Adult Congenital Heart Disease Patients Experience Similar Symptoms of Disease Activity

Abstract

Background

There is a lack of objective data on the symptoms characterizing disease activity among adults with congenital heart disease (ACHD). The purpose of this study was to elicit the most important symptoms from patients across the spectrum of ACHD and to examine whether reported symptoms were similar across the spectrum of ACHD as a foundation for creating a patient-reported outcome measure(s).

Methods and Results

We constructed a 39-item survey using input from physicians specializing in ACHD to assess the symptoms patients associate with disease activity. Patients (n=124) prospectively completed this survey and the results were analyzed based on underlying anatomy and disease complexity. A confirmatory cohort of patients (n=40) was then recruited prospectively to confirm the validity of the initial data. When grouped based on underlying anatomy, significant differences in disease-related symptom rankings were found for only six of thirty-nine symptoms. Six symptoms were identified which were of particular significance to patients regardless of underlying anatomy. Patients with anatomy of great complexity experienced greater overall symptom severity than those with anatomy of low or moderate complexity, attributable exclusively to higher ranking of 5 symptoms. The second patient cohort had symptom experiences very similar to that of the initial cohort, differing in only 5 of 39 symptoms.

Conclusions

This study identified 6 symptoms relevant to patients across the spectrum of ACHD, and remarkable homogeneity of patient experience, suggesting that a single disease-specific PRO can be created for quality and outcomes assessments.

There is a pressing need for a method to evaluate the quality of care for adult congenital heart disease (ACHD). This unique population of patients has grown significantly over the past 20 years, and currently the number of ACHD patients in the United States is estimated to be over 1.2 million - far exceeding the number of children with congenital heart disease^1,2. Nevertheless, little data is available to guide ACHD specialists in quantifying patient-reported outcomes (PROs) for this group. Without the ability to reproducibly evaluate PROs, ACHD research will continue to fall short in optimizing management paradigms to improve patients’ daily lives. To address this inability to quantify the impact of ACHD on patients’ lives, a reliable tool for assessing disease-specific PROs in ACHD is needed³.

Derivation of an ACHD-specific PRO tool, however, is a complex process. The ACHD population is characterized by variability in not only anatomic diagnosis, but also in genetic background and in early life medical and surgical care. This heterogeneity would be anticipated to result in a broad diversity of disease-related symptoms, and it is not clear whether or not a single tool for all patients with ACHD would be adequate to evaluate PROs in the ACHD population, or whether unique tools for each type of ACHD would be needed. Furthermore, there is little data available to indicate which symptoms are typically experienced by ACHD patients as a group. To resolve these questions, it is necessary to conduct a systematic evaluation of disease-specific symptoms experienced by ACHD patients across the anatomical spectrum. Accordingly, we investigated patients’ symptoms by surveying both ACHD healthcare providers and ACHD patients regarding disease-specific symptoms. The purpose of this investigation was to begin to define the key concepts to be incorporated into an ACHD-specific PRO and to determine whether or not similar symptoms were relevant across a broad spectrum of ACHD patients with differing pathophysiological abnormalities.

Methods

We conducted a prospective survey of both ACHD physicians and patients to identify important ACHD-related symptoms. Developing a PRO with appropriate content validity requires eliciting symptoms and limitations from patients through qualitative research methods, however patients with ACHD are so diverse that we first needed to determine whether or not a single measure, or multiple PROs, would be needed. This question demanded assessing the prevalence and importance of symptoms across the spectrum of ACHD. Although such efforts generally use the extant literature to define initial items to include in such surveys, there are few detailed descriptions of patients’ symptoms in ACHD. We thus sought to first generate a list from experienced clinicians, with open-ended responses from patients so that the design of future focus groups and interview guides could be developed. The protocol for this study was reviewed and approved by the institutional review boards at both Washington University (Wash U) and Massachusetts General Hospital (MGH).

Physician Survey

The first step in creating a pool of potentially important symptoms was to survey physicians specializing in the care of ACHD patients. To identify physicians experienced in the care of ACHD patients, we approached the ACHD physician members of the Alliance for Adult Research in Congenital Cardiology (AARCC, a multi-institutional ACHD research consortium) and asked them to provide a list of symptoms typically elicited at the time of ACHD patient visits and which they believed were related to ACHD. Six providers from 6 different institutions with broad United States (US) geographic representation offered to participate in this study. A total of 39 symptoms were identified. No physician-proposed symptoms were excluded with the goal of being as exhaustive as possible.

Patient Survey

The next step was to solicit feedback from patients on the importance and relevance of the 39 identified symptoms and to expand this list by having patients contribute additional suggestions. Using the list of symptoms generated, we constructed an ACHD patient survey. This survey included the following demographic variables: gender, age, offspring, long-term relationship status, presence of an implantable cardiac defibrillator (ICD), and primary cardiac diagnosis. Patients were then asked to rank the both the importance and the frequency with which they experienced each symptom identified as a part of the physician survey. Symptom impact and frequency were scored on separate 5-point Likert scales (Figure 1). To ensure that the symptom list was exhaustive, patients were also asked to provide a list of symptoms not identified by physicians or included on the survey, but which were of significance to them. Patients were approached non-selectively to complete the survey at the annual meeting of the Adult Congenital Heart Association (ACHA) in Chicago, Illinois from September 5–7, 2014 (100 participants) as well as in the Center for Adults with Congenital Heart Disease at Washington University School of Medicine (24 participants). In both settings patients were approached by a study investigator at a research table (at the ACHA meeting) or at a regularly scheduled outpatient cardiology visit (at Washington University) and offered participation in the study.

Figure 1.

Symptom survey developed by adult congenital heart disease specialists which was provided to patients.

Confirmatory Patient Cohort

To confirm the results of the patient survey, patients seen in the ACHD clinic at MGH over a 4-week period in April and May 2015 were consecutively approached and invited to participate in the study. Forty patients agreed to participate and completed the survey. These results were then compared to the initial sample.

Statistical Analysis

Basic descriptive statistics were evaluated on all survey responses, overall and stratified by lesion complexity. Using the diagnoses provided by subjects, survey responses were then grouped into low, moderate and high anatomic complexity based on the 2008 guidelines statement for the care of adults with congenital heart disease from the American College of Cardiology/American Heart Association. Symptom impact score for each survey item within each subject was compared between groups using the Kruskal-Wallis test⁴. Again using the diagnoses provided by subjects, the survey responses were then pooled into one of seven groups depending on underlying diagnosis and presumed associated long-term disease specific sequelae as described in Table 1. A composite score, derived by multiplying symptom impact and frequency score, for each survey item within each subject was then compared for each individual survey item between groups using ANOVA, treating Likert scaled data as continuous measures. Data within groups were summarized by the mean ± standard deviation (SD) for this analysis. To confirm these initial findings, given the small sample sizes in certain groups and non-normal distribution, data were treated as ordinal values and compared using the Kruskal-Wallis test. Ordinal data for this test were summarized by the median and interquartile range. These two methods for evaluating the data yielded similar results and we therefore employed the ANOVA analysis for identification of differences between the seven diagnostic groups.

Table 1.

Separation of diagnoses into groups

Group	Diagnoses	Number of Patients
1	AS, BAV, CoA, Subaortic stenosis, Shone’s	14
2	ASD, VSD, PDA, AVCD, TAPVR, PAPVR	24
3	Single ventricle	16
4	TGA, ccTGA	16
5	TOF, Ebstein anomaly, PS, PA, DORV	43
6	Truncus arteriosus	7
7	Eisenmenger syndrome	4

AS: aortic stenosis; CoA: coarctation of the aorta; ASD: atrial septal defect; VSD: ventricular septal defect; PDA: patent ductus arteriosus; AVCD: atrioventricular canal defect; TAPVR: totally anomalous pulmonary venous return; PAPVR: partially anomalous pulmonary venous return; TGA: transposition of the great arteries; ccTGA: congenitally corrected transposition of the great arteries; TOF: tetralogy of Fallot; PS: pulmonic stenosis; PA: pulmonary atresia; DORV: dual outlet right ventricle

Finally, we conducted an analysis to further investigate the significance of differences in relative symptom “importance” between groups. In this analysis, impact and frequency scores for each survey item within each subject were multiplied and standardized. To standardize we averaged the composite score for each subject over all 39 items. We then subtracted this average from the composite score for each individual item to generate a standardized score for each item. We derived this analysis as our goal was to identify symptoms of particular importance to subjects. ACHD has significant heterogeneity in terms of clinical status, lesion complexity, and degree of disability. In an asymptomatic individual, any symptom at all might be deemed important, whereas in a chronically ailing individual, or one with significant chronic limitation, many symptoms would be anticipated to be present much of the time, certain of which would have a greater and certain of which would have a lesser impact on their quality of life. Our goal was to use the employed technique to permit direct comparison of the scores between the asymptomatic and the chronically ailing patient with the goal of identifying symptoms of particular importance regardless of baseline clinical status. ANOVA was used to compare the standardized data between groups.

Comparison of the test cohort survey data to the confirmatory cohort was carried out in a similar fashion to the group-wise comparison in the test cohort: we first compared composite item scores between the two groups using ANOVA. We thereafter compared the standardized composite score for each item, derived as above, between the two groups using ANOVA. For all analysis significance was assigned at p≤0.05. Trend toward significance was defined as 0.05< p <0.1. All analysis was conducted using SAS® Software v 9.3 (SAS Institute Inc., Cary NC).

Results

Patient Population

One hundred and twenty-four patients completed the symptom survey in the test cohort which had broad representation of ACHD lesions (Table 1). The mean age of participants was 42.7±14.2 and 67% were female. Other clinical and demographic characteristics of these patients are found in Table 2. Among test group participants, 26 (21%) had lesions of low complexity, 53 (43%) had lesions of moderate complexity and 45 (36%) had lesions of great complexity.

Table 2.

Demographic data

Variable	Study Cohort (n=124)	Confirmatory Cohort (n=40)
Age (years ± SD)	42.7±14.2	43.6±16.3
Sex (female)	83 (67%)	25 (62.5%)
Relationship status (in long-term relationship)	79 (64%)	29 (72.5%)
Offspring (number ± SD)	0.9±1.2	1.25±1.0
Offspring (Yes)	56 (45%)	26 (65%)
ICD	17 (14%)	6 (15%)
Low complexity	26 (21%)	16 (40%)
Moderate complexity	53 (43%)	16 (40%)
Great complexity	45 (36%)	8 (20%)

ICD: Implantable cardiac defibrillator

Symptom Severity by Anatomy

We next sought to identify lesion-specific symptoms by separating patients into seven groups, pooling together patients with lesions believed by ACHD providers to produce similar symptoms. Notably, there were very few differences between the groups in symptoms rated as most troublesome. Among the 39 symptoms, significant differences were found in 6 and a trend towards different symptoms being most troublesome between groups was found for 2 (Table 3). On inspection of the symptoms with significant differences using analysis standardized to the mean overall score in each patient, the symptom “shortness of breath (windedness, trouble breathing) when I do things” scored greater than the mean score for all items in all groups except group 1. “Bluish or dusky colored skin” was rated highly only among patients in group 7. “Passing out or fainting” scored less than the mean score for all items in all groups, although to varying degrees. “Having to go to the hospital or emergency room” scored greater than the mean in groups 3 and 4. “Concerns with sexual function” scored greater than the mean in groups 3 and 7. ”Concern about my ability to care for my children” scored greater than the mean in groups 1 and 4. Among symptoms for which there was a trend toward difference between groups, “monitoring a blood thinning medication” scored greater than the mean in groups 2 and 6, while “feeling like I am not as attractive/ handsome/ beautiful as other people” scored greater than the mean only in group 7 (Table 4). Symptoms of particular importance in all groups included: trouble sleeping; fatigue; low energy levels; anxiety or stress about my health; depression, sadness, or feelings of helplessness or hopelessness; and cost of medical care including medications or tests.

Table 3.

Differences in survey responses by diagnostic group

Symptom	Group 1 (N=14)	Group 2 (N=24)	Group 3 (N=16)	Group 4 (N=16)	Group 5 (N=43)	Group 6 (N=7)	Group 7 (N=4)	P-value
Shortness of breath (windedness, trouble breathing) when I do things	5.64 ± 4.60	9.79 ± 6.67	10.63 ± 5.37	8.81 ± 4.40	8.19 ± 4.70	12.29 ± 2.87	13.33 ± 8.33	0.038
Shortness of breath (windedness, trouble breathing) when lying in bed	3.43 ± 4.48	5.63 ± 5.85	3.13 ± 2.80	4.50 ± 4.34	3.14 ± 3.42	5.43 ± 6.58	4.67 ± 4.04	0.34
Trouble sleeping	7.92 ± 7.64	11.78 ± 8.82	11.06 ± 7.19	7.25 ± 3.70	11.40 ± 7.00	5.33 ± 3.83	14.50 ± 7.78	0.12
Swelling of the legs or abdomen	1.86 ± 1.29	5.21 ± 6.98	7.19 ± 6.13	3.56 ± 4.41	5.40 ± 5.98	6.29 ± 8.16	5.33 ± 4.04	0.26
Fatigue	8.57 ± 7.47	10.04 ± 6.13	12.94 ± 6.38	9.13 ± 6.14	10.16 ± 6.16	11.71 ± 9.30	14.33 ± 9.24	0.48
Sleepiness	7.50 ± 5.85	9.26 ± 7.38	10.44 ± 5.24	8.38 ± 5.57	8.63 ± 6.38	7.57 ± 2.99	7.33 ± 2.89	0.87
Low energy levels	8.57 ± 6.95	9.33 ± 5.73	12.06 ± 7.43	10.75 ± 6.78	8.77 ± 5.57	11.29 ± 9.52	13.67 ± 4.04	0.48
Abdominal pain or stomach upset	4.77 ± 6.37	3.63 ± 3.03	5.88 ± 6.51	3.44 ± 3.27	5.10 ± 4.87	6.86 ± 6.87	7.00 ± 7.94	0.53
Chest pain or chest discomfort	5.83 ± 5.84	5.75 ± 5.78	7.50 ± 6.52	6.93 ± 4.95	4.79 ± 4.58	6.57 ± 6.37	6.33 ± 5.51	0.70
Leg pain	4.50 ± 5.98	4.42 ± 5.07	3.94 ± 3.86	2.50 ± 2.34	3.57 ± 4.24	2.57 ± 4.16	4.67 ± 4.04	0.81
Chronic pain (anywhere else in the body)	7.14 ± 7.77	6.26 ± 6.73	6.88 ± 8.37	5.25 ± 4.91	6.09 ± 6.18	3.71 ± 4.15	3.67 ± 4.62	0.90
Blueish or dusky colored skin	1.57 ± 1.50	2.04 ± 2.37	7.44 ± 7.27	1.69 ± 1.85	1.65 ± 1.31	3.00 ± 4.12	12.33 ± 3.51	<.001
Fast, hard or otherwise abnormal heartrate or palpitations	7.69 ± 6.82	9.75 ± 7.79	9.81 ± 6.42	9.94 ± 5.97	7.88 ± 6.30	6.00 ± 2.24	7.33 ± 2.89	0.67
Dizziness or lightheadedness	5.85 ± 4.67	5.17 ± 3.68	6.50 ± 5.73	6.56 ± 3.69	4.93 ± 3.48	6.29 ± 6.55	7.33 ± 2.89	0.73
Passing out or fainting	2.00 ± 2.04	1.38 ± 1.01	1.94 ± 2.49	4.06 ± 2.95	1.60 ± 1.90	1.57 ± 1.13	3.33 ± 4.04	0.003
Easy bleeding or bruising	4.64 ± 6.72	6.54 ± 5.82	10.25 ± 5.31	4.69 ± 5.10	5.91 ± 5.76	5.29 ± 4.64	7.00 ± 5.57	0.11
Headaches	7.93 ± 6.11	5.58 ± 4.69	8.19 ± 4.46	7.80 ± 5.28	6.60 ± 4.71	5.14 ± 5.11	8.00 ± 6.93	0.55
Having to go to the hospital or emergency room	2.29 ± 1.73	3.48 ± 3.00	7.81 ± 4.45	8.13 ± 4.97	3.65 ± 3.66	4.86 ± 2.48	5.33 ± 4.04	<.001
Concern about needing an operation/another operation	8.21 ± 6.25	5.79 ± 5.13	8.33 ± 6.91	8.88 ± 5.44	7.76 ± 5.47	9.43 ± 5.35	6.33 ± 5.51	0.61
Side effects from my medications	5.86 ± 5.71	4.92 ± 5.08	6.38 ± 5.91	6.00 ± 5.42	6.05 ± 6.53	4.86 ± 7.15	7.00 ± 1.41	0.98
Monitoring a blood-thinner medication	1.50 ± 1.87	6.67 ± 7.76	4.38 ± 4.19	3.69 ± 6.41	3.05 ± 5.60	7.14 ± 9.10	9.00 ± 13.86	0.09
Difficulty fulfilling my duties at work	4.17 ± 5.98	5.10 ± 6.12	6.75 ± 7.31	6.88 ± 7.92	4.88 ± 5.21	2.43 ± 2.44	8.33 ± 6.35	0.56
Difficulty fulfilling my social commitments or spending time with family and friends	5.29 ± 6.09	4.68 ± 3.73	6.56 ± 5.49	7.00 ± 5.03	4.91 ± 4.54	6.29 ± 4.92	10.00 ± 1.73	0.38
Difficulty doing leisure activities	5.54 ± 5.99	5.45 ± 4.34	5.86 ± 5.32	5.50 ± 5.19	5.31 ± 4.80	6.00 ± 4.65	8.00 ± 5.66	0.99
Inability to exercise	5.43 ± 5.68	7.96 ± 6.25	8.00 ± 6.82	9.56 ± 7.91	7.21 ± 6.16	12.00 ± 9.97	10.33 ± 5.13	0.39
Concerns with sexual function	3.29 ± 3.63	3.42 ± 4.09	9.56 ± 7.47	7.19 ± 7.77	4.81 ± 5.65	2.33 ± 2.16	16.00 ± 0.00	0.001
Anxiety or stress about my health	10.93 ± 7.38	9.00 ± 6.49	11.50 ± 6.84	10.38 ± 6.42	8.47 ± 6.69	9.57 ± 8.26	10.00 ± 1.73	0.75
Defibrillator or ICD firing	1.00 ± 0.00	1.75 ± 3.10	1.87 ± 2.39	1.00 ± 0.00	1.28 ± 1.36	2.67 ± 2.58	1.00 ± 0.00	0.47
Depression, sadness, or feelings of helplessness or hopelessness	8.43 ± 8.30	7.29 ± 6.20	8.25 ± 6.29	8.81 ± 6.26	5.90 ± 5.73	7.86 ± 8.25	11.33 ± 4.04	0.57
Uncertainty about the future	8.29 ± 7.64	8.33 ± 6.95	11.75 ± 7.63	9.50 ± 4.90	7.51 ± 6.78	7.71 ± 7.85	7.00 ± 7.94	0.55
Scars on my body	4.79 ± 4.35	4.04 ± 4.66	5.93 ± 6.93	5.94 ± 6.52	4.70 ± 5.92	6.57 ± 6.85	1.67 ± 1.15	0.79
Stigma associated with having a chronic health problem	5.64 ± 5.43	5.13 ± 6.44	7.69 ± 8.24	3.88 ± 3.07	4.67 ± 6.12	4.71 ± 4.23	11.33 ± 5.03	0.33
Feeling like I am not as attractive/handsome/beautiful as people without my health problems	6.07 ± 7.74	5.14 ± 5.38	7.36 ± 7.32	7.38 ± 7.99	4.60 ± 6.02	4.14 ± 5.40	16.67 ± 8.02	0.07
Cost of medical care including medications or tests	11.50 ± 10.13	8.30 ± 8.04	11.38 ± 6.97	10.44 ± 8.88	8.05 ± 6.50	7.17 ± 6.71	14.67 ± 6.11	0.42
Concern about my children having health problems like mine	6.43 ± 7.21	6.65 ± 8.40	5.53 ± 7.03	6.00 ± 6.85	4.71 ± 5.83	3.00 ± 3.00	1.00 ± 0.00	0.69
Concern about my ability to have children	2.86 ± 4.13	4.22 ± 6.20	6.93 ± 8.27	5.27 ± 7.23	3.16 ± 5.01	2.86 ± 2.41	1.00 ± 0.00	0.36
Concern about my ability to care for my children	5.21 ± 7.66	3.70 ± 4.84	6.67 ± 8.01	9.25 ± 7.45	3.79 ± 4.65	2.14 ± 3.02	1.00 ± 0.00	0.026
Feeling mentally slower than other people	4.43 ± 5.49	4.17 ± 5.01	8.19 ± 7.92	5.63 ± 5.76	4.40 ± 5.85	6.57 ± 6.21	9.00 ± 3.00	0.29
Feeling I am different than other people	7.57 ± 6.74	7.13 ± 8.25	9.69 ± 8.25	7.44 ± 4.90	6.53 ± 7.75	3.86 ± 4.06	11.33 ± 5.03	0.59

p-values reflect differences when comparing the average multiplied impact and frequency score within each group to the other groups. The numbers indicated are the average score ± SD in each group. Symptoms shaded blue are significantly different between groups. Symptoms shaded green have a trend toward significance. A trend toward significance was defined as a p-value of between 0.05 and 0.1.

Table 4.

Standardized differences in survey responses by diagnostic group

Symptom	Group 1 (N=14)	Group 2 (N=24)	Group 3 (N=16)	Group 4 (N=16)	Group 5 (N=43)	Group 6 (N=7)	Group 7 (N=4)	p-value
Shortness of breath (windedness, trouble breathing) when I do things	−0.13 ± 0.42	0.70 ± 0.92	0.53 ± 0.83	0.45 ± 0.71	0.61 ± 0.75	1.34 ± 0.66	1.06 ± 1.34	0.003
Shortness of breath (windedness, trouble breathing) when lying in bed	−0.50 ± 0.53	−0.11 ± 0.81	−0.81 ± 0.23	−0.48 ± 0.48	−0.52 ± 0.61	−0.19 ± 0.58	−0.61 ± 0.32	0.019
Trouble sleeping	0.46 ± 1.23	0.99 ± 1.42	0.60 ± 1.05	0.29 ± 0.88	1.25 ± 1.31	0.28 ± 1.04	0.88 ± 0.71	0.09
Swelling of the legs or abdomen	−0.69 ± 0.31	−0.12 ± 1.30	0.01 ± 1.16	−0.49 ± 0.85	−0.11 ± 0.99	0.20 ± 1.58	−0.35 ± 0.76	0.38
Fatigue	0.40 ± 0.75	0.79 ± 0.89	0.93 ± 0.75	0.49 ± 0.99	0.93 ± 0.76	0.94 ± 1.12	1.01 ± 0.97	0.33
Sleepiness	0.28 ± 0.67	0.49 ± 1.13	0.46 ± 0.59	0.30 ± 0.80	0.61 ± 0.89	0.35 ± 0.55	−0.05 ± 0.50	0.73
Low energy levels	0.52 ± 0.78	0.70 ± 0.97	0.75 ± 0.93	0.80 ± 0.93	0.68 ± 0.81	0.86 ± 1.16	1.13 ± 0.96	0.94
Abdominal pain or stomach upset	−0.30 ± 0.79	−0.35 ± 0.64	−0.30 ± 1.01	−0.56 ± 0.60	−0.10 ± 0.84	0.17 ± 1.32	−0.26 ± 0.91	0.44
Chest pain or chest discomfort	−0.15 ± 0.57	−0.12 ± 0.61	−0.08 ± 0.87	0.21 ± 1.33	−0.18 ± 0.66	0.05 ± 0.58	−0.30 ± 0.54	0.78
Leg pain	−0.34 ± 0.74	−0.27 ± 0.82	−0.61 ± 0.59	−0.72 ± 0.59	−0.40 ± 0.70	−0.74 ± 0.34	−0.61 ± 0.32	0.32
Chronic pain (anywhere else in the body)	0.35 ± 1.28	−0.11 ± 1.03	−0.22 ± 1.35	−0.09 ± 1.12	0.09 ± 1.08	−0.43 ± 0.62	−0.85 ± 0.59	0.52
Blueish or dusky colored skin	−0.77 ± 0.38	−0.71 ± 0.44	−0.04 ± 0.83	−0.97 ± 0.46	−0.80 ± 0.38	−0.67 ± 0.38	0.73 ± 0.67	<.001
Fast, hard or otherwise abnormal heartrate or palpitations	0.47 ± 1.18	0.61 ± 1.05	0.38 ± 0.88	0.62 ± 0.80	0.43 ± 0.89	0.10 ± 0.60	−0.19 ± 0.54	0.70
Dizziness or lightheadedness	0.09 ± 0.96	−0.10 ± 0.66	−0.18 ± 0.91	0.08 ± 0.74	−0.04 ± 0.68	0.07 ± 0.73	−0.05 ± 0.50	0.95
Passing out or fainting	−0.69 ± 0.39	−0.82 ± 0.33	−0.98 ± 0.49	−0.43 ± 0.76	−0.82 ± 0.43	−0.76 ± 0.36	−0.68 ± 0.87	0.06
Easy bleeding or bruising	−0.29 ± 1.03	0.18 ± 1.07	0.60 ± 1.05	−0.28 ± 0.80	0.05 ± 1.00	−0.06 ± 0.98	−0.14 ± 0.64	0.19
Headaches	0.88 ± 1.52	0.01 ± 0.79	0.14 ± 0.92	0.19 ± 0.87	0.24 ± 0.83	−0.19 ± 0.45	−0.11 ± 0.79	0.13
Having to go to the hospital or emergency room	−0.48 ± 0.79	−0.40 ± 0.51	0.06 ± 0.69	0.28 ± 0.76	−0.37 ± 0.62	−0.10 ± 0.52	−0.35 ± 0.76	0.008
Concern about needing an operation/another operation	0.76 ± 1.37	−0.00 ± 0.78	0.00 ± 0.92	0.44 ± 0.88	0.41 ± 0.79	0.72 ± 1.03	−0.30 ± 0.54	0.08
Side effects from my medications	0.09 ± 1.13	−0.11 ± 0.89	−0.13 ± 0.83	−0.15 ± 0.92	0.06 ± 0.89	−0.23 ± 0.99	0.09 ± 0.26	0.94
Monitoring a blood-thinner medication	−0.74 ± 0.40	0.23 ± 1.34	−0.52 ± 0.86	−0.56 ± 0.93	−0.50 ± 1.06	0.22 ± 1.49	0.01 ± 2.50	0.06
Difficulty fulfilling my duties at work	−0.24 ± 0.83	−0.27 ± 0.69	−0.14 ± 0.89	−0.15 ± 1.11	−0.19 ± 0.67	−0.62 ± 0.61	0.19 ± 1.06	0.82
Difficulty fulfilling my social commitments or spending time with family and friends	−0.21 ± 0.62	−0.23 ± 0.48	−0.09 ± 0.79	0.11 ± 0.77	−0.17 ± 0.66	−0.08 ± 0.50	0.46 ± 0.75	0.49
Difficulty doing leisure activities	−0.08 ± 0.82	−0.14 ± 0.62	−0.25 ± 0.54	−0.29 ± 0.67	−0.12 ± 0.59	0.01 ± 0.77	0.42 ± 1.17	0.78
Inability to exercise	−0.10 ± 0.61	0.51 ± 1.32	0.08 ± 0.87	0.44 ± 0.83	0.30 ± 1.14	1.03 ± 1.55	0.40 ± 0.45	0.34
Concerns with sexual function	−0.37 ± 0.77	−0.50 ± 0.45	0.29 ± 0.96	−0.10 ± 0.88	−0.13 ± 1.23	−0.53 ± 0.52	1.13 ± 0.49	0.07
Anxiety or stress about my health	1.19 ± 0.75	0.52 ± 0.77	0.66 ± 0.81	0.72 ± 1.02	0.46 ± 0.90	0.69 ± 1.36	0.46 ± 0.75	0.26
Defibrillator or ICD firing	−0.83 ± 0.36	−0.78 ± 0.43	−0.96 ± 0.78	−1.05 ± 0.36	−0.84 ± 0.35	−0.31 ± 0.70	−1.25 ± 0.32	0.032
Depression, sadness, or feelings of helplessness or hopelessness	0.32 ± 0.84	0.26 ± 1.06	0.09 ± 0.70	0.43 ± 0.88	0.04 ± 0.75	0.32 ± 1.31	0.56 ± 0.21	0.71
Uncertainty about the future	0.37 ± 0.87	0.35 ± 0.83	0.68 ± 1.22	0.62 ± 1.01	0.24 ± 0.87	0.26 ± 1.18	−0.22 ± 1.52	0.57
Scars on my body	−0.03 ± 0.95	−0.36 ± 0.66	−0.38 ± 0.89	−0.22 ± 0.95	−0.22 ± 1.00	−0.05 ± 0.72	−1.15 ± 0.27	0.55
Stigma associated with having a chronic health problem	−0.13 ± 0.50	−0.23 ± 0.76	−0.17 ± 1.15	−0.48 ± 0.61	−0.25 ± 0.89	−0.26 ± 0.79	0.49 ± 0.88	0.68
Feeling like I am not as attractive/handsome/beautiful as people without my health problems	−0.09 ± 0.92	−0.11 ± 0.80	−0.28 ± 0.93	−0.04 ± 1.09	−0.26 ± 0.94	−0.40 ± 0.83	1.37 ± 0.81	0.15
Cost of medical care including medications or tests	1.18 ± 1.44	0.42 ± 1.33	0.63 ± 0.93	0.62 ± 1.25	0.58 ± 1.26	0.31 ± 1.20	1.04 ± 0.67	0.65
Concern about my children having health problems like mine	0.23 ± 1.15	−0.01 ± 1.17	−0.46 ± 0.80	−0.12 ± 1.18	−0.19 ± 0.86	−0.61 ± 0.65	−1.25 ± 0.32	0.17
Concern about my ability to have children	−0.54 ± 0.66	−0.30 ± 1.08	−0.25 ± 1.17	−0.29 ± 1.33	−0.46 ± 0.93	−0.65 ± 0.44	−1.25 ± 0.32	0.72
Concern about my ability to care for my children	0.04 ± 1.23	−0.45 ± 0.66	−0.32 ± 0.98	0.41 ± 0.97	−0.29 ± 0.81	−0.76 ± 0.60	−1.25 ± 0.32	0.008
Feeling mentally slower than other people	−0.30 ± 0.75	−0.35 ± 0.65	−0.10 ± 1.02	−0.20 ± 1.04	−0.31 ± 0.83	0.11 ± 1.15	0.12 ± 0.30	0.81
Feeling I am different than other people	0.29 ± 0.84	0.19 ± 1.28	0.17 ± 0.99	0.11 ± 0.98	0.09 ± 1.09	−0.44 ± 0.60	0.49 ± 0.88	0.82

p-values reflect differences between groups in the average standardized multiplied impact and frequency score. The numbers indicated are the average score ± SD in each group. Standardization was performed by averaging the multiplied impact and frequency score for the total questionnaire and subtracting it from the multiplied impact and frequency score for each symptom. Symptoms shaded blue are those which were significantly different in table 3. Symptoms shaded green are those which had a trend toward significance in table 3.

Beyond the 39 symptoms proposed by physicians, there were eleven symptoms identified by 9 participants which were not listed on the survey (Table 5). None of these were mentioned by more than one participant.

Table 5.

Patient reported symptoms not on the survey

Patient-identified symptoms not present in the survey
1) Left rib pain and back pain 2) Coumadin and pregnancy conflict 3) Residual limitations from a prior stroke 4) Defibrillator site pain 5) Memory issues 6) Voice problems 7) Financial concerns/capacity to work 8) Wonder and worry about future care/insurance/health 9) Family resentment due to illness 10) Non-supportive friends 11) Dismissed and misdiagnosed

Symptom Severity by ACHD Complexity

Patients with lesions of great complexity reported a greater impact of symptoms related to heart disease (Table 6). This difference was attributable to significantly higher impact scores for the symptoms “bluish or dusky colored skin” (p=0.001), “having to go to the hospital or emergency room” (p<0.001), “concerns with sexual function” (p=0.018), “feeling mentally slower than other people” (p=0.001), and “feeling I am different than other people” (p=0.027). The only symptom for which there was a significant difference between patients with low and moderate complexity was “uncertainty about the future” (p=0.028).

Table 6.

Differences in survey responses by level of disease complexity

Symptom	p-value for differences between the three levels of complexity
Shortness of breath (windedness, trouble breathing) when I do things	0.161
Shortness of breath (windedness, trouble breathing) when lying in bed	0.317
Trouble sleeping	0.873
Swelling of the legs or abdomen	0.149
Fatigue	0.62
Sleepiness	0.384
Low energy levels	0.232
Abdominal pain or stomach upset	0.972
Chest pain or chest discomfort	0.115
Leg pain	0.794
Chronic pain (anywhere else in the body)	0.356
Blueish or dusky colored skin	0.001
Fast, hard or otherwise abnormal heartrate or palpitations	0.19
Dizziness or lightheadedness	0.077
Passing out or fainting	0.216
Easy bleeding or bruising	0.234
Headaches	0.388
Having to go to the hospital or emergency room	<0.001
Concern about needing an operation/another operation	0.66
Side effects from my medications	0.889
Monitoring a blood-thinner medication	0.485
Difficulty fulfilling my duties at work	0.829
Difficulty fulfilling my social commitments or spending time with family and friends	0.058
Difficulty doing leisure activities	0.543
Inability to exercise	0.138
Concerns with sexual function	0.018
Anxiety or stress about my health	0.495
Defibrillator or ICD firing	0.76
Depression, sadness, or feelings of helplessness or hopelessness	0.281
Uncertainty about the future	0.028
Scars on my body	0.338
Stigma associated with having a chronic health problem	0.761
Feeling like I am not as attractive/handsome/beautiful as people without my health problems	0.102
Cost of medical care including medications or tests	0.797
Concern about my children having health problems like mine	0.193
Concern about my ability to have children	0.291
Concern about my ability to care for my children	0.071
Feeling mentally slower than other people	0.001
Feeling I am different than other people	0.027

p-values reflect differences in symptom impact between patients with differing degrees of lesion complexity.

Confirmatory Analyses

To confirm the relative importance of the symptoms identified in the study cohort and the frequency with which they occurred, an independent confirmatory sample of 40 ACHD patients was recruited from MGH. Demographic characteristics of this confirmatory cohort are found in Table 2. When compared to the initial patient group, the confirmatory cohort were significantly less symptomatic, with an average score across all symptoms of 3.9±1.8, as compared with 6.2±2.2 in the initial group and higher scores for all of the 39 symptoms were observed (Table 7). To compare symptoms of particular importance between the two groups, we analyzed the standardized composite score. The confirmatory cohort largely confirmed the relative importance of the symptoms identified as of significance in the test cohort as shown in Figure 2. We found that the confirmatory cohort differed from the test cohort in only 5 of 39 total symptoms. Among these, “Sleepiness” and “Headaches”, which had been identified as important symptoms in the initial cohort were found to be of greater importance in the confirmatory cohort. The symptom “defibrillator or ICD firing” was found to be of below average importance in both the test and confirmatory cohorts. The symptom “concern about my children having health problems like mine” was of greater importance in the confirmatory cohort than the test cohort. The symptom “feeling I am different than other people” was found to be of greater importance in the initial cohort, than in the confirmatory cohort.

Table 7.

Differences in survey responses between the study and confirmatory cohorts

Symptom	Test Cohort (N=124)	Confirmatory Cohort (N=40)	p-value
Shortness of breath (windedness, trouble breathing) when I do things	8.97 ± 5.36	5.94 ± 4.67	0.003
Shortness of breath (windedness, trouble breathing) when lying in bed	4.00 ± 4.40	2.91 ± 3.93	0.19
Trouble sleeping	10.24 ± 7.19	7.42 ± 4.82	0.036
Swelling of the legs or abdomen	5.00 ± 5.87	1.97 ± 2.16	0.005
Fatigue	10.37 ± 6.58	7.89 ± 5.89	0.043
Sleepiness	8.73 ± 6.03	7.60 ± 5.68	0.32
Low energy levels	9.80 ± 6.41	7.69 ± 6.42	0.08
Abdominal pain or stomach upset	4.80 ± 5.00	3.94 ± 3.71	0.35
Chest pain or chest discomfort	5.85 ± 5.37	3.52 ± 3.30	0.019
Leg pain	3.72 ± 4.35	2.06 ± 1.84	0.040
Chronic pain (anywhere else in the body)	6.04 ± 6.45	4.48 ± 5.27	0.22
Blueish or dusky colored skin	2.81 ± 3.98	1.88 ± 1.96	0.19
Fast, hard or otherwise abnormal heartrate or palpitations	8.63 ± 6.42	4.74 ± 4.20	0.001
Dizziness or lightheadedness	5.64 ± 4.19	3.53 ± 2.93	0.007
Passing out or fainting	2.01 ± 2.19	1.45 ± 1.28	0.17
Easy bleeding or bruising	6.28 ± 5.80	4.33 ± 4.15	0.07
Headaches	6.86 ± 4.97	5.75 ± 3.97	0.22
Having to go to the hospital or emergency room	4.68 ± 4.09	3.15 ± 3.19	0.046
Concern about needing an operation/another operation	7.70 ± 5.65	4.89 ± 5.40	0.009
Side effects from my medications	5.78 ± 5.82	2.71 ± 2.80	0.003
Monitoring a blood-thinner medication	4.22 ± 6.37	2.47 ± 3.33	0.13
Difficulty fulfilling my duties at work	5.32 ± 6.09	3.86 ± 5.50	0.21
Difficulty fulfilling my social commitments or spending time with family and friends	5.61 ± 4.81	2.86 ± 3.07	0.002
Difficulty doing leisure activities	5.54 ± 4.87	2.48 ± 2.09	<.001
Inability to exercise	7.91 ± 6.71	4.66 ± 6.29	0.011
Concerns with sexual function	5.37 ± 6.09	2.86 ± 3.73	0.022
Anxiety or stress about my health	9.60 ± 6.68	6.32 ± 5.62	0.007
Defibrillator or ICD firing	1.45 ± 1.93	1.13 ± 0.71	0.35
Depression, sadness, or feelings of helplessness or hopelessness	7.41 ± 6.40	3.94 ± 4.27	0.004
Uncertainty about the future	8.57 ± 6.87	5.19 ± 5.78	0.012
Scars on my body	4.93 ± 5.69	3.09 ± 3.58	0.08
Stigma associated with having a chronic health problem	5.33 ± 6.06	2.82 ± 3.55	0.023
Feeling like I am not as attractive/handsome/beautiful as people without my health problems	5.85 ± 6.76	2.77 ± 2.57	0.009
Cost of medical care including medications or tests	9.38 ± 7.70	4.49 ± 5.68	<.001
Concern about my children having health problems like mine	5.37 ± 6.64	4.54 ± 5.27	0.50
Concern about my ability to have children	4.00 ± 5.86	2.17 ± 3.36	0.08
Concern about my ability to care for my children	4.89 ± 6.17	3.03 ± 3.42	0.09
Feeling mentally slower than other people	5.25 ± 5.98	3.85 ± 4.80	0.21
Feeling I am different than other people	7.26 ± 7.28	3.03 ± 3.55	0.001

p-values reflect differences when comparing the average multiplied impact and frequency score between the test and confirmatory cohorts. The numbers indicated are the average score ± SD in each group.

Figure 2.

Graphical representation of the standardized multiplied impact and frequency scores from the test (blue bars) and confirmatory (red bars) cohorts. Standardization was performed by averaging the multiplied impact and frequency score for the total questionnaire and subtracting it from the multiplied impact and frequency score for each symptom. Statistically significant differences are indicated by asterisks. Numbers correspond with the symptoms in the same order in which they are found in Table 6.

Discussion

A critical goal in optimizing care for the growing population of ACHD patients is to be able to quantify and monitor the symptoms among patients with disease. Prior to developing a formal PRO, however, it is critically important to elicit the most important symptoms to assess. In the present study we identified a group of symptoms of particular importance to patients with ACHD and examined how the frequency and importance of these symptoms varied across the spectrum of ACHD. Unexpectedly, the symptoms of greatest significance to ACHD patients are largely similar and independent of underlying cardiac diagnosis. To the best of our knowledge, the present study is the first to objectively investigate the patient reported importance of ACHD related symptoms. This study suggests that a single PRO might be feasible for evaluation of ACHD as a composite group.

Lesion specific differences in symptoms are few

Among the differences we found between patients with differing underlying cardiac anatomy, the symptom “shortness of breath (windedness, trouble breathing) when I do things” was rated highly by all patients, except those with left ventricular outflow tract (LVOT) obstructions (group 1). This finding is unexpected given that a classic symptom of LVOT stenosis is dyspnea with activity. The fact that members in group 1 of the test cohort did not rate this symptom highly may indicate that a great proportion of the patients had been adequately repaired with no residual obstruction. The present study was not designed to investigate this further as clinical and diagnostic data were not obtained.

“Having to go to the hospital or emergency room”, was of particular concern in patients with single ventricle and transposition of the great vessels (TGA). Given that these have been demonstrated to be the most common lesions found among ACHD patients who experienced an emergency admission, this finding is not surprising⁵. Nevertheless, while of greater concern for only certain groups of ACHD patients, hospitalization is an important event for patients and would be reasonable to include in a PRO.

“Concerns with sexual function” was rated as important, specifically by patients with either single ventricle or Eisenmenger’s syndrome. The reasons underlying this may be complex, potentially involving both self-image and physical capacity. There is conflicting data in the literature as to whether ACHD patients experience decreased sexual function compared to the general population, however women with complex lesions or cyanosis have been shown to have particularly impaired function^6,7,8. As our study population was predominantly female, this may explain why this emerged as such an important symptom.

“Concern about my ability to care for my children” was rated differently between groups, and was most highly rated among those with LVOT obstruction and TGA. The reasons for observed differences may be due to both the prevalence of offspring in each group and lesion-specific perception of future health risk. It would be interesting to perform an analysis of the importance of this symptom among those who do versus those who do not have offspring, but this was beyond the scope of the present study. We would hypothesize that concern over ability to care for children is directly related to the concepts “uncertainty about the future” and “anxiety or stress about my health”, both of which were found to be significant for all groups, among patients with children.

“Bluish or dusky colored skin” and “feeling like I am not as attractive/ handsome/ beautiful as other people” were relevant only in the relatively small group of Eisenmenger syndrome patients, likely due to the physically apparent manifestations of the disease. We will therefore consider employing these as symptoms to be assessed specifically when evaluating patients in this group.

The trend toward increased importance of “monitoring a blood thinning medication” among patients with shunt lesions or truncus arteriosus is interesting and unexpected. This finding may reflect a disproportionately high burden of atrial arrhythmias in the sample of shunt patients in the case of the former, and a high prevalence of mechanical valves among the latter. We did not collect the data that would be required to confirm these speculations as a part of the present study.

Disease complexity is associated with overall symptom burden

We found, not surprisingly, that overall symptom burden is greater among patients with disease of great complexity as compared to those with less complex ACHD^9,10. Some of the specific symptoms responsible for this difference are intuitive. For example, given that patients with cyanotic heart disease and Eisenmenger’s syndrome are categorized as having disease of great complexity, it is logical that “blueish or dusky colored skin” would be of particular concern for the group of ACHD patients with complex anatomy. In addition, patients with complex disease are known to be at greater risk for hospitalization compared to those with anatomy of low or moderate complexity, which might explain why “having to go to the hospital or emergency room” was of particular concern in this group^5,11. The other differences detected between patients with anatomy of varying complexity are for symptoms that may be related to self-image, physical capacity, perceived health status or overall psychological state and will need to be explored in future research.

Differences between the study and confirmatory cohort

The patients in the confirmatory cohort were overall less symptomatic than those in the test cohort across all symptoms queried. The reasons for this are not clear. Although the test cohort included a greater percentage of patients with lesions of great complexity, we demonstrated in the test cohort that the overall increased symptom burden associated with disease complexity was attributable to a narrow group of symptoms, whereas the observed symptom burden is significantly lower for 22 of 39 symptoms in the confirmatory cohort. This might reflect differences in participant’s clinical experiences at MGH, however is most likely to be due to the fact that the politically active patients at the ACHA were more likely to be forthcoming in reporting symptoms and more comfortable with self advocacy. Nevertheless, when standardized to average score, there were few differences in survey responses between the study and confirmatory cohorts, confirming the relative importance of the symptoms identified in the test cohort.

Among the 5 symptoms found to be significantly different between the two groups after standardization, we found “Sleepiness” and “Headaches” to score greater than the mean in both the study and confirmatory cohorts although to differing degrees, and “defibrillator or ICD firing” to be of less than the mean importance in both groups, also to differing degrees.

We found the symptom “feeling I am different than other people” to be of greater significance in the study cohort than in the confirmatory cohort. This symptom is psychologically complex and may reflect early life experience, external evidence of disease including operative scars or variability in physical appearance related to genetic syndromes, as well as overall current psychological state. One possible explanation for the observed difference between groups might be the greater number of patients with complex disease including cyanotic disease in the study cohort versus the confirmatory cohort. Nevertheless, given the psychological complexity associated with self-image, we cannot draw definitive conclusions.

The symptom “concern about my children having health problems like mine” was likely of greater importance to the confirmatory cohort because they were more likely to have children, although other variables may also have been responsible.

Limitations

There are several potential limitations that should be considered in interpreting our findings. First, the majority of survey respondents were attendees of the ACHA meeting, which would be anticipated to yield a more informed and potentially more affluent patient group than the general ACHD population. Furthermore, only interested patients agreed to complete the survey. The impact of these factors on reported symptoms is difficult to quantify. Nevertheless, the similarity of the responses in the clinic cohort at MGH is reassuring. Another potential concern is that although ACHD has a slight male preponderance, the majority of participants in the present study were female. This may suggest a biased sample. Finally, patients were categorized into groups based on underlying anatomy and repair. Although the anatomical diagnosis of participants recruited from WU and MGH were confirmed, those of participants at the ACHA meeting were based upon self-report, and were therefore potentially incorrect or incomplete. The data presented here is exploratory, hypothesis-generating and is largely descriptive in nature. This study is not intended to suggest that the survey employed is adequate to track patient reported outcomes.

Conclusions

The present study investigated, for the first time, the patient-reported disease-related symptoms of greatest importance to ACHD patients. Patients generally experience similar symptoms regardless of underlying anatomy. Based on these findings, we believe that a single PRO can be developed for patients with ACHD. In future work, we will employ focus groups and cognitive debriefing exercises with the goal of reducing the number of items and developing a PRO with good content validity.

What is Known.

• -Adult congenital heart disease is growing in prevalence.
• -No systematic investigation of disease specific symptoms of disease activity has been carried out in this population.

What the Study Adds.

• -This study provides systematic investigation of symptoms of greatest importance to adult congenital heart disease patients.
• -It also provides a solid foundation on which to begin construction of a patient reported outcome tool.