once 
° 
More than once, 
less than daily 
° 
Daily 
° 
Frequently each day 
° 
I Don’t Know 
Shortness of 
breath 
° 
None or once 
° 
More than once, 
less than daily 
° 
Daily 
° 
Frequently each day 
° 
I Don’t Know 
 
4.) In terms of their overall quality of life, how do you expect their heart failure health status to change over 
the following year: 
O 
Significant 
Improvement 
O 
Mild Improvement 
O 
Remain Stable 
O 
Mild Worsening 
O 
Significant 
Worsening 
 
5.) What has the biggest impact on your patient’s quality of life? 
O 
Heart Failure 
O 
Other 
Cardiovascular 
Problems 
O 
Other Medical 
Problems 
O  
Heart Failure 
and Other 
Medical 
Problems 
Equally 
O  
Non-medical 
Reasons 
 
O  
None of the 
Above