Patient-reported Outcomes in Clinical Studies of Patients with Hypertrophic Cardiomyopathy

Abstract

Objectives:

This study aimed to characterize patient-reported outcomes (PROs) in registered clinical studies of participants with hypertrophic cardiomyopathy (HCM).

Background:

Therapy for HCM is primarily targeted toward alleviation of symptoms and improvement in function and quality of life. Yet, the contemporary landscape of PROs in HCM clinical research has not been investigated.

Methods:

ClinicalTrials.gov was queried to identify clinical studies of HCM that reported PROs as outcome measures. All studies of HCM as the disease condition were included, and PROs were identified using specific search terms in the Outcome Measures field. Study characteristics were collected and compared between those that did versus did not report PROs.

Results:

From November 1987 to February 2022, 181 studies including participants with HCM were registered on ClinicalTrials.gov. Of these, 35 (19%) included PROs as outcome measures. Studies reporting PROs were more likely to be designated as interventional (85.7% vs. 46.6%; p<0.001) and to involve randomization (65.7% vs. 24.7%; p=0.003) compared with those that did not report PROs. Prior to 2007, no clinical studies that reported PROs were registered in ClinicalTrials.gov; however, PRO reporting has increased over the last 15 years. Of the 66 PRO tools or domains included as outcome measures, the Kansas City Cardiomyopathy Questionnaire was the most often used.

Conclusions:

Only approximately one in five registered clinical studies of participants with HCM report PROs. As medical, percutaneous, and surgical therapies for HCM continue to advance, HCM-specific PRO tools that assess the impacts of these new treatments on meaningful patient-related endpoints are urgently needed.

Graphical Abstract

INTRODUCTION

Hypertrophic cardiomyopathy (HCM) is among the most common genetic cardiovascular disorders in the United States, with an estimated prevalence of 1:500 persons. Its symptomatology is complex, characterized by any combination of chest discomfort, rest and exertional dyspnea, post-prandial limitations, effort intolerance, presyncope, syncope, palpitations, and fatigue (1); these symptoms occur in both obstructive and non-obstructive HCM. In some patients, symptoms of heart failure (HF), including orthopnea, paroxysmal nocturnal dyspnea, and edema, are also present. A variety of cardiac structural and functional derangements, including left ventricular outflow tract obstruction, diastolic dysfunction, microvascular disease, myocardial bridging, arrhythmias and conduction disease, mitral regurgitation, contribute to HCM symptoms.

Cross-sectional studies have demonstrated the adverse impact of HCM on health-related quality of life, physical functioning, and psychiatric health (2–4). These symptomatic and quality of life limitations are driving factors in the clinical management of HCM, such as titration of medical therapy, exercise prescriptions, and referral for septal reduction therapy (1, 5). Decisions to escalate medical therapy and proceed with invasive therapeutic interventions are typically made through combining 1) objective functional parameters, such as those obtained through cardiopulmonary exercise testing, 2) subjective clinician assessment assisted by symptom assessment scales such as New York Heart Association class (1), and 3) patient preferences through shared decision making. However, validated measures that comprehensively capture and communicate the patient perspective in HCM are lacking.

Patient-related outcomes (PROs) assessment tools offer the opportunity to understand patients’ experience of the impacts of their disease on their health status, inclusive of symptoms; physical, social, and emotional function; and quality of life. In HF, standardized patient-reported health status surveys have been proven to be reliable and sensitive tools to assess baseline disease status, response to treatment, and prognosis (6, 7), and PRO tools are being increasingly incorporated into pivotal clinical studies as designated outcome measures. However, the contemporary landscape of the use of PROs in clinical studies of HCM has yet to be rigorously described. In this study, we sought to assess PRO reporting in clinical studies of participants with HCM over the last two decades. We hypothesized that a minority of registered clinical studies of participants with HCM would include PROs as outcomes.

METHODS

The ClinicalTrials.gov database was queried to identify registered studies of participants with HCM that reported PROs as outcomes. Studies of participants with HCM were identified through searching the keyword “hypertrophic cardiomyopathy” in the “Condition” field. No date or other search filters were applied. Studies that included PROs as outcomes were identified by searching 50 unique PRO terms in the Outcome Measures field (Supplemental Material). PRO terms queried included generic assessment tools and phrases (e.g., “symptom”, “quality of life”) and PROs specific to HCM as well as atrial fibrillation (8) and cardiomyopathy and HF (9) as these are most frequently used, best validated, and are comorbidities and complications of HCM. ClinicalTrials.gov study records were individually reviewed to identify and collect specific PRO measurement tools for the studies that reported PROs as outcomes, and, if available, publications linked to each study were reviewed to identify whether outcome reporting occurred as documented in the ClinicalTrials.gov entry.

Statistical Methods

Characteristics of registered studies reporting PRO terms were compared with those that did not report such terms among their outcome measures. The frequencies of use of specific and generic PRO measures were collected. Continuous variables were described with medians and interquartile ranges (IQR) and categorical variables as percentages (%). Intergroup comparisons were performed using Wilcoxon rank sum test for continuous variables and the Fisher’s exact/chi-squared test for categorical variables, as appropriate. All statistical tests were two-sided, and a P-value <0.050 was considered statistically significant. All analyses and visualizations were performed with Stata/IC 16.1 (College Station, Texas) and RStudio Version 1.3.1093 (Boston, Massachusetts). As publicly available data were used for this analysis, institutional review board approval was not sought.

RESULTS

A total of 181 unique registered studies that included participants with HCM were identified through ClinicalTrials.gov query (Table 1). Studies were first posted from November 4, 1999 to February 25, 2022. The average number of studies registered per year was 8, though the majority of studies (60.2%) were first posted between 2015 and 2022. The median number of outcomes reported per study was 2 (IQR 1, 6). Three studies (1.7%) enrolled males only; the remainder (98.3%), including all studies that reported PROs as outcomes, enrolled patients of female and male sex. Prior to 2007, there were no studies that reported PROs as an outcome registered in ClinicalTrials.gov.

Table 1:

Characteristics of Clinical Studies of Hypertrophic Cardiomyopathy, Stratified by Inclusion of Patient-Reported Outcomes

Registered Study Characteristic	Overall N = 181 n (%)	No PROs Reported N = 146 n (%)	PROs Reported N = 35 n (%)	P-value
Sex of Enrolled Participants, n (%)				0.39
Male only	3 (1.7%)	3 (2.1%)	0 (0.0%)
All sexes	178 (98.3%)	143 (97.9%)	35 (100.0%)
Number of Total Reported Outcomes, median (IQR)	2 (1, 6)	2 (1, 4)	6 (4, 7)	<0.001
Study Type, n (%)				<0.001
Interventional	98 (54.1%)	68 (46.6%)	30 (85.7%)
Observational	83 (45.9%)	78 (53.4%)	5 (14.3%)
Study Allocation Design, n (%)				0.012
Not available	25 (13.8%)	20 (13.7%)	5 (14.3%)
Non-Randomized	7 (3.9%)	5 (3.4%)	2 (5.7%)
Randomized	59 (32.6%)	36 (24.7%)	23 (65.7%)
Observational or Other	90 (49.7%)	85 (58.2%)	5 (14.3%)
Intervention, n (%)				0.220
Behavioral	5 (2.8%)	1 (0.7%)	4 (11.4%)
Biological	2 (1.1%)	2 (1.4%)	0 (0.0%)
Device	20 (11.0%)	14 (9.6%)	6 (17.1%)
Diagnostic Test	7 (3.9%)	6 (4.1%)	1 (2.9%)
Drug	50 (27.6%)	37 (25.3%)	13 (37.1%)
Genetic	1 (0.6%)	1 (0.7%)	0 (0.0%)
Other	19 (10.5%)	14 (9.6%)	5 (14.3%)
Procedure	19 (10.5%)	16 (11.0%)	3 (8.6%)
Radiation	1 (0.6%)	1 (0.7%)	0 (0.0%)
Unavailable	57 (31.5%)	54 (37.0%)	3 (8.6%)
Study Phase, n (%)
Not Applicable	39 (21.5%)	26 (17.8%)	13 (37.1%)	0.380
Phase 1	11 (6.1%)	10 (6.8%)	1 (2.9%)
Phase 2	29 (16.0%)	21 (14.4%)	8 (22.9%)
Phase 2 | Phase 3	3 (1.7%)	2 (1.4%)	1 (2.9%)
Phase 3	9 (5.0%)	4 (2.7%)	5 (14.3%)
Phase 4	7 (3.9%)	5 (3.4%)	2 (5.7%)
Unavailable	83 (45.9%)	78 (53.4%)	5 (14.3%)
Enrollment, n (%)				0.350
<100	93 (51.4%)	73 (50.0%)	20 (57.1%)
100–499	57 (31.5%)	44 (30.1%)	13 (37.1%)
500–999	7 (3.9%)	7 (4.8%)	0 (0.0%)
1000–1499	3 (1.7%)	3 (2.1%)	0 (0.0%)
>1500	21 (11.6%)	19 (13.0%)	2 (5.7%)
Funding Body, n (%)				0.140
Industry	27 (14.9%)	20 (13.7%)	7 (20.0%)
National Institutes of Health	24 (13.3%)	24 (16.4%)	0 (0.0%)
Other	105 (58.0%)	82 (56.2%)	23 (65.7%)
Other & Industry	15 (8.3%)	12 (8.2%)	3 (8.6%)
Other & National Institutes of Health	10 (5.5%)	8 (5.5%)	2 (5.7%)
Number of Sites, n (%)				0.13
1	133 (73.5%)	110 (75.3%)	23 (65.7%)
> 1	39 (21.5%)	28 (19.2%)	11 (31.4%)
Not available	9 (5.0%)	8 (5.5%)	1 (2.9%)
Study Site Locations, n (%)				0.12
U.S. sites among study locations	76 (42.0%)	65 (44.5%)	11 (31.4%)
Non-U.S. study site locations	96 (53.0%)	73 (50.0%)	23 (65.7%)
Missing	9 (5.0%)	8 (5.5%)	1 (2.9%)
Year First Posted, n (%)				0.020
1999–2006	26 (14.4%)	26 (17.8%)	0 (0.0%)
2007–2014	46 (25.4%)	34 (23.3%)	12 (34.3%)
≥ 2015	109 (60.2%)	86 (58.9%)	23 (65.7%)
Status, n (%)				0.17
Active, not recruiting	10 (5.5%)	7 (4.8%)	3 (8.6%)
Completed	69 (38.1%)	60 (41.1%)	9 (25.7%)
Enrolling by invitation	8 (4.4%)	8 (5.5%)	0 (0.0%)
Not yet recruiting	2 (1.1%)	1 (0.7%)	1 (2.9%)
Recruiting	43 (23.8%)	29 (19.9%)	14 (40.0%)
Suspended	2 (1.1%)	2 (1.4%)	0 (0.0%)
Terminated	5 (2.8%)	4 (2.7%)	1 (2.9%)
Unknown status	37 (20.4%)	30 (20.5%)	7 (20.0%)
Withdrawn	5 (2.8%)	5 (3.4%)	0 (0.0%)
Results Available, n (%)	14 (7.7%)	8 (5.5%)	6 (17.1%)	0.020

Among the 181 studies, 35 (19%) included PRO terms in their primary and/or secondary outcomes measures (Figure 1). Compared with those that did not report PROs, studies that included PROs as outcomes reported a significantly greater number of total outcomes overall (median 6 [IQR 4, 7] vs. 2 [IQR 1, 4]; p<0.001). Studies reporting PROs were more likely to be classified as interventional (85.7% vs. 46.6%; p<0.001) and to involve randomization (65.7% vs. 24.7%; p=0.012) compared with those that did not report PROs as outcomes. There were no significant differences between studies that did versus did not report PROs with regard to intervention type investigated (p=0.220). In addition to enrolling adults aged 18 years and older, 3 studies that reported PROs (8.6%) included children aged 6 to 18 years.

Figure 1.

Number of Clinical Studies of Participants with Hypertrophic Cardiomyopathy, Stratified by Inclusion of Patient-Reported Outcomes as Outcome Measures and by Year of First Report to ClinicalTrials.gov. Abbreviations: PROs = patient-reported outcomes.

No study that reported PROs was solely funded by the National Institutes of Health; two of the 35 (5.7%) were supported by the National Institutes of Health and an additional funder. Among phase 1–4 studies, PROs were most often deployed in those in phase 2 (n=8, 22.9%). Similar proportions of studies with and without PRO reporting occurred at a single study site (65.7% with PROs vs. 75.3% without PROs; p = 0.13). The largest number of sites involved in a trial reporting PROs as an outcome was 71, compared with 67 sites for the largest study that did not report PROs. Ninety-four percent of studies that reported PROs as outcomes enrolled fewer than 500 participants.

Only a quarter of studies that reported PROs as outcomes were designated as completed (n=9), whereas 40% were recruiting. In contrast, 41% of studies that did not report PROs were completed (n=60) and 19.9% (n=29) were recruiting. A significantly higher proportion of studies that reported PROs as outcomes were designated as having results available in ClinicalTrials.gov (17.1% vs. 5.5%, p=0.020). The number of studies including PROs as outcome measures (n=23, 65.7%) was higher in the most recent seven years of reporting (2015 to 2022) compared with the period between 2007 and 2014 (n=12, 34.3%).

Table 2 lists the PRO measures reported among the 35 registered studies that included PRO terms in their primary or secondary outcomes measures. There were 66 PRO tools or domains listed as outcome measures as 13 studies employed multiple PROs (Figure 2). Six of the 35 studies (17%) designated PRO measures as primary outcomes. The Kansas City Cardiomyopathy Questionnaire (KCCQ), including its component summary scores, was the most highly utilized PRO measure (n=14/35, n=2 as primary outcome). The 36-Item Short Form Survey (n=6) and the Minnesota Living with Heart Failure Questionnaire (MLHFQ) (n=6) were also commonly used. Psychiatric health domains were assessed in nine studies (26%) with ten distinct tools specific to anxiety and depression. An assessment tool specific to HCM, Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ), was used in one study, and no measurement tool specific to atrial fibrillation was used. In seven reported outcome entries on ClinicalTrials.gov, a specific PRO measure was not identified.

Table 2:

Patient-reported Outcome Measures or Phrases Reported Among 35 Registered Studies that Included Patient-reported Outcome Terms

PRO Measures or Phrases	Number of Times Reported as PRO Measure, n (%) Total N = 66
Change in Attitudes and Trust	1 (1.5%)
Change in Health Behaviors	1 (1.5%)
Change in Intolerance of Uncertainty Using the Intolerance of Uncertainty Scale	1 (1.5%)
Change in Perceived Health Adapted From SF-12	1 (1.5%)
Change in Preferences for Whole Genome Sequencing Information	1 (1.5%)
Change in Shared Decision Making Adapted from the Control Preferences Scale	1 (1.5%)
Changes in Genomic Literacy	1 (1.5%)
Duke Activity Status Index (DASI)	1 (1.5%)
Decisional Regret	1 (1.5%)
Echelle de Motivation envers l’Activité Physique en contexte de Santé’ (A motivation scale toward health-oriented physical activity) (EMAPS)	1 (1.5%)
EQ5D-5L	4 (6.1%)
General Anxiety Disorder-7 (GAD-7)	1 (1.5%)
Hospital Anxiety and Depression Scale (HADS)	1 (1.5%)
Hamilton Anxiety Rating Scale (HAM-A)	1 (1.5%)
Hamilton Depression Rating Scale (HAM-D17)	1 (1.5%)
HCM Symptom Questionnaire (HCMSQ)	1 (1.5%)
Kansas City Cardiomyopathy Questionnaire (KCCQ)	14 (21.2%)
Minnesota Living with Heart Failure Questionnaire (MLHFQ)	6 (9.1%)
Multiplex Initiative adapted scale for self efficacy	1 (1.5%)
Dyspnea Numeric Rating Scale (NRS)	1 (1.5%)
Patient Health Questionnaire (PHQ)-9	1 (1.5%)
Pediatric Cardiac Quality of Life Inventory (PCQLI)	1 (1.5%)
Pediatric Quality of Life Inventory (PedsQL)	2 (3.0%)
Patient-Reported Outcomes Measurement Information System (PROMIS) Questionnaire	1 (1.5%)
Patient Understanding of Study Results	1 (1.5%)
Psychological Impact Addressed by Multidimensional Impact of Cancer Risk Assessment (MICRA)	1 (1.5%)
Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)	1 (1.5%)
Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16)	1 (1.5%)
Ricci and Gagnon questionnaire	1 (1.5%)
Seattle Angina Questionnaire (SAQ)	2 (3.0%)
36-Item Short Form Survey (SF36)	6 (9.1%)
“quality of life” and/or “questionnaire”	5 (7.6%)
“symptoms”	2 (3.0%)

Figure 2. Representation of Patient-reported Outcome (PRO) Tools Reported in the 35 Registered Studies that Included PRO Terms in Primary or Secondary Outcomes Measures, Stratified by PRO Type.

Box sizes are proportional to frequency of PRO tool use. Most relevant PRO tools are labeled. Abbreviations: GAD-7 = General Anxiety Disorder-7; HADS = Hospital Anxiety and Depression Scale; HAM-A = Hamilton Anxiety Rating Scale; HAM-D17 = Hamilton Depression Rating Scale; HCMSQ = HCM Symptom Questionnaire; KCCQ = Kansas City Cardiomyopathy Questionnaire; MLHFQ = Minnesota Living with Heart Failure Questionnaire; NRS = Dyspnea Numeric Rating Scale; PedsQL = Pediatric Quality of Life Inventory; PCQLI = Pediatric Cardiac Quality of Life Inventory; PHQ-9 = Patient Health Questionnaire; PROMIS = Patient-Reported Outcomes Measurement Information System Questionnaire; QIDS-SR16 = Quick Inventory of Depressive Symptomatology-Self Report; SAQ = Seattle Angina Questionnaire; SF36 = 36-Item Short Form Survey.

All studies that had results available according to their respective ClinicalTrials.gov entries did have at least one associated publication and did report PROs in their corresponding publications (n=9/35, 25.8%). In these nine studies, 24 PRO measures in total were used, of which 18 were distinct. Of these 18 PRO tools, four PRO measures related to cardiac symptoms — HCMSQ (n=1), Dyspnea Numeric Rating Scale (NRS) (n=1), KCCQ (n=4), MLHFQ (n=4) — were used in eight distinct studies (Supplemental Table 1). Six of the eight studies investigated the impact of drug therapy on objective measures of functional capacity (i.e., change in peak oxygen consumption) or on left ventricular outflow tract gradient; one investigated effect of biventricular pacing on change in peak oxygen consumption; and one investigated effect of exercise training on change in peak oxygen consumption. In six of the eight studies, there was concordance between improvement in the objective functional measure and improvement in the cardiac PRO measure. The remaining two studies did not demonstrate statistically significant concordant changes in the cardiac PRO measure.

DISCUSSION

In this analysis, we provide the first systematic description of the use of PROs in clinical studies of patients with HCM. Using the ClinicalTrials.gov repository, we found that fewer than one in four clinical studies of patients with HCM have reported or plan to report PROs as outcome measures. While the majority of studies that reported PROs involved randomization or an intervention, the dearth of observational studies that reported PROs highlights the insufficient evidence base on the exploration and development of PROs in HCM. Of the minority of studies with results available to date, all those that were designed to report PROs as primary or secondary outcome measures did report PRO assessment results in their corresponding publications.

While enrolling large numbers of participants with HCM into clinical studies itself is challenging due to underdiagnosis and lack of awareness of the disease (1, 4), our analysis nevertheless yields interesting insights into potential barriers to incorporating PRO instruments into clinical studies. First, we found that the majority of studies that reported PROs occurred at a single study site and enrolled fewer than 500 participants, suggesting that wider adoption of PROs across multiple sites and larger participant populations may be logistically challenging. We also demonstrated that despite proximity to clinical care, PROs were infrequently reported as outcomes in phase 3 or phase 4 studies. Time to complete PRO instruments may be a perceived barrier as existing multi-domain questionnaires and surveys can take 10 minutes to complete (10, 11), which may discourage investigators from incorporating them into already complex study protocols. Fortunately, recent pivotal clinical trials in HCM have demonstrated successful strategies to encourage PRO completion. The EXPLORER-HCM trial provides one such example as the KCCQ was administered electronically before other study procedures occurred using a study-specific app on a provisioned handheld device (12). Second, we found that a minority of studies that reported PROs designated them as primary outcomes and that these studies reported a significantly higher number of total primary and/or secondary outcomes, suggesting that these clinical studies were and are designed to assess outcomes beyond those that are solely patient-related. Notably, a recent randomized trial of the sodium-glucose cotransporter-2 inhibitor canagliflozin in patients with HF investigated a patient-reported health status measure (KCCQ) as a primary outcome and collected PRO data completely remotely (13). Exploration of similar remote patient engagement strategies may offer a path forward to incorporating PROs in more HCM clinical studies.

Third, we report that the majority of HCM clinical studies have been registered in the ClinicalTrials.gov repository within the last seven years, demonstrating the growing interest and resources being dedicated to advancing knowledge of this no longer “rare” disease. Recent randomized trials of cardiac myosin inhibitors in HCM have incorporated PROs (i.e., HCMSQ, KCCQ, Dyspnea Numeric Rating Scale, EQ5D-5L) (14, 15). The recent U.S. Food and Drug Administration approval of mavacamten (16) has ushered in a new era of molecular therapy for HCM as well as a new era for PROs in HCM. Improvement in health status and quality of life were key outcomes in the phase 3 EXPLORER-HCM trial, a placebo-controlled, randomized trial that was the first and largest clinical study of its kind to prospectively measure PROs in obstructive HCM (12, 17). Given the increasing enthusiasm surrounding HCM, this is an optimal time to raise awareness of the importance of incorporating PROs a priori into future clinical studies. Moreover, in addition to being used as endpoints in clinical studies, PRO scores may also be used as screening or inclusion criteria to enrich for specific participant populations.

Fourth, we catalogued the reporting of 24 distinct PRO tools in clinical studies of this cohort of pediatric and adult participants, emphasizing the lack of validated HCM-specific PRO instruments in contemporary research and practice. The KCCQ was most often used, extrapolating from its robust validation evidence in cardiomyopathy and HF (9). Nearly a decade ago, a prospective single center study first demonstrated that the KCCQ, particularly the components of physical limitation and the overall summary scores, moderately correlated with physician-assigned New York Heart Association functional class and percent predicted peak oxygen consumption derived from cardiopulmonary exercise testing in patients with HCM (18). These general relationships were recapitulated in the EXPLORER-HCM trial (12). The KCCQ was found to have good psychometric performance in a post-hoc analysis of this trial; however, patients specifically noted that the symptom burdens of atrial fibrillation, palpitations, dizziness, chest pain/angina, and syncope were not adequately captured through the KCCQ (17). Furthermore, associations between health status measures and objective functional status assessments have yet to be confirmed in different populations of patients with HCM, such as those with non-obstructive HCM or those with HCM and systolic dysfunction. Validation of the KCCQ in patients with symptomatic obstructive HCM is a welcome step forward in emphasizing the importance of patient-centered outcomes in this disease.

Fifth, we found that multiple PRO tools assessing mood, anxiety, and depression were used in clinical studies, highlighting the significant comorbid psychiatric burden patients with HCM endure. In 2020, Zaiser et al. conducted a qualitative interview study of 27 patients with HCM in order to develop a conceptual model of the HCM patient experience and found that patients reported emotional impacts and feeling anxious or depressed as frequently as they reported having limitations to physical activities (4). In a post-hoc analysis of EXPLORER-HCM, patients noted that the mental toll of their HCM experience may not be adequately captured by the KCCQ (17). HCM therapies are largely targeted toward cardiopulmonary symptom relief and improvement in functional status, and there is relatively little formal guidance on the management of psychiatric comorbidities of patients with HCM. By its nature as a genetic disease, patients with HCM assume additional and unique burdens regarding the impacts of their disease and their genetics on family members, especially those first-degree relatives who may also be at risk for HCM. As such, the development and validation of a PRO measure that incorporates the distinct psychiatric health trajectory of patients with HCM would be highly valuable to optimize the comprehensive care of this population.

Finally, while this analysis could not facilitate exploration of PRO reporting with respect to different patient sex or historically underrepresented racial/ethnic groups, sex- and race-based disparities in symptom status at presentation in patients with HCM (19–21); in HCM outcomes (19–22); and in health status and quality of life metrics in patients with HF (23, 24) are well recognized. Widespread assessment of PRO measures in patients with HCM in research and in routine clinical care may help rectify such disparities and should be prioritized.

Limitations of this analysis include exclusion of relevant clinical studies and study characteristics. However, the broad inclusion PRO search terms, standardized nature of the ClinicalTrials.gov database, and manual review of study publications mitigate these issues.

Overall, in this analysis, we characterize the current state of PRO reporting in clinical studies of patients with HCM. Future research is needed to develop and validate HCM-specific PRO tools and to investigate and differentiate longitudinal health status trajectories in subgroups of patients with HCM.

CONCLUSIONS

Despite the acceleration of clinical research in HCM over the past three decades, a minority of clinical studies include PROs as outcome measures. While other cardiovascular disease states such as atrial fibrillation and heart failure have disease-specific PROs, only one tool, the KCCQ, has been validated in HCM, the most common genetic cardiovascular disease in the United States. We demonstrate that the physical, social, functional, and quality-of-life limitations that are experienced by patients with HCM are complex and may not be comprehensively captured by existing PRO measurement tools, signaling the potential to develop and validate disease-specific health status measures for HCM. As we enter the age of novel molecular therapeutics for HCM, opportunities to incorporate PROs into study design and outcome reporting should be embraced.

Clinical Perspectives.

Competency in Medical Knowledge:

A minority of clinical studies performed in patients with HCM to date report PROs as outcome measures. Only one PRO tool, the KCCQ, has been validated in studies of patients with HCM; however, HCM-specific symptoms such as atrial fibrillation, palpitations, dizziness, chest pain/angina, syncope, and psychiatric impacts are not adequately assessed by existing PRO tools.

Translational Outlook:

Future research is needed to develop and validate PRO tools that adequately capture HCM-specific symptoms and longitudinal health status trajectories in patients with varying HCM subphenotypes.

Acronyms and Abbreviations:

HCM

hypertrophic cardiomyopathy

HCMSQ

Hypertrophic Cardiomyopathy Symptom Questionnaire

HF

heart failure

IQR

interquartile range

KCCQ

Kansas City Cardiomyopathy Questionnaire

MLHFQ

Minnesota Living with Heart Failure Questionnaire

PRO(s)

patient-reported outcome(s)