Abstract
INTRODUCTION:
Mixed evidence suggests that nocturia may be related to major adverse cardiovascular events (MACE). Our objective was to estimate the association between nocturia, quantified on bladder diaries, and MACE.
METHODS:
From 2021–2024, the Lower Urinary Tract Network (LURN II) observational study enrolled participants with or without nocturia. Baseline characteristics, patient-reported outcomes, and bladder diary data were collected and joined with MACE outcomes from the electronic medical records at a single site. Participants with a diagnosis of a MACE outcome before LURN II enrollment were excluded. Estimates of the associations between the number of nocturia events, nocturia volumes, and the proportion of daily urine made at night, or nocturnal polyuria index (NPI), and ranked MACE outcomes were generated. Associations were estimated using Bayesian proportional odds ordinal models with skeptical priors. Model covariates included age and sex.
RESULTS:
Of the 146 participants, 10.3% developed a MACE. Median follow-up time (IQR) was 31.5 (18.7) months. The probability of an association between NPI and MACE outcomes was 98% (adj OR 1.01, credible interval, 1.00, 1.02). The probability of an association between number of nocturia episodes and MACE was 84% (adj OR 1.09, credible interval 0.93,1.29). The probability of an association between NPI with male sex and MACEs was 0.98 and with female sex and MACEs was 0.00005 (adj OR 1.01, 95% credible interval 1.00, 1.02).
CONCLUSION:
Nocturnal polyuria index (NPI), especially in males, and number of nocturia episodes have a high probability of being associated with major adverse cardiovascular event outcomes.
Introduction:
Nocturia is a common lower urinary tract symptom, with 50% of individuals over the age of 50 having symptoms that can significantly impact their quality of life. According to the International Continence Society, nocturia is defined as “waking to pass urine during the main sleep period,” in which the nocturia event must be preceded by sleep1,2 and must be diagnosed on a 72-hour bladder diary.1 In clinical practice, treatment is guided by patient bother. Nighttime urination can be due to several conditions, such as detrusor dysfunction with numerous small volume voids during sleep or an overproduction of urine during the sleeping hours (nocturnal polyuria). Successful treatment relies on appropriately diagnosing the underlying cause.
Emerging evidence suggests that the symptom of nocturia may not only be associated with a bladder pathology or excessive fluid intake, but also with other pathologies such as sleep, kidney, and cardiovascular disorders.3–6 Although the association between lower urinary tract symptoms and cardiovascular health is evolving, researchers have hypothesized that causes of nocturia, including possible electrolyte dysregulation and metabolic changes in water homeostasis, may be linked to early cardiovascular pathologies.7 However, there are several important limitations of the existing research in this area. The diagnosis of nocturia is often self-reported without substantiated bladder diaries (ICS criteria) or with validated self-reported measures of lower urinary tract conditions.4–6,8 In the cardiovascular literature, major adverse cardiovascular events (MACE) are often used, but there are no studies investigating the association between nocturia and MACE. MACE includes all-cause mortality, cardiac death, non-fatal cardiac bypass, non-fatal percutaneous coronary intervention, non-fatal acute coronary syndrome, non-fatal congestive heart failure, and non-fatal hospitalization for cardiac-related issues.9 Moreover, the temporal relationship between nocturia and MACE has not yet been described in a population with well-defined nocturia using information collected from a bladder diary.
The objective of this study was to evaluate the relationship between nocturia and its associated parameters and MACE outcomes using a combination of bladder diary data and electronic health record (EHR) query. The primary aim was to determine the probability of an association between the number of nocturia episodes and MACE. Secondary outcomes were to determine the probability of an association between total nighttime urine volume and calculated nocturnal polyuria index (NPI) defined as the proportion of daily urine produced at night, and MACE outcomes, respectively.
Methods:
Study Population and Design
The Lower Urinary Tract Network (LURN) II Observational Cohort Study was an observational National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) funded, multi-center study from six clinical sites across the United States from 2021–2024. In this study, adult men and women with and without bothersome urgency and/or urgency urinary incontinence were enrolled.10 A subset of LURN II participants from one clinical site was utilized due to data availability. LURN data, including baseline demographics, patient-reported outcomes, medical history, medication history, and bladder diary information, were extracted and collated with electronic health record (EHR) data. The bladder diaries were completed by the LURN participants and included 3-days of data collection, noting the timing of voids, volume of voids, and sleep/wake cycles during the 72-hour collection. From the bladder diaries, the total volume of daily urine production, total nighttime urine volume, and nocturnal polyuria index (NPI), or the proportion of urine production at night, were calculated.
The site’s EHR data was queried manually for MACE outcomes. The MACE variables were collected in a cross-sectional fashion after the individual completed the LURN II study. These variables included all-cause mortality, cardiac death, non-fatal cardiac bypass, non-fatal percutaneous coronary intervention, non-fatal acute coronary syndrome, non-fatal congestive heart failure, and non-fatal hospitalization for cardiac-related issues. These MACE outcomes of interest were determined after review of prior literature and based on expert opinion from cardiology. LURN participants with a diagnosis of a MACE outcome before LURN II enrollment were excluded. We excluded patients with MACE as they had a known cardiac condition and are predisposed to having future cardiac events. Given that the patients with MACE would be at a significantly higher risk of a repeat MACE, we determine that we could not extrapolate these patients into a “general population” with a generalized risk into our study cohort.
Study Objectives
The primary aim was to estimate the probability of an association between the number of nocturia events on bladder diaries and ranked MACE outcomes. The MACE outcomes were ranked in a pre-specified order of fatal and non-fatal events of potential severity: all-cause mortality, cardiac death, non-fatal cardiac bypass, non-fatal percutaneous coronary invention, non-fatal acute coronary syndrome, non-fatal congestive heart failure, non-fatal hospitalization for cardiac-related issues, and no MACE event for the analysis. Secondary aims were to estimate the probability of an association between the volume of nighttime urine production and ranked MACE outcomes, in addition to NPI, or proportion of daily urine made at night, and ranked MACE outcomes.
Statistical Analysis
Demographic and clinical characteristics between participants with and without development of MACE outcomes were compared using standard mean differences (SMD) for each variable.11 For interpretation of the SMDs, 0.2, 0.5, and 0.8 were determined to be small, medium, and large differences.11,12 Multiple imputation with chained equations was utilized for the imputation of missing data.13 Using Rubin’s rules, the imputed datasets were each independently analyzed, and the results were pooled for outcomes. Bayesian proportional odds ordinal models were utilized to determine the association between nocturia-related variables (number of nocturia events, volume of nighttime urine production, or NPI) and ranked MACE outcomes.14 NPI was calculated by the total volume of nighttime voided volume divided by the total volume of daily voided urine volume. Model fixed effect predictors include age and sex. These were determined by relationships described by directed acyclic graphs (DAGs), in which it was noted that obstructive sleep apnea (OSA) and diuretic use had confounding relationships with the outcome of interest (MACE) as both OSA and diuretic use have relationships with both the predictor (nocturia or its parameters) and the outcome of interest (MACE). Therefore, these predictors were not included as they distort relationships that are observed from model. Therefore, an a priori decision was made to exclude obstructive sleep apnea and diuretic use from the models. A positive association between the nocturia-related variables and relevant covariates was defined as OR >1. Default priors were used from the rmsb package including weakly informed priors centered on no effect for the regression coefficients and intercepts have a monotonic ordering constraint.14 Sex-related differences were explored using a conditional probability statement of the effect of NPI and sex on MACE outcomes. Probabilities of association were extracted from the posterior distributions of each model. All analyses were performed using R, version 12, 2024, Vienna, Austria.15
Results
Of the 180 participants enrolled in LURN II Observational Cohort study at the study site, 146 were included, of which 47 were male and 99 were female. Exclusion criteria included the presence of MACE before LURN II enrollment and incomplete records (Figure 1). In this study, 10.3% of participants developed a MACE diagnosis after enrollment in LURN 2. Median follow-up time (IQR) from LURN II enrollment to query for MACE outcome was 31.5 (18.7) months. Mean (+/− SD) age of the total cohort was 66.0 (+/− 13.5) years with a mean body mass index of 29.8 (+/− 8.57) kg/m2. Participants had baseline medical conditions, as listed in Table 1. Seventy-five percent were taking a diuretic medication at the time of enrollment in the LURN II study. At the time of query for MACE diagnosis, diuretic use had decreased to 24.7%. The median (IQR) of nocturia episodes was 1 (0.5, 2). In this cohort, 7% of participants had 0 episodes of nocturia/night, 41% with 1 episode/night, 35% with 2 episodes/night, and 16% with 3 or more episodes/night. Median (IQR) nocturia volume was 473 (288, 724) milliliters.
Figure 1:
Description of the population and presence of MACE outcomes in the study population
Table 1:
Demographic characteristics between MACE and no MACE groups. Data listed as N/n%. Standardized Mean Differences (SMD) were calculated with 95% confidence intervals.
| Total (n=146) |
MACE (n=15) |
No MACE (n=131) |
SMD (95% CI) | |
|---|---|---|---|---|
| Age (years) Mean (SD) |
66.0 (13.5) | 71.5 (8.5) | 65.4 (13.8) | 0.3 (0–0.8) |
| Missing | 1 (0.7%) | 0 (0%) | 1 (0.8%) | |
| Sex n(%) |
0.2 (0–0.6) | |||
| Male | 47 (32.2%) | 7 (46.7%) | 40 (30.5%) | |
| Female | 99 (67.8%) | 8 (53.5%) | 91 (69.5%) | |
| Body Mass Index Mean (SD) |
29.8 (8.6) | 33.8 (7.2) | 29.5 (8.6) | 0.3 (0–0.7) |
| Missing | 17 (11.6%) | 5 (33.3%) | 12 (9.2%) | |
| Hypertension n(%) |
65 (44.5%) | 9 (60.0%) | 56 (42.7%) | 0.2 (0–0.7) |
| Diabetes n(%) |
25 (17.1%) | 5 (33.3%) | 20 (15.3%) | 0.2 (0–0.7) |
| Direutic Use n(%) |
110 (75.3%) | 8 (53.5%) | 102 (77.9%) | 0.3 (0–0.8) |
| Hyperlipidemia n(%) |
62 (42.5%) | 7 (46.7%) | 55 (42.05) | 0.1 (0–0.5) |
| Obstructive Sleep Apnea n(%) |
35 (24.0%) | 8 (53.3%) | 27 (20.6%) | 0.4 (0–0.8) |
| Current Smoking n(%) |
5 (3.4%) | 0 (0%) | 5 (3.8%) | 0.1 (0–0.6) |
| Nocturia n(%) |
54 (37.5%) | 4 (26.7%) | 50 (38.2%) | 0.5 (0–1.0) |
| Unable to determine | 17 (11.6%) | 0 (0%) | 17 (13.0%) | |
| Missing | 71 (48.6%) | 11 (73.3%) | 60 (45.8%) | |
| Nocturnal Polyuria Index Mean (SD) |
17.4 (15.9) | 25.5 (12.7) | 17.0 (16.1) | 0.3 (0–0.8) |
| Missing | 75 (51.4%) | 11 (73.3%) | 64 (48.9%) |
The descriptive analysis suggested small differences in age between those with and without MACE diagnosis, as noted by a standardized mean difference (SMD), of 0.3 (95%CI [0, 0.75]) with absolute values of 71.5 +/− 8.5 years versus 65.4 +/−13.8 years. Similarly, small differences were seen with diuretic medication use (SMD 0.3, 95% CI [0, 0.74]); (53.5% versus 77.9%) presence of OSA (SMD 0.4, 95% CI [0, 0.84]; (53.5% versus 20.6%), and BMI (SMD 0.3, 95% CI [0, 0.75]); (33.8 +/− 7.2 kg/m2 versus 29.5 +/−8.6 kg/m2) (Table 1). In comparing MACE outcomes by sex, there was a difference in acute coronary syndrome in male patients as evidenced by a SMD of 0.4 (95% CI [0.07, 0.77]), as demonstrated by 10.6% versus 1.0% event rate in men and women, respectively (Table 2). Additionally, there was a difference in NPI between those with and without MACE (Figure 2).
Table 2:
Rates of MACE events compared by sex. Data listed as N/n%. Standardized Mean Differences (SMD) were calculated with 95% confidence intervals. There were no incidences of cardiac bypass, hospitalization for cardiac indications, or cardiac death in this cohort.
| MACE condition | Male Participants N=47 (N/n%) |
Female Participants N=99 (N/n%) |
SMD (95% CI) |
|---|---|---|---|
| Acute Coronary Syndrome/Ischemic Heart Disease | 5 (10.6%) | 1 (1.0%) | 0.42 (0.07–0.77) |
| Percutaneous Coronary Intervention | 0 (0%) | 2 (2.0%) | 0.2 (0–0.55) |
| Congestive Heart Failure | 1 (2.1%) | 5 (5.1%) | 0.16 (0–0.51) |
| All-Cause Mortality | 1 (2.1%) | 0 (0%) | 0.21 (0–0.56) |
Figure 2:
Comparison of NPI between patients who developed MACE and who did not develop MACE after initial enrollment in LURN 2.
The probability of any association between NPI and MACE outcomes was 98% (adjusted OR 1.01, 95% credible interval 1.00, 1.02). The probability of any association between number of nocturia episodes and MACE outcomes was 84% (adjusted OR 1.09, 95% credible interval 0.93, 1.29). The probability of any association between the nocturia volumes and MACE outcomes was 11% (adjusted OR 0.99, 95% credible interval 0.97, 1.00).
Sex-related differences were evaluated using a conditional probability statement of the effect of NPI and male sex on MACE outcomes. The probability of any association between NPI in a male participant and MACE outcomes was 98% (adjusted OR 1.01, 95% credible interval 1.00, 1.02). In a similar evaluation, the probability of any association between NPI in a female participant and MACE outcomes was 0.00005 (adjusted OR 0.43, 95% credible interval 0.28, 0.68).
Discussion
Our study demonstrated that there was a (0.98) probability that increasing nightly urine production as measured using the NPI was associated with MACE outcomes. In addition, there was a 0.98 probability of a positive association between NPI and male sex with MACE outcomes. In our study, male participants demonstrated a higher rate of acute coronary syndrome (five events; event rate 10.6%); however, there were only fifteen MACE outcomes in the total cohort. Therefore, this could have influenced our findings. It has been established that male sex is associated with MACE outcomes.16 However, more recent literature also highlights gender-based disparities in diagnosis of MACE events in women and worsening outcomes for women with MACE.17 Therefore, we should still consider both sexes at risk for MACE when approaching patients with symptoms of nocturia.
Although the exact mechanism is not clear, nocturia may represent a sign of mild abnormal water homeostasis and regulation.18,19 With time, the mechanisms for renal function, thirst, and volume maintenance become less robust, as the neuro-renal axis ages. In this setting, older individuals, especially as they develop nocturia and lower urinary tract symptoms, can have this delicate balance impacted by both intrinsic and iatrogenic causes.18 Additionally, timing of certain medications, such diuretic medications, also have an impact on nocturia.
Clinicians are perhaps most familiar with nocturia as a complaint in the setting of diuretic use. Our longitudinal study found that 75% of participants were taking diuretics at the time of LURN enrollment. This number decreased to only 25% two years later at the time of development of MACE outcomes. We could hypothesize that this reduction in diuretic use after LURN II enrollment in some participants could be related to undesired worsening of nocturia symptoms; if that is the case, cessation of previously prescribed diuretic medication use could potentially increase risk for downstream MACE events such as hospitalization for heart failure. We considered this because those with MACE outcomes had lower diuretic use rates. Moreover, most of the cohort was not on a diuretic medication at the time of follow-up EHR query, and we found that 1 in 10 participants did have a MACE occurrence. Therefore, this study emphasizes that future cardiovascular risk should still be considered in patients with nocturia even if they are not on diuretics presently, and further evaluation with a bladder diary is recommended. Although previous evidence has linked nocturia and certain cardiovascular outcomes, much of this data relied on large database studies with EHR that lack a detailed description of the nocturia phenotype. In addition, the accuracy of EHR coding remains uncertain, especially since complete assessment and diagnosis requires a 72-hour bladder diary.
This study has several strengths. It used bladder diaries to more accurately assess nocturia, and we had ongoing access to participants’ EHRs, for manual review of MACE. Additionally, we found a 10% rate of MACE event after approximately 3 years, which is comparable to the 6.9% rate of MACE development in other large insurance-based studies.20 Therefore, although in a small cohort, our rate of MACE development in our population is generalizable and on par with expected trends. Inclusion of both males and females improves the generalizability of the findings. Additionally, the use of Bayesian method was a strength in our exploratory approach. Bayesian modeling provides more stable estimates of the conditional probabilities and uncertainty for parameters in each model, especially when using a small cohort containing several important ordinal cardiovascular outcomes.
The study also has limitations. The sample size was restricted to a single site in the LURN study. This was due to the need for resources to extract site electronic record data, which was beyond the scope of LURN. Given the secondary analysis of an established data set, complete socioeconomic factors could not be collected. Because the study was retrospective, we could not determine the status of nocturia at the time of MACE diagnosis, and causality cannot be inferred. Based on our model, we were unable to evaluate the number or threshold of nocturia events at which clinicians should be concerned regarding a future MACE event. Finally, we elected not to model individual MACE events separately due to the low event rate in each category. Instead, modeled MACE outcomes as a ranking of cardiovascular outcomes.
Conclusions
Given the data in this study, there is a high probability of an association with MACE development and nocturia, especially in males. This association is detected using the calculated NPI from a bladder diary and episodes of nocturia on a bladder diary. Given that nocturia is a common complaint and there is a high probability of its association with MACE, improved surveillance could be used to benefit cardiovascular health.
Why This Matters:
Nocturia is common in adults, and the prevalence increases with age. Nocturia impacts quality of life in addition to being associated with falls and fractures, cognitive impairment, and depression. Prior literature has demonstrated associations between the presence of nocturia and major adverse cardiovascular events (MACE). However, studies utilizing coding for the diagnosis of nocturia are limited by recall bias and inaccuracies in coding. This study used bladder diaries to document the frequency of nighttime voids and voided volumes to understand the association of nocturia and future MACE. We demonstrated that there is a high probability that an association exists between the proportion of urine produced at night in 24 hours (nocturnal polyuria index) and MACE. These findings suggest that the nocturnal polyuria index may be a useful marker for MACE outcomes that warrants further study.
Funding:
NIH/NIDDK Grant: 2U24DK099879
Conflict of interest statement:
E. Jelovsek: Institutional funding: NIDDK, NICHD, and FDA. Royalties: UpToDate. Advisory Board: Collamedix
C. Amundsen: Research Grant:NIDDK, NICHD, NIAMS, FDA; Data Safety Monitoring Board: PCORI; Research Grant and Consultant: BlueWind Medical
S. Greene: Research support from the Duke University Department of Medicine Chair’s Research Award, American Heart Association, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Otsuka, Pfizer, and Sanofi; has served on advisory boards or as consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Corcept Therapeutics, Corteria Pharmaceuticals, CSL Vifor, Cytokinetics, Idorsia, Lexicon, Lilly, Merck, Novo Nordisk, Otsuka, Recordati, Roche Diagnostics, Sanofi, scPharmaceuticals, Sumitomo, and Tricog Health; and has received speaker fees from AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Lexicon, Novo Nordisk, and Roche Diagnostics.
The other authors (A. Sinha, J. Arrington, A. Bashi) have no conflicts of interest.
Footnotes
Statement of presentation: This will be presented as an oral presentation at the American Urogynecology Society Pelvic Floor Disorders Week Meeting 2025, Vancouver, BC.
Abstract Presentation: This paper was presented by Dr. Jasmine Arrington (co-author/resident physician), but the work was completed by Dr. Annika Sinha (first author/fellow physician)
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