Abstract
Polypharmacy exacerbates lower urinary tract symptoms (LUTS). Japan exhibits a higher prevalence of concomitant medication use in drug therapy than other countries. Previous age- and sex-specific reports exist; however, none include patients of all ages. Therefore, this retrospective study determined the impact of polypharmacy and its associated risk factors on LUTS exacerbation in outpatients with urological conditions. We included patients receiving medication who visited the Department of Urology at the Gifu Municipal Hospital (Gifu, Japan) between January, 2018 and December, 2018. The association between LUTS and polypharmacy and the risk factors for LUTS exacerbation were investigated. Patients were categorized into two groups according to their polypharmacy status. We performed propensity score matching and compared the International Prostate Symptom Score (IPSS) between the groups using the unpaired t-test. Multiple logistic regression analysis was performed to examine the risk factors, including “polypharmacy” and “taking multiple anticholinergic medications” for LUTS exacerbation. When comparing the IPSS between the groups, the polypharmacy group was found to have significantly higher scores than the non-polypharmacy group in six items, including “total score” and “storage score.” Multiple logistic regression analysis results showed high significance in three items, including “polypharmacy” (odds ratio (OR) = 1.67, 95% confidence interval (CI): 1.03–2.71) and “taking multiple anticholinergic medications” (OR = 8.68, 95% CI: 1.05–71.7). In conclusion, this study revealed that “polypharmacy” and “taking multiple anticholinergic medications” were risk factors for LUTS. Particularly, “polypharmacy” is associated with storage symptom exacerbation. Therefore, eliminating “polypharmacy” and “taking multiple anticholinergic medications” is expected to improve LUTS.
INTRODUCTION
Polypharmacy, which refers to the use of multiple drugs in the same patient, focusing solely on the total number of drugs a patient takes without considering whether they have the same disease, has recently become an issue. Hashimoto et al. reported an association between polypharmacy and the use of medications that cause lower urinary tract symptoms (LUTS), suggesting that polypharmacy exacerbates LUTS.1) The number of concomitant medications used in drug therapy in Japan is larger than that in other countries,2) and eliminating multiple drug use is subject to evaluation in terms of reimbursement. Kojima et al. previously reported an increased incidence of adverse drug events, including falls, in hospitalized patients taking six or more drugs.3) Additionally, an increased risk of urinary incontinence (UI) has been reported in hospitalized older patients taking five or more medications.4) However, this study considered hypertension, diabetes mellitus, and stroke as confounding factors and did not account for the effects of other diseases. Moreover, specific diseases may influence the worsening of LUTS, as depression is a risk factor for LUTS.5) Therefore, discussing polypharmacy and LUTS is important, considering the impact of the disease.
LUTS result in a decreased QOL.6) Its prevalence in adults varies from 61.4 to 86.0%7,8) and increases with age, regardless of sex.8) The International Prostate Symptom Score (IPSS),9) frequently used as a measure of LUTS, is an index for evaluating the severity of benign prostatic hyperplasia (BPH); however, it is widely used in urology for urinary tract diseases besides BPH, and its validity in Japanese translation10) and usefulness in women have been reported.11)
Identifying the risk factors for LUTS is crucial for preventing LUTS. Although previous age- and sex-specific reports exist,12,13) none of them included patients of all ages. LUTS are common in older individuals; however, the prevalence of moderate to severe LUTS in those aged <40 years is reportedly 5.0%,12) and the possibility that LUTS are involved in the QOL decline in younger patients cannot be denied. Therefore, exploring the risk factors for LUTS in patients of all ages is important. To achieve this, the impact of polypharmacy and its associated risk factors on LUTS exacerbation in outpatients with urological conditions should be identified.
Therefore, this retrospective study aimed to determine the impact of polypharmacy and its associated risk factors on LUTS exacerbation in outpatients with urological conditions.
MATERIALS AND METHODS
Study ParticipantsEligible patients were defined as those who visited the outpatient clinic of the Department of Urology at Gifu Municipal Hospital (Gifu, Japan) between January 1, 2018 and December 31, 2018 (first-visit patients excluding emergency outpatients) and were taking at least one drug at the time of the visit. The exclusion criteria were patients with unknown medications.
Details of the StudyThe study was conducted retrospectively using electronic medical records, and its parameters were sex; age; diseases; medications used at the time of the hospital visit (excluding topical drugs for local action); IPSS; and the medical records of physicians, pharmacists, and nurses. Diseases were classified using the International Statistical Classification of Diseases and Related Health Problems, 10th Revision.14) The IPSS is an index of LUTS comprising the following seven items: voiding (“incomplete emptying,” “intermittency,” “weak stream,” and “straining”) and storage (“frequency,” “urgency,” and “nocturia”) symptoms. A total score of 0–7, 8–19, and 20–35 is rated as mild, moderate, and severe, respectively.15) In this study, the total score of the four items of voiding symptoms was defined as “voiding score,” while that of the three items of storage symptoms was defined as “storage score.”
Statistical AnalysesAssessment of the Impact of Polypharmacy on LUTSPolypharmacy was defined as taking five or more medications,16) and patients were categorized into the polypharmacy and non-polypharmacy groups. Multiple logistic regression analysis was performed using polypharmacy as the objective variable and age, sex, and disease as explanatory variables to estimate the propensity scores and perform propensity score matching. Furthermore, matching was performed 1 : 1 using the nearest-neighbor matching method.
For matching data, we used an unpaired t-test to investigate differences in the total IPSS, voiding score, storage score, and scores for each item.
Exploring Risk Factors for LUTS ExacerbationAnticholinergic drugs were all drugs with anticholinergic effects, as defined by the Anticholinergic Drug Scale.17) Reports have shown that 82.2% of older patients who visit urologists as outpatients are polypharmacists.18) Additionally, many commonly prescribed medications have anticholinergic properties (e.g., anti-emetics, antispasmodics, bronchodilators, antiarrhythmics, antihistamines, analgesics, antihypertensive medications, and antiparkinsonism medications). Over 30% of older residents in nursing homes in the United States also reported taking two or more anticholinergic medications19); therefore, we defined a cutoff value of 2 for this study. Multiple logistic regression analysis was performed using the severity of the IPSS at the time of visit (classified into the following two groups: moderate or severe and mild) as the objective variable, and the study items where the number of patients in both groups was at least five as explanatory variables.
Statistical significance was set at p < 0.05, and all statistical analyses were performed using IBM SPSS Statistics for Windows, version 24.0 J (IBM Corp., Armonk, NY, U.S.A.).
Ethical ApprovalThis study protocol was approved by the Ethics Committees of Gifu Municipal Hospital (Approval Number: 580) and Gifu Pharmaceutical University (Approval Number: 2-40).
RESULTS
Assessment of the Impact of Polypharmacy on LUTSOverall, 594 patients were included in this study. After excluding 150 patients whose medications were unknown, 444 were finally included in the analysis.
Of these, 155 (34.9%) and 289 (65.1%) patients were stratified into the polypharmacy and non-polypharmacy groups, respectively. Propensity score matching identified 102 patients in the polypharmacy and non-polypharmacy groups (Fig. 1).
Table 1 presents the patient characteristics before propensity score matching. The proportion of male individuals was 74.5% (331 patients), and the mean age of the study population was 66.6 ± 14.6 years (mean ± standard deviation (S.D.)). Since the diseases included diseases of patients who visited the urology department as outpatients, 100 and 49.5% of the patients had “diseases of the genitourinary system” and “diseases of the circulatory system,” respectively.
Table 1. Characteristics of the Study Participants
| Total (n = 444) | Polypharmacy (n = 155) | Non-polypharmacy (n = 289) | p |
|---|
| Sex (n (%)) | | | | 0.819 |
| Male | 331 (74.5) | 117 (75.5) | 214 (74.0) | |
| Female | 113 (25.5) | 38 (24.5) | 75 (26.0) | |
| Age (years, mean ± S.D.) | 66.6 ± 14.6 | 73.2 ± 10.4 | 63.1 ± 15.3 | < 0.001* |
| Diseases (n (%)) |
| Certain infectious and parasitic diseases | 2 (0.5) | 2 (1.3) | 0 (0.0) | 0.121 |
| Neoplasms | 71 (16.0) | 34 (21.9) | 37 (12.8) | 0.015* |
| Diseases of the blood and blood-forming organs and disorders involving immune mechanisms | 6 (1.4) | 2 (1.3) | 4 (1.4) | 1.000 |
| Endocrine, nutritional, and metabolic diseases | 161 (36.3) | 87 (56.1) | 74 (25.6) | < 0.001* |
| Mental and behavioral disorders | 21 (4.7) | 14 (9.0) | 7 (2.4) | 0.004* |
| Diseases of the nervous system | 15 (3.4) | 7 (4.5) | 8 (2.8) | 0.410 |
| Diseases of the eye and adnexa | 20 (4.5) | 12 (7.7) | 8 (2.8) | 0.028* |
| Diseases of the ear and mastoid process | 3 (0.7) | 2 (1.3) | 1 (0.3) | 0.280 |
| Diseases of the circulatory system | 220 (49.5) | 109 (70.3) | 111 (38.4) | < 0.001* |
| Diseases of the respiratory system | 15 (3.4) | 6 (3.9) | 9 (3.1) | 0.784 |
| Diseases of the digestive system | 48 (10.8) | 34 (21.9) | 14 (4.8) | < 0.001* |
| Diseases of the skin and subcutaneous tissue | 1 (0.2) | 0 (0.0) | 1 (0.3) | 1.000 |
| Diseases of the musculoskeletal system and connective tissue | 17 (3.8) | 11 (7.1) | 6 (2.1) | 0.016* |
| Diseases of the genitourinary tract | 444 (100) | 155 (100) | 289 (100) | — |
| Pregnancy, childbirth, and the puerperium | 5 (1.1) | 2 (1.3) | 3 (1.0) | 1.000 |
| Certain conditions originating in the perinatal period | 1 (0.2) | 0 (0.0) | 1 (0.3) | 1.000 |
| Congenital malformations, deformations, and chromosomal abnormalities | 0 (0.0) | 0 (0.0) | 0 (0.0) | — |
| Symptoms, signs, and abnormal clinical and laboratory findings, not elsewhere classified | 1 (0.2) | 0 (0.0) | 1 (0.3) | 1.000 |
| Injury, poisoning, and certain other consequences of external causes | 1 (0.2) | 0 (0.0) | 1 (0.3) | 1.000 |
| IPSS (mean ± S.D.) |
| Total score | 9.60 ± 8.43 | 12.04 ± 9.16 | 8.29 ± 7.69 | < 0.001* |
| Voiding score | 4.85 ± 5.58 | 6.15 ± 5.98 | 4.16 ± 5.22 | < 0.001* |
| Incomplete emptying | 1.91 ± 1.74 | 1.38 ± 1.88 | 1.09 ± 1.66 | 0.098 |
| Intermittency | 0.93 ± 1.64 | 1.34 ± 1.85 | 0.71 ± 1.47 | 0.003* |
| Weak stream | 1.77 ± 2.03 | 2.22 ± 2.11 | 1.54 ± 1.94 | 0.001* |
| Straining | 0.95 ± 1.67 | 1.22 ± 1.82 | 0.81 ± 1.56 | 0.140 |
| Storage score | 4.75 ± 4.18 | 5.88 ± 4.47 | 4.13 ± 3.87 | < 0.001* |
| Frequency | 1.91 ± 1.93 | 2.26 ± 2.05 | 1.72 ± 1.83 | 0.005* |
| Urgency | 1.11 ± 1.73 | 1.44 ± 1.92 | 0.93 ± 1.59 | 0.003* |
| Nocturia | 1.73 ± 1.50 | 2.19 ± 1.57 | 1.48 ± 1.40 | < 0.001* |
* p < 0.05. IPSS, International Prostate Symptom Score; S.D., standard deviation.
Table 2 presents the patient characteristics after propensity score matching. The mean age was 70.5 ± 10.1 and 70.9 ± 11.3 years in the polypharmacy and non-polypharmacy groups, respectively. Additionally, 75 (73.5%) and 79 (77.5%) male individuals were in the polypharmacy and non-polypharmacy groups, respectively, without significant differences. The diseases were also not significantly different across the categories.
Table 2. Characteristics of the Patients after Propensity Score Matching
| Total (n = 204) | Polypharmacy (n = 102) | Non-polypharmacy (n = 102) | p |
|---|
| Sex (n (%)) | | | | 0.626 |
| Male | 154 (75.5) | 75 (73.5) | 79 (77.5) | |
| Female | 50 (24.5) | 27 (26.5) | 23 (22.5) | |
| Age (years, mean ± S.D.) | 70.7 ± 10.7 | 70.5 ± 10.1 | 70.9 ± 11.3 | 0.800 |
| Diseases (n (%)) |
| Certain infectious and parasitic diseases | 0 (0.0) | 0 (0.0) | 0 (0.0) | — |
| Neoplasms | 31 (15.2) | 17 (16.7) | 14 (13.7) | 0.697 |
| Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism | 1 (0.5) | 1 (1.0) | 0 (0.0) | 1.000 |
| Endocrine, nutritional, and metabolic diseases | 99 (48.5) | 50 (49.0) | 49 (48.0) | 1.000 |
| Mental and behavioral disorders | 7 (3.4) | 4 (3.9) | 3 (2.9) | 1.000 |
| Diseases of the nervous system | 9 (4.4) | 5 (4.9) | 4 (3.9) | 1.000 |
| Diseases of the eye and adnexa | 6 (2.9) | 2 (2.0) | 4 (3.9) | 0.683 |
| Diseases of the ear and mastoid process | 1 (0.5) | 0 (0.0) | 1 (1.0) | 1.000 |
| Diseases of the circulatory system | 130 (63.7) | 63 (61.8) | 67 (65.7) | 0.662 |
| Diseases of the respiratory system | 3 (1.5) | 2 (2.0) | 1 (1.0) | 1.000 |
| Diseases of the digestive system | 18 (8.8) | 10 (9.8) | 8 (7.8) | 0.806 |
| Diseases of the skin and subcutaneous tissue | 0 (0.0) | 0 (0.0) | 0 (0.0) | — |
| Diseases of the musculoskeletal system and connective tissue | 7 (3.4) | 4 (3.9) | 3 (2.9) | 1.000 |
| Diseases of the genitourinary system | 204 (100) | 102 (100) | 102 (100) | — |
| Pregnancy, childbirth, and the puerperium | 3 (1.5) | 2 (2.0) | 1 (1.0) | 1.000 |
| Certain conditions originating in the perinatal period | 0 (0.0) | 0 (0.0) | 0 (0.0) | — |
| Congenital malformations, deformations, and chromosomal abnormalities | 0 (0.0) | 0 (0.0) | 0 (0.0) | — |
| Symptoms, signs, and abnormal clinical and laboratory findings, not elsewhere classified | 0 (0.0) | 0 (0.0) | 0 (0.0) | — |
| Injury, poisoning, and certain other consequences of external causes | 0 (0.0) | 0 (0.0) | 0 (0.0) | — |
S.D., standard deviation.
Table 3 shows the results of the statistical analysis. “Total score” (polypharmacy group: 12.35 ± 9.87 [mean ± S.D.], non-polypharmacy group: 8.82 ± 7.92, p = 0.006) and “storage score” (polypharmacy group: 6.23 ± 4.74, non-polypharmacy group: 4.27 ± 3.89, p = 0.002) were significantly higher in the polypharmacy group than in the non-polypharmacy group. For each item, the polypharmacy group had significantly higher values for the following four items than the non-polypharmacy group: “intermittency,” (polypharmacy group: 1.37 ± 1.87, non-polypharmacy group: 0.83 ± 1.52, p = 0.026) “frequency,” (polypharmacy group: 2.48 ± 2.12, non-polypharmacy group: 1.69 ± 1.90, p = 0.006) “urgency,” (polypharmacy group: 1.52 ± 1.98, non-polypharmacy group: 0.89 ± 1.49, p = 0.012) and “nocturia” (polypharmacy group: 2.23 ± 1.66, non-polypharmacy group: 1.70 ± 1.45, p = 0.017).
Table 3. Comparison of the International Prostate Symptom Scores between Groups
| Polypharmacy (n = 102) | Non-polypharmacy (n = 102) | p |
|---|
| Total score | 12.35 ± 9.87 | 8.82 ± 7.92 | 0.006* |
| Voiding score | 6.13 ± 6.39 | 4.55 ± 5.67 | 0.065 |
| Incomplete emptying | 1.55 ± 1.99 | 1.05 ± 1.60 | 0.050 |
| Intermittency | 1.37 ± 1.87 | 0.83 ± 1.52 | 0.026* |
| Weak stream | 2.06 ± 2.09 | 1.65 ± 1.90 | 0.145 |
| Straining | 1.15 ± 1.80 | 1.02 ± 1.77 | 0.613 |
| Storage score | 6.23 ± 4.74 | 4.27 ± 3.89 | 0.002* |
| Frequency | 2.48 ± 2.12 | 1.69 ± 1.90 | 0.006* |
| Urgency | 1.52 ± 1.98 | 0.89 ± 1.49 | 0.012* |
| Nocturia | 2.23 ± 1.66 | 1.70 ± 1.45 | 0.017* |
Values are expressed as mean ± S.D. * p < 0.05. Unpaired t-test.
Of the included patients, 48.4% (215 patients) had moderate or severe IPSS (Fig. 2).
Table 4 presents the patient characteristics. The proportion of male individuals was 74.5% (331 patients), and the mean age of the study population was 66.6 ± 14.6 years (mean ± S.D.). Additionally, the mean number of drugs taken was 4.05 ± 3.16. Since we enrolled only patients who visited the urology department as outpatients, 100 and 49.5% of the patients had “diseases of the genitourinary system” and “diseases of the circulatory system,” respectively.
Table 4. Characteristics of the Patients for the Exploration of Risk Factors for Worsening Lower Urinary Tract Symptom
| IPSS | p |
|---|
| Total (n = 444) | Mild (n = 229) | Moderate or severe (n = 215) |
|---|
| Sex (n (%)) | | | | 0.157 |
| Male | 331 (74.5) | 164 (71.6) | 167 (77.7) | |
| Female | 113 (25.5) | 65 (28.4) | 48 (22.3) | |
| Age (years, mean ± S.D.) | 66.6 ± 14.6 | 63.6 ± 13.4 | 69.9 ± 15.1 | < 0.001* |
| Drugs used (n, mean ± S.D.) | 4.05 ± 3.16 | 3.56 ± 2.91 | 4.57 ± 3.31 | 0.001* |
| Polypharmacy | 155 (34.9) | 61 (26.6) | 94 (43.7) | < 0.001* |
| Taking multiple anticholinergic medications | 12 (2.7) | 1 (0.4) | 11 (5.1) | 0.002* |
| Diseases (n (%)) |
| Certain infectious and parasitic diseases | 2 (0.5) | 1 (0.4) | 1 (0.5) | 1.000 |
| Neoplasms | 71 (16.0) | 32 (14.0) | 39 (18.1) | 0.246 |
| Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism | 6 (1.4) | 4 (1.7) | 2 (0.9) | 0.686 |
| Endocrine, nutritional, and metabolic diseases | 161 (36.3) | 84 (36.7) | 77 (35.8) | 0.921 |
| Mental and behavioral disorders | 21 (4.7) | 9 (3.9) | 12 (5.6) | 0.504 |
| Diseases of the nervous system | 15 (3.4) | 7 (3.1) | 8 (3.7) | 0.795 |
| Diseases of the eye and adnexa | 20 (4.5) | 8 (3.5) | 12 (5.6) | 0.362 |
| Diseases of the ear and mastoid process | 3 (0.7) | 2 (0.9) | 1 (0.5) | 1.000 |
| Diseases of the circulatory system | 220 (49.5) | 117 (51.1) | 103 (47.9) | 0.508 |
| Diseases of the respiratory system | 15 (3.4) | 8 (3.5) | 7 (3.3) | 0.795 |
| Diseases of the digestive system | 48 (10.8) | 18 (7.9) | 30 (14.0) | 0.047* |
| Diseases of the skin and subcutaneous tissue | 1 (0.2) | 0 (0.0) | 1 (0.5) | 0.484 |
| Diseases of the musculoskeletal system and connective tissue | 17 (3.8) | 5 (2.2) | 12 (5.6) | 0.083 |
| Diseases of the genitourinary system | 444 (100) | 229 (100) | 215 (100) | — |
| Pregnancy, childbirth, and the puerperium | 5 (1.1) | 1 (0.4) | 4 (1.9) | 0.203 |
| Certain conditions originating in the perinatal period | 1 (0.2) | 1 (0.4) | 0 (0.0) | 1.000 |
| Congenital malformations, deformations, and chromosomal abnormalities | 0 (0.0) | 0 (0.0) | 0 (0.0) | — |
| Symptoms, signs, and abnormal clinical and laboratory findings not elsewhere classified | 1 (0.2) | 0 (0.0) | 1 (0.5) | 0.484 |
| Injury, poisoning, and certain other consequences of external causes | 1 (0.2) | 0 (0.0) | 1 (0.5) | 0.484 |
* p < 0.05. IPSS, International Prostate Symptom Score; S.D., standard deviation.
Multivariate analysis was performed with IPSS severity as the objective variable and 14 items, each having at least five individuals in two of the surveyed groups, as the explanatory variables. Figure 3 shows the results. The proportion of patients with moderate or higher IPSS was significantly higher in the three categories of “age (≥ 65 years)” (odds ratio (OR) = 2.11, 95% confidence interval (CI): 1.36–3.26, p = 0.001), “polypharmacy,” (OR = 1.67, 95% CI: 1.03–2.71, p = 0.039), and “taking multiple anticholinergic medications” (OR = 8.68, 95% CI: 1.05–71.7, p = 0.045). In contrast, the proportion of patients with moderate or higher IPSS was significantly lower in “diseases of the circulatory system” (OR = 0.610, 95% CI: 0.390–0.955, p = 0.031).
DISCUSSION
We conducted a retrospective study using electronic medical records to evaluate the impact of polypharmacy and its risk factors on LUTS exacerbation in outpatients visiting the urology department. When comparing the IPSS scores between the polypharmacy and non-polypharmacy groups, the polypharmacy group was found to have significantly higher scores than the non-polypharmacy group in six items, including “total score” and “storage score.” Multivariate analysis results also showed that “polypharmacy” significantly increased the risk of having moderate and severe IPSS, even after adjusting for confounding factors. These findings indicate that polypharmacy exacerbates LUTS, particularly “storage symptoms.” Drugs believed to affect LUTS include oral estrogens, α-blockers, angiotensin-converting enzyme (ACE) inhibitors, loop diuretics, and calcium channel blockers.15,20,21) Of these, calcium channel blockers have been reported to contribute to LUTS exacerbation.15) However, oral estrogens, α-blockers, ACE inhibitors, and loop diuretics have also been reported to affect UI, which is one of the storage symptoms.20,21) After matching, patients were taking oral estrogens (polypharmacy group: 1.0% [1 patient], non-polypharmacy group: 0.0% [0 patients], p = 1.000), α-blockers (polypharmacy group: 35.3% [36 patients], non-polypharmacy group: 15.7% [16 patients], p = 0.002), ACE inhibitors (polypharmacy group: 5.9% [6 patients], non-polypharmacy group: 3.9% [4 patients], p = 0.748), and loop diuretics (polypharmacy group: 11.8% [12 patients], non-polypharmacy group: 0.0% [0 patients], p < 0.001).
“Storage score” was compared between the polypharmacy and non-polypharmacy groups in patients not taking α-blockers and those not taking loop diuretics to evaluate the impact of α-blockers and loop diuretics, showing significant differences in the results of this study. The polypharmacy group was found to have a significantly higher “storage score” than the non-pharmacy group in patients not taking α-blockers and loop diuretics (data not shown).
While the effect of α-blockers and loop diuretics on “storage score” cannot be ruled out, the observation that the polypharmacy group had significantly higher “storage score” even in patients not taking these medications suggests that polypharmacy affects the “storage score,” even when the effects of α-blockers and loop diuretics are excluded. A previous study reported that 60.5% of older patients who visited a specialist for UI treatment took medications that exacerbated LUTS as described above22) and that taking five or more medications increases the likelihood of taking medications that affect LUTS (adjusted OR = 4.9; 95% CI, 3.1–7.9).22) Polypharmacy was defined as taking five or more medications in our study; therefore, patients in the polypharmacy group may be at a higher risk for taking medications that affect LUTS.
Generally, the more comorbidities patients have, the more drugs they take. Therefore, some patients may take more than five drugs, each of which is essential for their treatment. A previous study also reported that the mean number of medications taken by older outpatients (aged ≥65 years) visiting the urology clinic and the percentage of patients with polypharmacy were 6.48 ± 2.46 and 82.2%, respectively.18) However, in our study, the mean number of drugs taken by patients and the percentage of patients with polypharmacy were 4.05 ± 3.16 and 34.9%, respectively, which is lower than those reported in the previous study. One reason for this result could be that the mean age of the patients in this study was lower than that in the previous study since we included patients of all ages who visited the urology department as outpatients.
On average, 1.31 ± 1.25 potentially inappropriate medications (PIMs) were prescribed to older outpatients with urological symptoms, and 18.9 ± 0.15% of patients were taking PIMs.18) Therefore, we consider that minimizing the number of medications taken through interventions, such as prescription drug optimization, may reduce LUTS severity. We further consider it necessary to periodically examine the IPSS for patients taking more than five drugs.
Multivariate analysis results in this study showed that “taking multiple anticholinergic medications” significantly increased the risk of having moderate and severe IPSS, even after adjusting for disease-related confounding factors. Anticholinergics are used to treat Parkinson's disease, depression, UI, and allergies,23) and 20–50% of older individuals reportedly take anticholinergic medications.24) Urinary retention is a known adverse drug event for LUTS caused by anticholinergic drugs.23) An increased risk of urinary retention has been reported as the anticholinergic burden increases (adjusted OR = 2.13; 95% CI, 1.79–2.55).25) A recent British study reported that the anticholinergic burden has increased up to 9-fold in the last 25 years due to increased polypharmacy.26) None of the patients in our study reported urinary retention. However, patients taking multiple anticholinergic medications had significantly higher rates of moderate or severe IPSS, suggesting that they were experiencing some LUTS. Therefore, we consider that by regularly examining the IPSS, treatment can be initiated before severe adverse drug events, such as urinary retention, occur.
According to the multivariate analysis results, “age (≥ 65 years)” significantly increased the risk of moderate and severe IPSS, even after adjusting for confounding factors. The prevalence of LUTS, such as BPH, overactive bladder, and UI, is known to increase with age.8) Therefore, IPSS severity would logically be significantly higher in older individuals aged >65 years, and we believe that regular medical checkups should be promoted to provide appropriate treatment for older patients and confirm that the IPSS can prevent LUTS severity.
Furthermore, multivariate analysis results showed that “diseases of the circulatory system” significantly reduced the risk of having moderate and severe IPSS, even after adjusting for disease-related confounding factors. Hypertension is one of the most common cardiovascular diseases worldwide. Among the patients with cardiovascular disease in this study, 86.8% (191/220) had hypertension. According to the 2019 Japanese Society of Hypertension Guidelines for the Management of Hypertension,27) the five first-line drugs for hypertension are calcium antagonists, angiotensin receptor blockers (ARBs), ACE inhibitors, diuretics, and beta-blockers. Of these drugs, ARBs have been reported to reduce the IPSS significantly,28) and approximately 60–70% of patients with hypertension in Japan are prescribed ARBs.29) Additionally, 66.8% of patients with hypertension in Japan were reportedly taking calcium channel blockers,29) which can exacerbate LUTS, whereas 73.6% (162/220) of those with “diseases of the circulatory system” in this study were taking calcium channel blockers. However, ARBs alone and in combination with other antihypertensive drugs have been reported to significantly lower IPSS.30) Among the patients in this study, 90 were taking ARBs and calcium channel blockers, and since 55.6% (90/162) of patients on calcium channel blockers were on ARBs, it can be assumed that this resulted in a decrease in the IPSS. Acute coronary syndrome (ACS) is another condition classified as a cardiovascular disease. According to the Japanese Circulation Society 2018 Guidelines on Diagnosis and Treatment of Acute Coronary Syndrome,31) 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors are strongly recommended for the secondary prevention of ACS. HMG-CoA reductase inhibitors have been reported to improve LUTS,28) and 85.4% of patients with ACS take HMG-CoA reductase inhibitors for secondary prevention.32) However, patients in our study were taking ARBs (diseases of the circulatory system: 53.6% [118 patients], non-diseases of the circulatory system: 9.4% [21 patients], p < 0.001) and HMG-CoA reductase inhibitors (diseases of the circulatory system: 28.2% [62 patients], non-diseases of the circulatory system: 16.5% [37 patients], p = 0.004). Since a higher percentage of patients with “diseases of the circulatory system” take ARBs and HMG-CoA reductase inhibitors, we consider that “diseases of the circulatory system” results in a significantly lower IPSS. Overall, these results suggest that many patients experiencing “diseases of the circulatory system” are taking ARBs and HMG-CoA reductase inhibitors, resulting in improved IPSS values. Additionally, “diseases of the circulatory system” significantly reduced the IPSS in multivariate analysis, although no significant differences were found in univariate analysis among our study patients. The rationale may be because the effects of polypharmacy and ARB use on the IPSS were offset in univariate analysis in “diseases of the circulatory system,” where a higher proportion of polypharmacy (which raises the IPSS) and ARB use (which lowers the IPSS) was observed. However, in multivariate analysis, only polypharmacy was included as a confounding factor, suggesting that “diseases of the circulatory system” was an improving factor. Since this study aimed to evaluate the impact of polypharmacy, including taking multiple anticholinergic medications, on the IPSS, we do not consider the results of this study to be affected.
In the United Kingdom, nurses working at clinics specializing in dysuria and physical therapists specializing in teaching pelvic floor muscle training began working as continence advisors in 1980. Subsequently, in 1990, there were approximately 300 continence advisors, and every area in the entire United Kingdom had these professionals dedicated to improving excretory care within their communities. Similar movements are spreading throughout Europe, the United States, and Singapore. Furthermore, in Japan, the 2016 revision of reimbursement established a urinary independence guidance fee, which was subsequently revised into an additional fee for urinary independence support and an outpatient urinary independence guidance fee in the 2020 reimbursement revision. Therefore, urinary care has become increasingly important. However, pharmacists were not included as members of the urinary care team, which is one of the criteria for calculation. As our study revealed, “polypharmacy” and “taking multiple anticholinergic medications” are both risk factors for LUTS. Additionally, pharmacist participation in urologic care teams has been reported to improve the status of LUTS.33) Therefore, pharmacists should be actively involved in improving LUTS, including their participation in urinary care teams.
This study had some limitations. First, it had a single-center retrospective design. Therefore, in the future, conducting a prospective survey at multiple facilities to gather more evidence to support our study’s results will be necessary. Furthermore, we could not rule out the possibility of bias in the reporting of medications used or in the description of medical records by healthcare providers. This study could not determine the disease severity based on the data in the medical records, as disease severity can have a significant impact on polypharmacy and LUTS. Others were unable to consider the type of drug due to the limited number of variables that could be entered in the multiple logistic regression analysis. Therefore, considering the effect of the type of medication was another limitation of this study.
In conclusion, this study revealed that “polypharmacy” and “taking multiple anticholinergic medications” are risk factors for LUTS. “Polypharmacy” is particularly associated with the exacerbation of storage symptoms. Therefore, eliminating “polypharmacy” and “taking multiple anticholinergic medications” is expected to improve LUTS.
Conflict of Interest
The authors declare no conflict of interest.
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