Benign neoplasm of the heart increases the risk of first
ischemic stroke: a
population-based cohort study
Ming-May Lai
1,2, Tsai-Chung Li
3,4,5, Cheng-Li Lin
6,7, Fung-Chang
Sung
6,7,
Cheng-Chieh Lin
1,2,5,8,9, Chiu-Shong Liu
1,2,8, and Chia-Hung Kao
10,11*
Introduction
Benign tumors constitute 80% of primary cardiac neoplasms, and myxomas are the most common type (75% being atrial
myxomas), followed by lipomas and papillary fibroelastomas (1). Although histologically benign, these tumors may be harmful because of embolic hemodynamic sequelae (1–5). Patients with benign primary cardiac tumors appear to benefit from complete resections performed during cardiectomies or transplantations (6). Although surgeons have asserted that the surgical excision of benign cardiac tumors is associated with low operative risk levels and yields excellent results (7–13), certain patients remain hesitant to undergo the procedure. Reports of benign cardiac tumor
embolization have estimated that this risk ranges from 12% to 45% (14). However, the risk of embolization was only assessed among patients exhibiting benign cardiac tumors who received operations. This study investigated the incidence of first ischemic stroke among patients with benign neoplasms of the heart who did or did not undergo operations.
Methods
National Health Insurance Research Database
Details regarding the National Health Insurance (NHI)
population-based cohort database of Taiwan, the NHI Research
Database (NHIRD), were published in a previous study (15). The NHI program began in March 1995 and incorporated 13 insurance
programs that provided health care to 99% of the residents in Taiwan. The program is contracted with 97% of the hospitals and clinics in Taiwan, and covers comprehensive medical services, including outpatient and inpatient care, dental care, physical therapy, preventive care, and prescriptions. The National Health Research Institutes manages the NHIRD. The diagnoses recorded
in the NHI claim records were coded according to the diagnostic criteria of the International Classification of Diseases, 9th Revision, ClinicalModification (ICD-9-CM).We ensured that all data
were anonymously analyzed. In addition, this study was approved by the Ethics Review Board of China Medical University (CMUREC-101-012).
Study sample
A retrospective cohort study was conducted using two study groups: a benign cardiac tumors group and a matched noncardiac tumor control group.We excluded patients with a history of ischemic stroke (ICD-9-CM codes 433, 434) or malignant neoplasms
of the heart (ICD-9-CM code 164·1). The case group comprised adult patients with a first-time diagnosis of benign cardiac tumors (ICD-9-CM code 212·7) between January 1, 2000 and December 31, 2009. People who lacked benign cardiac tumor-related medical claims matched based on gender, age, comorbid status, and index date were randomly assigned to the control group. The index date for the patients in the case group was the date on which the diagnosis of a benign cardiac tumor was first registered. The index date for the control group was determined by matching the year of the index dates derived from the case group.Other comorbidities presented before the index date are listed as follows:
hypertension (ICD-9-CM codes 401 to 405), diabetes mellitus (ICD-9-CM code 250), hyperlipidemia (ICD-9-CM code 272), endocarditis (ICD-9-CM codes 063·42, 074·22, 039-20-039·24, 098·84, 112·81, 115·04, 115·14, 115·94, 421·0–421·9, 424·9), atrial fibrillation (AF, ICD-9-CM code 427·31), ischemic heart disease (9-CM codes 410–414), congestive heart failure (CHF; ICD-9-CM code 428), and peripheral artery occlusive disease (PAOD; ICD-9-CM codes 443–444). We calculated the person-years for each study participant until the diagnosis of ischemic stroke (ICD-9-CM codes 443–444) or December 31, 2009, for those censored as losses to follow-up, death, termination of insurance, or other causes. The identification numbers of all of the people in the NHIRD were encrypted for confidentiality. Data were censored for patients who withdrew from the NHI during the study
period.
We compared the distributions of gender, age, and the proportions of comorbidities between the case and control groups by
using the chi-squared test to calculate the categorical variables. The incidence of ischemic stroke per 1000 person-years in each of the cohorts was calculated. A Cox proportional hazard regression analysis was used to estimate the crude and adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) based on a comparison of the incidence of ischemic stroke between the case and
control groups. The HRs were adjusted for hypertension, diabetes mellitus, hyperlipidemia, endocarditis, atrial fibrillation, ischemic heart disease,CHF, and PAOD. The absolute risk reduction (ARR) of ischemic stroke was calculated for the patients with benign neoplasms of the heart who did or did not undergo operations. All statistical analyses were performed using the sas, Version 9·3, statistical software suite (SAS Institute, Cary, NC, USA). The statistical significance level was set at P < 0·05.
Results
There were 717 adults with benign cardiac tumors, and the prevalence was 0·004% among the general adult population of Taiwan.
Benign cardiac tumors were common among women (469; 65·4%) aged 21–96 years (mean 60·1 ± 16·1 years; median 62 years).
After excluding patients with a history of ischemic stroke and malignant neoplasms of the heart, 587 patients were in the benign cardiac tumor group and 5870 were in the control group; Table 1 lists their demographic and clinical characteristics. Approximately 74% of benign cardiac tumor patients were older than 50
years and 67% of the study participants were women. Compared with those in the control group, those in the case group were more likely to be diagnosed with hypertension, diabetes, endocarditis, atrial fibrillation, ischemic heart disease, and CHF (Table 1). Thirty-three first ischemic stroke events occurred among the benign cardiac tumor cases. The incidences of first ischemic stroke in the case and control groups were 13·3 and 6·7 per 1000 person-years, respectively. Table 2 shows the results of the stroke risk analysis of the case and control cohorts stratified according to age, gender, and comorbidity. The aHR of first ischemic stroke for the case group was 1·77 (95% CI: 1·20–2·63). The aHRs of first
ischemic stroke were higher among women with benign cardiac tumors compared with women in the control group (aHR: 2·19, 95% CI: 1·37–3·51), whereas no difference existed between men with and without benign cardiac tumors (aHR: 1·29, 95% CI: 0·63–2·63). In this study, there were no differences in the gender composition of the age subgroups.
The aHRs of first ischemic stroke were higher among younger patients (<50 years) with benign cardiac tumors compared with those in the control group (aHR: 22·9, 95% CI: 4·17–126·0). Among patients who do not have comorbidities, the aHRs of first ischemic stroke were higher among those with benign cardiac tumors compared with those in the control group (aHR: 2·20, 95% CI: 1·32–3·66).
Four hundred thirteen patients with benign cardiac tumors
received operations; their ages ranged from 22 to 89 years (mean 58·4 ± 14·4 years; median 59·5 years). Table 3 displays the incidence rates of first ischemic stroke among patients with benign
neoplasms of the heart who did or did not undergo operations, showing incidence rates of 9·1 and 28·8 per 1000 person-years, respectively. The crude HR of first ischemic stroke for the operation group was 0·34 (95% CI: 0·17–0·68). Regarding patients with a benign neoplasms of the heart who received operations, the ARR of first ischemic stroke was 19·7 per 1000 person-years, compared with the nonoperation group. However, after adjusting for hypertension, diabetes mellitus, hyperlipidemia, endocarditis,
atrial fibrillation, ischemic heart disease, CHF, and PAOD, those with benign cardiac tumors exhibited no difference in the risk of
ischemic stroke regardless of whether they underwent surgical operations. The aHR of first ischemic stroke for the operation
group was 0·48 (95% CI: 0·23–1·04) compared with the nonoperation group.
Discussion
Based on clinical diagnoses, the prevalence of benign cardiac tumors was 0·004% among the general adult population of Taiwan. The NHIRD comprised records on 18 million adults, and only 717 cases of benign cardiac tumors were identified. Lam et al. determined that the autopsy incidence of primary heart tumors was 0·056% (16). The autopsy prevalence of primary cardiac
tumors is typically accepted to be 1 out of 2000, and that of secondary cardiac tumors is 1 out of 100 autopsies (17). Benign tumors constitute 80–90% of primary cardiac neoplasms (6,17). The prevalence of benign cardiac tumors in this study was lower compared with that of other studies based on autopsy series (16– 18). Clinically, patients with benign cardiac tumors may be asymptomatic and these tumors may be incidentally discovered during evaluations for seemingly unrelated problems or physical findings. Therefore, the frequency of neoplasms in this study was underestimated compared with that in autopsy studies, because only patients who were referred for imaging were considered, rather than a cross-sectional sample of the general population. In Taiwan, benign cardiac tumors are more common among
women (65·4%) than among men. We found no studies investigating the epidemiology of benign cardiac tumors, except cardiac
myxomas. Cardiac myxomas are the most common primary cardiac tumor found in adults, representing as much as 83% of all diagnosed primary tumors of the heart (19). Thiene et al. determined that cardiac myxomas represented 66% of the benign
bioptic cardiac tumors found in patients, most of which were women (62·5%) (17). Other studies have reported that cardiac myxomas can be encountered among any age group; however, most reported cases occur in the third to sixth decades of life (20). Biopsies were not performed on all patients in this study; therefore, no histological classification is available, calling to question
whether all reported lesions were benign tumors. However, no patients in the operation group were diagnosed with malignant neoplasms of the heart after the surgical procedure.
After excluding patients with a history of ischemic stroke and malignant neoplasms of the heart, 74% of the benign cardiac tumor patients were older than 50 years (range 21–96 years; mean 60·2 ± 16·0 years, median 61·3 years).
Patients with benign cardiac tumors were at an increased risk of ischemic stroke.A total of 33 first ischemic stroke events occurred among 587 benign cardiac tumor patients followed for 2491 person-years. The incidences of first ischemic stroke in the case and control groups were 13·3 and 6·7 per 1000 person-years, respectively. Because patients who exhibited strokes prior to the
tumor diagnosis date were excluded, the cohort may have been biased toward benign prognostic cardiac tumors; however, the incidence of stroke among patients without benign cardiac
tumors was similar to that observed in another study (21). Table 2 lists the risk of stroke by age (in decades), demonstrating that the aHRs of first ischemic stroke were higher among younger patients (<50 years) with benign cardiac tumors compared with those in the control group (aHR: 22·9, 95% CI: 4·17–126·0), whereas no difference existed between elderly patients (≥50 years) with and without benign cardiac tumors. We always recommend that patients with cardiac myxomas receive surgical excision because of the embolic hemodynamic sequelae of tumors and the low operative mortality rate. However, no significant difference in the risk of ischemic stroke was observed between elderly patients who exhibited or did not exhibit benign cardiac tumors. Although the structural and anatomic characteristics of tumors strongly influence the risk of embolization, these results should be considered
when suggesting treatment options.
Women with benign cardiac tumors exhibited an increased risk of ischemic stroke, and the aHR of first ischemic stroke was 2·19, whereas no difference existed between men with and without benign cardiac tumors. This is a notable finding; however, no previous studies have investigated how gender differences affect the risk of embolic events associated with cardiac tumors. This is the first cohort study evaluating the risk of ischemic stroke among patients with benign cardiac tumors among the general population.
Operation did not significantly reduce the risk of ischemic stroke among patients with benign cardiac tumors.Cardiac tumor operations are often recommended if the general condition of a patient is strong; thus, we excluded patients with a history of
stroke. The incidences of first ischemic stroke in patients with a benign neoplasm of the heart who did or did not undergo operations
were 9·1 and 28·8 per 1000 person-years, respectively. No patients developed stroke prior to the surgical procedure. The crudeHR of first ischemic stroke for the operation group was 0·34 (95% CI: 0·17–0·68). Among the 587 patients with benign cardiac tumors, the patients who received operations (413, 70·4%) were
younger compared with the nonoperation patients (58 ± 14 years vs. 64 ± 19 years; P < 0·05). Nonetheless, after adjusting for age, gender, and comorbidities, the patients exhibited no difference in the risk of ischemic stroke regardless of whether they underwent operations. The aHR of first ischemic stroke for the operation group was 0·48 (95% CI: 0·23–1·04) compared with that of the nonoperation group. Several risk factors, such as AF, endocarditis, and heart failure, are significantly common among cardiac tumor patients; these may have falsely supported the nonsignificant aHR among the operation and nonoperation patients. However, this analysis was a cohort study; besides, it lacked data regarding the operative indications, perioperative morbidity, and postoperative conditions, and further randomized controlled trials are required to confirm the results.
A strength of this study is its nationwide, population-based design; however, the findings are subject to certain limitations. First, detailed information regarding the smoking status, physical activity levels, body mass index, type of imaging performed to detect the tumor, reasons why patients underwent such imaging, structural and anatomic tumor characteristics, pathology reports, operative indications, perioperative morbidity, and postoperative conditions, all ofwhich are potential confounding factors,were not available in the NHIRD. We could not directly contact the study participants to gather information because the NHIRD maintains patient anonymity. Furthermore, the evidence derived from a cohort study is typically of lowermethodological quality than that derived from randomized, controlled clinical trials because a cohort study design is subject to biases related to confounder adjustment. Thus, despite the meticulous study design and adequate adjustment for confounding factors, unmeasured or unknown confounders may have affected the results. Finally, the NHI claims data are primarily intended for use in administrative billing and have not undergone scientific verification. However, these data represent 99% of the population of Taiwan,and theNHI reimbursement policy is universally applied. Therefore, the data regarding the diagnoses used in the analysis were highly reliable.
