Abstract
BACKGROUND:
Differences in comorbid conditions in patients with heart failure compared with population controls, and whether differences exist by type of heart failure or age, have not been well documented.
METHODS:
The prevalence of 17 chronic conditions were obtained in 2643 patients with incident heart failure from 2000 to 2013 and controls matched 1:1 on sex and age from Olmsted County, Minnesota. Logistic regression determined associations of each condition with heart failure.
RESULTS:
Among 2643 matched pairs (mean age 76.2 years, 45.6% men), the comorbidities with the largest attributable risk of heart failure were arrhythmia (48.7%), hypertension (28.4%), and coronary artery disease (33.9%); together these explained 73.0% of heart failure. Similar associations were observed for patients with reduced and preserved ejection fraction, with the exception of hypertension. The risk of heart failure attributable to hypertension was 2-fold higher in patients with heart failure with preserved ejection fraction (38.7%) than in patients with heart failure with reduced ejection fraction (17.8%). Hypertension, coronary artery disease, arrhythmia, and diabetes were more strongly associated with heart failure in younger (≤75 years) compared to older (>75 years) persons.
CONCLUSIONS:
Patients with heart failure have a higher prevalence of many chronic conditions than controls. Similar associations were observed in patients with reduced and preserved ejection fraction, with the exception of hypertension, which was more strongly associated with heart failure with preserved ejection fraction. Finally, some cardiometabolic risk factors were more strongly associated with heart failure in younger persons, highlighting the importance of optimizing prevention and treatment of risk factors and, in particular, cardiometabolic risk factors.
Keywords: Case-control study, Heart failure, Risk factors
INTRODUCTION
Heart failure is a major public health concern, being a frequent cause of hospitalizations and a significant contributor to health care expenditures in the United States.1–4 Most patients with heart failure are elderly and have multimorbidity,5 and comorbid conditions play a prominent role in heart failure outcomes, with more than half of hospitalizations and deaths in patients with heart failure as a result of noncardiovascular causes.6,7 However, differences in the burden of comorbid conditions in patients with heart failure compared with population controls has not been well documented. In addition, the changing case mix of heart failure over time has resulted in an increasing proportion of patients with heart failure with preserved ejection fraction,7,8 who have, on average, 1 additional comorbid condition than patients with heart failure with reduced ejection fraction.5 Thus, understanding which comorbid conditions are the strongest risk factors for heart failure and whether differences exist by type of heart failure is warranted. Furthermore, patients with heart failure with preserved ejection fraction tend to be older than those with reduced ejection fraction,5 and thus, an understanding of whether age modifies the risk factors for heart failure is needed. We conducted a case-control study in a community in Southeast Minnesota including patients with incident heart failure and matched community controls. The goal was to characterize risk factors for heart failure and to identify differences in risk factors (if any) by heart failure type and by age.
METHODS
Study Population
This study utilized the Rochester Epidemiology Project, a records-linkage system capturing health care provided to residents of Olmsted County, Minnesota.9–12 Olmsted County is relatively isolated from other urban centers and only a few providers deliver the vast majority of health care to local residents. Thus, virtually the entire health care experience of the Olmsted County population is captured. This study was approved by the Mayo Clinic and Olmsted Medical Center Institutional Review Boards.
Incident Heart Failure Cases and Controls
Residents in Olmsted County, Minnesota, with a first-ever International Classification of Diseases-9th Revision, Clinical Modification (ICD-9-CM) code 428 from 2000 to 2013 were identified from inpatient and outpatient encounters from all providers in the Rochester Epidemiology Project. A random sample of 50% of heart failure diagnoses were selected for manual validation from 2000 to 2006, whereas 100% were selected from 2007 to 2013.13,14 The heart failure diagnoses were validated using the Framingham Criteria.15 The entire medical record was reviewed, which on average spanned 4 decades,16 and those with a diagnosis of heart failure prior to the study period (ie, those with prevalent heart failure) were excluded. The closest ejection fraction within 90 days before or after diagnosis was used to categorize patients as having reduced (<50%) or preserved (≥50%) ejection fraction. For each heart failure case, a community control was matched 1:1 on sex, age (within 1 year), and calendar year of diagnosis.
Ascertainment of Comorbidities
For each case-control pair, the case’s date of incident heart failure was used as the index date. Comorbidities were ascertained using a list of comorbidities defined by the US Department of Health and Human Services for studying multimorbidity,17,18 with modifications excluding conditions with very low prevalence and adding anxiety (17 conditions total; Supplemental Table 1). Diagnostic codes were available starting in 1975 and the earliest index date for a case-control pair was 2000. Thus, all diagnostic codes were retrieved within the 25 years prior to index to ensure a consistent lookback period for all cases and controls. We required 2 occurrences of a code (either the same or 2 different codes within the code set for a given condition) separated by more than 30 days and within the 25 years prior to index to confirm the diagnosis. The first code date was used as the index date of the comorbidity.
Statistical Analysis
Analyses were performed using SAS, version 9.4. Chi-square tests were used to compare the prevalence of comorbidities in heart failure cases compared to controls. Conditional logistic regression was used to estimate associations of each comorbidity with heart failure adjusting for all other comorbidities. Attributable risks were calculated using the estimates from the multivariable-adjusted model and the following formula: Attributable risk (AR) = pe [(OR-1)/OR], where pe = proportion of cases with the exposure and OR = multivariable-adjusted odds ratio. Attributable risks were calculated assuming complete elimination of the comorbidities in addition to reductions of 25% and 50% in prevalence of the comorbidity, as well as select combinations of comorbidities. Attributable risks were not calculated for protective factors. All analyses were repeated separately for heart failure with reduced ejection fraction cases and their matched controls and heart failure with preserved ejection fraction cases and their matched controls. For heart failure cases missing information on ejection fraction (n = 528), the value was imputed based on a model that included age, sex, and index year along with all possible interactions, quadratic effects for age and year, and all comorbidities. The analyses were performed on 5 data sets, and the results were combined using Rubin’s rules.19 Finally, interactions of age with each comorbidity were tested and the P values were adjusted for multiple comparisons by controlling for the false discovery rate.20 For comorbidities that reached significance, the odds ratios and attributable risks were calculated separately among those aged ≤75 years and those aged >75 years.
RESULTS
Among 2643 heart failure case-control pairs, 45.6% were men and the mean age was 76.2 years. On average, heart failure cases had 2 additional comorbidities compared to matched controls (Table 1). Of the list of 17 conditions, dementia was the only one that was not more prevalent in heart failure cases than controls. When stratified by type of heart failure, similar prevalence of arthritis, asthma, cancer, schizophrenia, and anxiety were observed in heart failure with reduced ejection fraction cases and controls, whereas a higher prevalence of these conditions was observed in heart failure with preserved ejection fraction cases compared to controls (Supplemental Table 2). Patients with reduced ejection fraction were younger (mean age 72.7 years) and more likely male (58.8%) compared to patients with preserved ejection fraction (mean age 77.5 years; 38.3% men).
Table 1.
Prevalence of Comorbidities in Heart Failure Cases and Controls
| Heart Failure Cases (n = 2643) | Controls (n = 2643) | P Value | |
|---|---|---|---|
| Hypertension | 2183 (82.6) | 1666 (63.0) | <0.001 |
| Coronary artery disease | 1418 (53.7) | 633 (24.0) | <0.001 |
| Arrhythmia | 1913 (72.4) | 1067 (40.4) | <0.001 |
| Hyperlipidemia | 1777 (67.2) | 1574 (59.6) | <0.001 |
| Stroke | 617 (23.3) | 377 (14.3) | <0.001 |
| Arthritis | 1656 (62.7) | 1452 (54.9) | <0.001 |
| Asthma | 347 (13.1) | 206 (7.8) | <0.001 |
| Cancer | 1126 (42.6) | 1033 (39.1) | <0.001 |
| Chronic kidney disease | 819 (31.0) | 291 (11.0) | <0.001 |
| Chronic obstructive pulmonary disease | 1058 (40.0) | 577 (21.8) | <0.001 |
| Dementia | 338 (12.8) | 320 (12.1) | 0.453 |
| Depression | 790 (29.9) | 514 (19.4) | <0.001 |
| Diabetes | 1204 (45.6) | 764 (28.9) | <0.001 |
| Osteoporosis | 572 (21.6) | 503 (19.0) | 0.018 |
| Schizophrenia | 144 (5.4) | 95 (3.6) | 0.001 |
| Substance abuse disorder | 224 (8.5) | 82 (3.1) | <0.001 |
| Anxiety disorder | 462 (17.5) | 335 (12.7) | <0.001 |
| Number of comorbidities | |||
| Mean (SD) | 6.3 (2.7) | 4.3 (2.6) | <0.001 |
| Median (IQR) | 6 (5-8) | 4 (2-6) | <0.001 |
| Number of comorbidities | <0.001 | ||
| 0 | 64 (2.4) | 221 (8.4) | |
| 1 | 61 (2.3) | 194 (7.3) | |
| 2 | 112 (4.2) | 257 (9.7) | |
| 3 | 181 (6.8) | 363 (13.7) | |
| 4 | 231 (8.7) | 378 (14.3) | |
| 5 | 314 (11.9) | 342 (12.9) | |
| 6 | 412 (15.6) | 309 (11.7) | |
| 7 | 384 (14.5) | 261 (9.9) | |
| 8 | 328 (12.4) | 171 (6.5) | |
| 9 | 259 (9.8) | 86 (3.3) | |
| 10 | 150 (5.7) | 36 (1.4) | |
| 11 | 84 (3.2) | 17 (0.6) | |
| ≥12 | 63 (2.4) | 8 (0.3) |
Values are n (%) unless otherwise specified.
IQR = interquartile range; SD = standard deviation.
After adjustment for all other conditions, hyperlipidemia was less common in patients with heart failure, and only hypertension, coronary artery disease, arrhythmia, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, and substance abuse remained significantly more common in patients with heart failure compared to controls (Figure 1). The conditions with the largest attributable risks for heart failure were arrhythmia (48.7%), coronary artery disease (33.9%), and hypertension (28.4%; Figure 1, Table 2). When combined, arrhythmia, coronary artery disease, and hypertension had an attributable risk of 73.0%, meaning that if these conditions can be assumed to be causal, 73% of heart failure would be avoided if all 3 conditions were eliminated from the population (Table 2). A 25% reduction in the prevalence of all 3 conditions corresponds to a 25.1% reduction in heart failure.
Figure 1.
Odds ratios (95% confidence intervals) and attributable risks for heart failure by presence of individual comorbidities after adjustment for all other comorbidities.
Attributable risks were not calculated for protective factors.
AR = attributable risk; CAD = coronary artery disease; CI = confidence interval; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; OR = odds ratio.
Table 2.
Attributable Risk of Heart Failure (%) With Varying Reductions in Comorbidities
| Comorbidity | Reduction in comorbidity (%) |
||
|---|---|---|---|
| 25% | 50% | 100% | |
| Individual Comorbidities | |||
| Hypertension | 7.2 | 14.4 | 28.4 |
| Coronary artery disease | 8.1 | 17.5 | 33.9 |
| Arrhythmia | 12.2 | 24.4 | 48.7 |
| Hyperlipidemia | — | — | — |
| Stroke | 0.4 | 0.8 | 1.5 |
| Arthritis | — | — | — |
| Asthma | 0.3 | 0.5 | 1.0 |
| Cancer | — | — | — |
| Chronic kidney disease | 4.8 | 9.3 | 18.3 |
| Chronic obstructive pulmonary disease | 4.0 | 7.7 | 15.6 |
| Dementia | 0.3 | 0.6 | 1.2 |
| Depression | 1.1 | 2.2 | 4.5 |
| Diabetes | 4.6 | 8.4 | 17.3 |
| Osteoporosis | 0.4 | 0.8 | 1.6 |
| Schizophrenia | — | — | — |
| Substance abuse disorder | 1.0 | 2.2 | 4.1 |
| Anxiety | — | — | — |
| Combinations of Comorbidities | |||
| Hypertension + CAD | 14.7 | 29.2 | 51.7 |
| Hypertension + Arrhythmia | 18.6 | 35.0 | 62.5 |
| CAD + Arrhythmia | 19.4 | 37.1 | 63.8 |
| Hypertension + CAD + Arrhythmia | 25.1 | 45.7 | 73.0 |
| Hypertension + CAD + Arrhythmia + CKD + COPD + Diabetes | 34.2 | 57.2 | 81.9 |
Attributable risks were not calculated for protective factors.
CAD = coronary artery disease; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease.
Arthritis was less common in patients with heart failure with reduced ejection fraction compared to controls (Figure 2A). Compared to controls, hypertension was more common in patients with preserved ejection fraction (odds ratio 1.80, 95% confidence interval [CI] 1.35-2.41) but not in patients with reduced ejection fraction (Figure 2A and B). The conditions with the largest attributable risks for both types of heart failure were arrhythmia (49.1% for reduced and 48.6% for preserved ejection fraction) and coronary artery disease (37.2% for reduced and 31.7% for preserved ejection fraction; Figure 2, Table 3). However, the attributable risk due to hypertension was 2-fold higher for heart failure with preserved (38.7%) than reduced (17.8%) ejection fraction. When combined, arrhythmia, coronary artery disease, and hypertension had an attributable risk of 70.0% for heart failure with reduced ejection fraction and 76.6% for heart failure with preserved ejection fraction (Table 3). When considering a 25% reduction in the prevalence of all 3 conditions, the corresponding attributable risks are 23.5% for reduced and 26.8% for preserved ejection fraction.
Figure 2.
Odds ratios (95% confidence intervals) and attributable risks for heart failure by presence of individual comorbidities after adjustment for all other comorbidities.
(A) Heart failure with reduced ejection fraction; (B) heart failure with preserved ejection fraction.
Attributable risks were not calculated for protective factors.
AR = attributable risk; CAD = coronary artery disease; CI = confidence interval; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; OR, odds ratio.
Table 3.
Attributable Risk of Heart Failure With Reduced and Preserved Ejection Fraction (%) With Varying Reductions in Comorbidities
| Comorbidity | Heart Failure with Reduced Ejection Fraction Reduction in comorbidity (%) |
Heart Failure with Preserved Ejection Fraction Reduction in comorbidity (%) |
||||
|---|---|---|---|---|---|---|
| 25% | 50% | 100% | 25% | 50% | 100% | |
| Individual Comorbidities | ||||||
| Hypertension | 4.5 | 9.1 | 17.8 | 9.9 | 19.6 | 38.7 |
| Coronary artery disease | 8.8 | 19.1 | 37.2 | 7.8 | 16.4 | 31.7 |
| Arrhythmia | 12.1 | 25.3 | 49.1 | 12.4 | 23.8 | 48.6 |
| Hyperlipidemia | — | — | — | — | — | — |
| Stroke | 0.4 | 0.8 | 1.5 | 0.2 | 0.3 | 0.6 |
| Arthritis | — | — | — | 0.2 | 0.3 | 0.6 |
| Asthma | — | — | — | 1.2 | 2.3 | 4.5 |
| Cancer | — | — | — | — | — | — |
| Chronic kidney disease | 4.4 | 8.7 | 16.3 | 5.0 | 9.8 | 19.7 |
| Chronic obstructive pulmonary disease | 3.0 | 5.9 | 12.0 | 4.9 | 9.2 | 18.4 |
| Dementia | 0.5 | 0.9 | 1.7 | 0.2 | 0.4 | 0.8 |
| Depression | 1.1 | 2.1 | 4.2 | 1.1 | 2.1 | 4.5 |
| Diabetes | 4.1 | 8.3 | 17.0 | 5.0 | 8.4 | 17.5 |
| Osteoporosis | — | — | — | 0.8 | 1.6 | 3.4 |
| Schizophrenia | — | — | — | 0.3 | 0.5 | 1.0 |
| Substance abuse disorder | 0.8 | 2.1 | 3.9 | 1.2 | 2.3 | 4.5 |
| Anxiety | — | — | — | 0.1 | 0.2 | 0.4 |
| Combinations of Comorbidities | ||||||
| Hypertension + CAD | 12.9 | 26.2 | 47.4 | 16.6 | 32.6 | 57.3 |
| Hypertension + Arrhythmia | 16.0 | 31.8 | 57.4 | 21.1 | 38.3 | 67.9 |
| CAD + Arrhythmia | 19.9 | 38.8 | 64.7 | 19.2 | 36.0 | 63.3 |
| Hypertension + CAD + Arrhythmia | 23.5 | 43.9 | 70.0 | 26.8 | 48.0 | 76.6 |
| Hypertension + CAD + Arrhythmia + CKD + COPD + Diabetes | 31.7 | 54.3 | 78.4 | 36.6 | 60.2 | 85.4 |
Attributable risks were not calculated for protective factors.
CAD = coronary artery disease; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease.
Significant interactions with age were observed for 4 conditions: hypertension, coronary artery disease, arrhythmia, and diabetes. Each of these 4 conditions were more strongly associated with heart failure in those aged ≤75 years compared to those aged >75 years (Supplemental Table 3). The attributable risks for heart failure were higher for those aged ≤75 years for hypertension, coronary artery disease, and diabetes but were similar across age groups for arrhythmia (Supplemental Table 4). Higher attributable risks for heart failure with preserved ejection fraction were observed for all 4 conditions for those aged ≤75 years. However, for heart failure with reduced ejection fraction, higher attributable risks were observed for the oldest age group for coronary artery disease and arrhythmia. Finally, the attributable risk due to hypertension was higher for patients with preserved than reduced ejection fraction for both age groups, with more extreme differences in those aged >75 years (7.9% for reduced vs 31.5% for preserved ejection fraction) compared to those ≤75 years (25.2% for reduced vs 45.5% for preserved ejection fraction).
DISCUSSION
Patients with heart failure have, on average, 2 additional comorbid conditions compared to age- and sex-matched controls without heart failure. Arrhythmia, hypertension, and coronary artery disease had the largest attributable risk of heart failure and, taken collectively, explained 73.0% of heart failure cases. When stratified by type of heart failure, those with preserved ejection fraction had a 2-fold higher attributable risk due to hypertension compared to patients with reduced ejection fraction. Furthermore, hypertension, coronary artery disease, arrhythmia, and diabetes were more strongly associated with heart failure in persons aged ≤75 years compared to persons aged >75 years.
Risk Factors for Heart Failure
Previous studies have reported on the relative contribution of risk factors to the development of heart failure, but few have included a comprehensive assessment of comorbid conditions. Hypertension, coronary artery disease, and diabetes have been most commonly studied and have been shown to be strongly associated with the development of heart failure in multiple studies.21–28 However, attributable risks varied widely across studies, which may be due in part to differences in demographics of the cohorts studied; differences in how heart failure was defined and how the risk factors were ascertained; and differences in the number and types of risk factors included among the studies. The attributable risks of heart failure ranged between 13% and 62% for coronary artery disease, 10% and 59% for hypertension, and 3% and 12% for diabetes.22,24,26,28 In the current contemporary study, which includes patients of all ages with incident heart failure within a community, we observed attributable risks of 33.9% for coronary artery disease, 28.4% for hypertension, and a larger risk attributable to diabetes than previously reported at 17.3%. We also found that arrhythmia had the largest attributable risk for heart failure at 48.7%. However, few prior studies have included arrhythmias, and the attributable risks were very low ranging from 2% to 24% in 2 studies.24,29
The current study expands on prior studies by assessing a large number of comorbid conditions and including not only well-known cardiovascular risk factors but also noncardiovascular conditions. We found that 2 noncardiovascular conditions, chronic kidney disease, and chronic obstructive pulmonary disease also exhibited high attributable risks for heart failure (18.3% and 15.6%, respectively). We also reported attributable risks for combinations of risk factors because there is significant overlap in the risk factors and the individual attributable risks cannot be summed. We found that arrhythmia, hypertension, and coronary artery disease taken collectively explained 73.0% of heart failure, meaning that if these 3 risk factors could be eliminated in the population, 73% of heart failure could be avoided. Furthermore, because achieving complete elimination of risk factors is not feasible in the population, we provided important information on the attributable risks for heart failure in relation to a 25% or 50% reduction in risk factors, which represents a more feasible goal than complete risk factor elimination. If a 25% reduction in the prevalence of the top 3 risk factors were obtained, our estimates indicated that we could expect 25.1% fewer heart failure cases.
Differences in Risk Factors by Ejection Fraction and Age
The case mix of heart failure has been changing over time, resulting in an increasing proportion of patients with preserved ejection fraction.7,8 Patients with preserved ejection fraction tend to be older and have an average of 1 additional comorbid condition than patients with reduced ejection fraction.5 Despite these differences, we found that the attributable risks were similar across heart failure types for most of the top risk factors. However, we found a striking difference in the risk attributable to hypertension, which was 2-fold higher in patients with preserved ejection fraction. A study of Australian adults aged ≥60 years reported similar results with hypertension being a significant risk factor for patients with preserved but not reduced ejection fraction.23 This study also reported that both atrial fibrillation and diabetes were risk factors for only heart failure with preserved ejection fraction; however, our study found arrhythmia and diabetes to risk factors for both types of heart failure with similar attributable risks for preserved and reduced ejection fraction. Furthermore, our study found significant interactions with age and hypertension, coronary artery disease, arrhythmia, and diabetes, whereby each of these conditions were more strongly associated with heart failure in those aged ≤75 years compared to those aged >75 years. A study using linked electronic medical records in England similarly found stronger associations with younger ages for hypertension, diabetes, and atrial fibrillation; however, this study did not include coronary artery disease.29
Implications
With an expected increase in the prevalence of heart failure as the population ages, and estimates of lifetime risk of heart failure ranging between 20% and 46%,27,30–33 efforts to prevent and manage risk factors are crucial. Ideal cardiovascular health (defined by absence of cardiovascular disease along with no smoking and ideal levels of healthy diet, physical activity, body weight, total cholesterol, blood pressure, and fasting blood glucose) is virtually non-existent in the population (prevalence of <1%).1 Thus, small reductions in risk factors could have a substantial impact on the cardiovascular health of the population and in reducing new-onset heart failure in the population.
Limitations and Strengths
We acknowledge some limitations. First, we used a modified list of chronic conditions defined by the US Department of Health and Human Services. Thus, additional conditions, including some geriatric conditions, may differ in heart failure cases compared to controls. Second, we lacked information on severity of the chronic conditions to determine the impact of severity on risk of heart failure. Third, our results may not be generalizable to all populations, including those that differ in racial, ethnic, and sociodemographic characteristics compared to Olmsted County, Minnesota. Nevertheless, our results may be generalizable to a large region of the United States because the Olmsted County population is representative of the state of Minnesota and the Midwest region of the United States.10
Despite the aforementioned limitations, our study has several strengths. Importantly, our data are comprehensive and represent the experience of a community. First, we included patients with incident heart failure without restrictions on age, insurance coverage, or diagnosis setting (inpatient or outpatient). Second, all heart failure was manually validated using the Framingham Criteria. Third, we had available data from echocardiograms to characterize patients into heart failure with reduced compared with preserved ejection fraction, allowing us to investigate differences in risk factors by type of heart failure. Finally, the Rochester Epidemiology Project records-linkage system allowed the matching of population-based controls and incorporation of data from multiple providers, resulting in nearly complete capture of patients’ medical history for both heart failure cases and their matched controls.
CONCLUSIONS
Compared to age- and sex-matched controls, patients with heart failure have a higher prevalence of many chronic conditions. Arrhythmia, hypertension, and coronary artery disease had the largest attributable risk of heart failure, and together these 3 conditions explained 73% of heart failure. Similar associations were observed in patients with reduced and preserved ejection fraction, with the exception of hypertension, which was more strongly associated with heart failure with preserved ejection fraction. Hypertension, coronary artery disease, arrhythmia, and diabetes were more strongly associated with heart failure in younger (≤75 years) compared to older (>75 years) persons. Optimizing prevention and treatment of hypertension, arrhythmia, and coronary artery disease would prevent most cases of heart failure.
Supplementary Material
CLINICAL SIGNIFICANCE.
Hypertension, coronary artery disease, and arrhythmia are more common in patients with heart failure than in population controls; together these 3 conditions explained 73% of heart failure.
Similar associations were observed for types of heart failure, except hypertension was more strongly associated with heart failure with preserved ejection fraction.
Some cardiometabolic risk factors were more strongly associated with heart failure in younger persons.
Small reductions in risk factors could substantially reduce new-onset heart failure.
Acknowledgments
Funding: This study was supported by grants from the National Institutes of Health (R01 HL120859 and R01 AG034676). The funding sources played no role in the design, conduct, or reporting of this study.
Footnotes
Conflicts of Interest: None.
SUPPLEMENTARY DATA
Supplementary data to this article can be found online at https://doi.org/10.1016/j.amjmed.2019.10.030.
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