Constipation and Incident Cardiovascular Disease: A Nationwide, Real-World Cohort Study

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Constipation and Incident Cardiovascular Disease:A Nationwide, Real-World Cohort Study

 AuthorsIwasaki Kentaro Ejiri kejiri1@s.okayama-u.ac.jp Kaneko Suzuki Toru Miyoshi Masuda Shinsuke Yuasa Authors Info & Affiliations Publication JACC: Asia Preprint

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Background

The association of constipation with incident cardiovascular disease (CVD) has been suggested; however, there are few studies including general population and assessing whether constipation can improve the predictive performance for future CVD. This study aims to quantify the association of constipation with the risk and attribution of developing CVD using a nationwide epidemiological database in Japan. In 1,516,763 individuals without prior CVD from the DeSC database between April 2014 and November 2022, constipation was defined by International Classification of Diseases-10th revision code before the initial health checkup. We assessed the association of constipation with incident CVDs including myocardial infarction (MI), angina pectoris, stroke, heart failure (HF), atrial fibrillation (AF), and a composite of them using multivariable Cox models.

Results

Constipation was observed in 186,448 individuals (12.3%), showing a significant association with composite and each CVD, particularly with HF (HR: 1.30; 95% CI: 1.29-1.32 and HR: 1.32; 95% CI: 1.29-1.34, respectively). Followed by hypertension, constipation was the second highest population attributable fractions for the composite CVD, stroke, HF, and AF. Adding constipation to the established risk factors showed a modest but significant improvement in the prediction for the CVDs (net reclassification improvement for composite CVD: 0.122; 95% CI: 0.116-0.127; P< 0.001).

Conclusions

In individuals without prior CVD, constipation was associated with incident CVDs including myocardial infarction, angina pectoris, stroke, HF, and AF. Constipation may be promising for the prediction of future CVD other than established risk factors, suggesting the importance of constipation not just as a quality-of-life issue but as a potential cardiovascular risk in the general population. Constipation is one of the most prevalent gastrointestinal disorders involving approximately 15% of the general population and associated with reducing quality of life.¹ Constipation may influence the cardiovascular system through a variety of pathophysiological pathways, including those pertaining to blood pressure, altered arterial stiffness, and gut microbiota.2,3

Several preceding studies have suggested an epidemiological association between constipation and future cardiovascular disease (CVD) in the general population.4-6 The Danish population-based matched cohort study revealed an association between constipation and the onset of CVD including myocardial infarction (MI), ischemic stroke, venous thrombosis, heart failure (HF), and atrial fibrillation (AF).5 In the study including post-menopausal women, only severe constipation was associated with an increased risk of CVD.6 However, there are a few important caveats in those studies. First, most of these studies evaluated the association of constipation with ischemic cardiovascular diseases (eg, MI and stroke) but not with other CVDs other than ischemic diseases (eg, HF and AF), which may show unique association with constipation.7 Second, most of these studies included a relatively biased population from a healthy community such as only female or older individuals,4,6 allowing for uncertainty regarding the association of constipation with cumulative incidence of CVD in the general population. Finally, to the best of our knowledge, there is no study that assesses whether constipation can improve the predictive performance for the occurrence of CVD over traditional risk factors. Additionally, because constipation is common in the general population, it is important to elucidate the association of constipation with future CVD in public health.

To address these issues, we examined the magnitude of the effect of constipation on the occurrence of CVDs including MI, angina pectoris (AP), stroke, HF, and AF in the general population and assessed whether the addition of constipation as a risk factor to the established traditional cardiovascular risk factors could improve the prediction performance for cardiovascular events using nationwide real-world data in Japan.

Methods

Study population

The present study was a population-based observational cohort study based on nationwide real-world data, the DeSC database (DeSC Healthcare, Inc).8 The DeSC database collects data on individual health insurance records and health checkup data (eg, anthropometric measurements and blood tests). This database stores inpatient and outpatient administrative claims data. Diagnoses (confirmed or suspected) are registered using the International Classification of Diseases-10th Revision (ICD-10). We identified 2,562,218 individuals for whom we could obtain data on health checkups from April 2014 through November 2022, including body mass index, hemoglobin A1c, blood pressure, and lipid profile, more than 6 months after insurance enrollment. Individuals were excluded from study participation if they met any of the following criteria: prior history of CVD, such as MI, AP, stroke, HF, and AF (n = 423,925 [16.5%]); prior history of kidney replacement therapy (eg, dialysis, n = 477 [0.02%]); missing data on cigarette smoking (n = 102,775 [4.0%]); missing data on alcohol consumption (n = 207,173 [8.1%]); and missing data on physical inactivity (n = 311,105 [12.1%]). Finally, the study cohort included 1,516,763 individuals.

Ethical considerations

The present study was approved by the Ethics Committee of The University of Tokyo (Approval no. 2021010NI) and was conducted in accordance with the Declaration of Helsinki. Because all data in the DeSC database are anonymized, informed consent of individual participants was not required.

Definition of constipation

Individuals with constipation were defined as those with a confirmed diagnosis of constipation (ICD-10 code K590) before the initial health checkup.

Outcomes

Our primary outcome was incident CVDs including MI (ICD-10 codes I210–I214 and I219), AP (ICD-10 codes I200, I201, I208, and I209), stroke (ICD-10 codes I630, I631–I636, I638, I639, I600-I611, I613-I616, I619, I629, and G459), HF (ICD-10 codes I500, I501, I509, and I110), and AF (ICD-10 codes I480, I481, I482, I483, I484, and I489). We also investigated the composite CVD event including all of the above outcomes. We only used confirmed diagnosis records for the definition of each CVD incident (ie, any suspected diagnosis was excluded from the analysis). Clinical outcomes were collected between April 2014 and November 2022. Individuals were censored at outcome occurrence, insurance withdrawal (including death), or the end of the study follow-up until November 2022.

Covariate

Information on covariates was retrieved regarding initial health checkup and medication status from the database. Hypertension was defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg, and/or if an individual was prescribed antihypertensive medications. Diabetes was defined as a hemoglobin A1c level ≥6.5% and/or if an individual was prescribed antidiabetic medications (including insulin). Dyslipidemia was defined as a low-density lipoprotein cholesterol level ≥140 mg/dL and/or a high-density lipoprotein cholesterol level <40 mg/dL and/or a triglyceride level ≥150 mg/dL, and/or if an individual was prescribed lipid lowering medications. Smoking status (current or noncurrent/never smoker), the frequency of alcohol consumption (every day or not every day), and physical activity (inactive or active) were assessed using information from the self-administered questionnaire.

Statistical analysis

Basic characteristics stratified by constipation were summarized as the median with interquartile interval (Q1-Q3) for continuous variables and as numbers (%) for categorical variables. The significance of differences was determined using the Mann-Whitney U test or the chi squared test. We plotted the cumulative incidence of CVD according to the constipation status using the Kaplan-Meier method and compared the cumulative incidence of CVD using the log-rank test. To assess the association between constipation and the incidence of CVD, we also estimated HR and 95% CI using Cox proportional hazards regression models. Model 1 is an unadjusted model. Model 2 adjusted for age and sex. Model 3 further adjusted for body mass index, hypertension, diabetes, dyslipidemia, cigarette smoking, alcohol consumption, and physical inactivity. We assessed the proportional hazards assumption for Cox regression models using the Schoenfeld residuals. The population attributable fraction (PAF) was calculated using the formula: PAF = pd × (relative risk − 1)/relative risk, where pd is the proportion of cases exposed to the risk factor. We estimated relative risk from HR in the analysis. Predictive ability was assessed using change in the c-index and the net reclassification improvement (NRI).

We conducted a few sensitivity analyses. First, we excluded individuals who had constipation but who had not received constipation medications. Second, we did further stratification for those with constipation who were prescribed laxatives, those without laxatives, and those without constipation. Third, we excluded individuals who had a history of other gastrointestinal diseases (ICD-10 codes K20-K938, except for K590). Fourth, we examined the association between constipation and the incidence of CVD among individuals with a 1-year follow-up period (ie, the induction period). Finally, we assessed the association among several subgroups including age (<65 and ≥65 years), sex, and those with or without hypertension. We ran the same Cox models above in all sensitivity analyses. A 2-tailed P < 0.05 was set as statistical significance. All statistical analyses were performed using Stata software (version 18; StataCorp LLC).

Results

Baseline characteristics

The study cohort included 1,516,763 individuals with the median age of 63 years (Q1-Q3: 49-68 years); 45.4% were male (Figure 1). Of these, a total of 186,448 individuals (12.3%) had a history of constipation. The baseline characteristics of the study participants are summarized in Table 1. In individuals with a history of constipation were more frequently older and female compared with those without a history of constipation. Participants with constipation had higher risk profile in most CVD risk factors (eg, hypertension, diabetes, and dyslipidemia) than those without constipation, except for cigarette smoking and alcohol consumption.

Figure 1 Study Flow Chart

We identified 2,562,218 individuals for whom we could obtain data on health checkups from April 2014 through November 2022, including body mass index, hemoglobin A1c, blood pressure, and lipid profile, more than 6 months after insurance enrollment. Individuals were excluded from study participation if they met any of the following criteria: prior history of cardiovascular disease, such as myocardial infarction, angina pectoris, stroke, heart failure, and atrial fibrillation (n = 423,925); prior history of kidney replacement therapy (n = 477); missing data on cigarette smoking (n = 102,775); missing data on alcohol consumption (n = 207,173); and missing data on physical inactivity (n = 311,105). Finally, the study cohort included 1,516,763 individuals.

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