Abstract
Purpose
Treatment of benign prostatic hyperplasia (BPH) with 5 alpha-reductase inhibitors (5ARIs) is associated with low adherence to medication. Although studies have evaluated the impact of 5ARI therapy on long-term reduction in prostate volume and the need for prostate surgery, these results may not be extrapolated to the real-world due to lower adherence in the real-world compared to a clinical trial. The aim of this study was to evaluate drug adherence and long-term clinical outcomes in patients treated with 5ARIs therapy for lower urinary tract symptoms related to benign prostatic hyperplasia in a real-world setting.
Methods
We accessed longitudinal, pharmacy payment claim records from the Partners Healthcare System from January 2009 to July 2018. We identified individuals with more than one dispensation of 5ARIs for diagnosis of BPH and lower urinary tract symptoms. Adherence was calculated using proportion of days covered (PDC). We collected demographic and clinical variables during the first year since the initiation of 5ARIs. The outcome of the study was 5ARIs treatment failure defined by the occurrence of a BPH related surgery. A Cox proportional hazards model was used to estimate median time to surgical intervention in high adherent and low adherent patients.
Results
Patients with low level of adherence to 5ARIs were more likely to need surgical intervention (95% confidence interval [CI]: 1.02 to 1.59, p = 0.036) after adjusting for age, BPH stage, the presence of hematuria, bladder stone, and type of 5ARIs. The presence of bladder stones (hazard ratio [HR] = 1.70, 95% CI: 1.02 to 2.86, p = 0.043) and finasteride use (HR = 1.41, 95% CI: 1.01 to 1.98, p = 0.050) were significant risk factors for surgical intervention.
Conclusion
Low level of adherence to 5ARIs treatment in patients with BPH is associated with poor patient outcomes. Therefore, intervention strategies are needed to increase adherence to 5ARIs treatment after patients’ diagnosis.
Introduction
Benign prostatic hyperplasia (BPH) is one of the most commonly diagnosed medical conditions in older men. U.S. population-based studies showed an age-related increase in prevalence of BPH, which rises to nearly 50% in men by their eighth decade of life1. BPH is a chronic disease associated with a gradual deterioration of lower urinary tract symptoms (LUTS). Pharmacological treatments such as alpha blockers and 5 alpha-reductase inhibitors (5ARIs) are commonly used to improve LUTS and prevent serious outcomes such as acute urinary retention (AUR). Nevertheless when medical therapy fails, invasive interventions become necessary.
5ARIs are among the most commonly used pharmacological treatments for BPH, particularly for patients with larger prostates2,3. They act by inhibiting the enzyme 5α-reductase, thus promoting prostatic apoptosis, reducing prostate size and improving urinary symptoms. In practice, poor adherence to 5ARIs is a well-recognized problem. A study showed 1-yr adherence to 5ARIs for BPH was only 29%, and patients on combined therapies had an even higher discontinuation rate4. Although multiple clinical trials showed 5ARIs could reduce the risk of AUR or the need for surgery5–9, the relationship between levels of adherence and long-term clinical outcomes has not been determined.
The aim of this study was to evaluate drug adherence and long-term clinical outcomes in patients administered 5ARIs for LUTS related to BPH. We conducted this study using population health management claims data, which included statistics on health status, health care utilization and costs for patients. Claims data also record medication dispenses, which can be a reliable source to evaluate medication adherence and indicate medication-refill behavior among patients with chronic diseases such as BPH10–12. Furthermore, using direct claims data as a measure of medication adherence can eliminate potential recall biasThe aim was to evaluate drug adherence and long-term clinical outcomes in patients administered 5ARIs therapy for LUTS related to benign prostatic hyperplasia.
Methods
Data sources
Our study relied on Medicare claims data for male beneficiaries age 65 and older and aligned to Partners Healthcare within the NextGen Accountable Care Organization. Partners HealthCare in Boston, Massachusetts was founded by Brigham and Women’s Hospital and Massachusetts General Hospital. It has one of the largest health care networks in North America including hospitals, community health centers, physician practices, and post-acute care facilities.
Data included medical and pharmacy claims data from January 2012 thru December 31, 2017 and merged clinical and demographic information. Comprehensive clinical information from each patient was generated during the course of patient care from multiple clinical and administrative computing systems. Information on BPH treatment such as pharmacy information, medical diagnoses, and initial visit information was captured. Computerized pharmacy records for 102,240 5ARI prescriptions dispensed for 5,700 clinic patients were generated during the study period using International Classification of Diseases (ICD) codes. All data were de-identified.
Study population
Twenty-three percent (n=5,700) of all patients who were diagnosed with BPH during the study period were prescribed 5ARIs (including finasteride and dutasteride) with claims that contain the following diagnosis codes: 600.0 to 600.3, and 600.9. Patients with more than one dispensation of 5ARIs for a diagnosis of BPH commencing in the period January 2012 to December 2017 were enrolled in the study on the date their first prescription for 5ARIs was dispensed. Patients who received 5ARIs before July 2012 were excluded to ensure that all individuals had not been prescribed 5ARIs for at least six months before the initiation of 5ARIs treatment. Patients with a diagnosis of prostate cancer (185, 198.82, 233.4, 236.5, 239.5, V10.46) or bladder cancer (188, 198.1, 223.3, 233.7, 236.7, 239.4, V10.51) at any time during the follow up were also excluded from analysis.
Pharmacy-based adherence
Figure 1 demonstrates the study design scheme. We evaluated automated pharmacy records for the twelve months following the date 5ARI treatment was started. Adherence was calculated using proportion of days covered (PDC)13, which is supported by the International Society for Pharmaceutical Outcomes Research14. PDC is defined as the ratio of days that a patient supplied with medication to the total number of days in a year (PDC1yr=[1-(days without medication)/365]). For example, PDC1yr =0.80 means that a patient had enough medication 80% of the time in the first year of 5ARIs treatment. High level of adherence to medication in chronic disease was defined as PDC ⩾ 80% in many studies15–17. Thus, we categorized adherence to medication into binary outcomes, where patients had either a high level of adherence (PDC ≥ 0.80) or a low level of adherence (PDC < 0.80). We also conducted sensitivity analyses for adherence measured up to two and three years from the date 5ARIs were initiated.
Figure 1:
Study design scheme
Demographic and clinical variables
Baseline information was collected on the date patients were dispensed their first 5ARI regimen including age, race, veteran status, marital status, education level, smoking status, and alcohol use. Pharmacy information was also collected including brand name, and dosage. Comorbidity within the first year of follow-up was evaluated based on the diagnosis data using ICD codes. Severity risk factors such as hematuria and bladder stones as well as hypertension, diabetes, erectile dysfunction, and mental disorder were included in the analysis. BPH related complications were evaluated using the Thomson Medstat Disease Staging coding methods18. This method is a coding criterion based on ICD diagnosis codes and supported by the Healthcare Cost and Utilization Project as a classification system. Patients were categorized into uncomplicated (stage 1) or complicated BPH (stage 2 or more) based on ICD codes during the first year of evaluation.
BPH related surgery
The outcome of the study was 5ARI treatment failure defined by the occurrence of a BPH related surgery. This included surgical treatment and minimally invasive therapy using Current Procedural Terminology (CPT) codes (52601, 52612, 52614, 52620, 52640, 52647, 52648, 55801, 55821, 55831, 52850, 52852, and 52853). We evaluated the outcome starting one year after the initiation of 5ARIs. The time to 5ARI treatment failure was defined as the time from the index date to the first BPH related surgery. All patients were followed until the 5ARI failure, death, loss follow up, or the end of study (12/31/2018).
Statistical Analysis
Univariate and multivariate Cox proportional hazards regression analysis was performed to determine the relative hazard of 5ARIs treatment failure by the level of adherence to 5ARIs, controlling for other factors. All analysis was done using STATA.
Results
We identified 3,107 patients for study inclusion (Figure 2). The majority of the patients who initiated their first 5ARI treatment during the study period were white males who were non-smokers and non-alcohol users with an average age of 77.5 (Table 1). 89.1% of the study cohort was treated with finasteride, and only 10.9% was treated with dutasteride. BPH stage was evaluated during the first year of the follow-up. The majority of patients (91.2%) were characterized with stage 1 level of BPH severity (i.e., without bladder outlet obstruction, hydronephrosis, renal failure, sepsis, or shock). Patients categorized as stage 1 were less likely to fail compared to patients categorized as stage 2 or more.. 8% of the patients presented with hematuria and 3.3% with bladder stones. 23.5% of the study cohort was also diagnosed with hypertension, 9.1% with diabetes, 3.5% with mental disorder and 3.1% with erectile dysfunction. The mean follow-up time was 1354 days, during which 373 (12.0%) received BPH related surgery.
Figure 2:
Sample selection flowchart
Table 1:
Patient Characteristics
| Characteristics | Values | (%) |
|---|---|---|
| No. patients | 3107 | |
| Medication adherence (first year) | ||
| High (PDC≥0.8) | 2327 | 74.9 |
| Low (PDC<0.8) | 780 | 25.1 |
| Age (year) | ||
| <70 | 554 | 17.8 |
| 70–79 | 1516 | 48.8 |
| ≥80 | 1037 | 33.4 |
| Race | ||
| White | 2587 | 83.3 |
| Others | 225 | 7.2 |
| Unknown | 295 | 9.5 |
| Veteran Status | ||
| Yes | 1023 | 32.9 |
| No | 1412 | 45.4 |
| Unknown | 672 | 21.6 |
| Marital Status | ||
| Single | 758 | 24.4 |
| Married | 2008 | 64.6 |
| Unknown | 341 | 11.0 |
| Education Level | ||
| High school or below | 951 | 30.6 |
| College or above | 1140 | 36.7 |
| Unknown | 1016 | 32.7 |
| Alcohol use | ||
| No | 1051 | 33.8 |
| Yes | 785 | 25.3 |
| Unknown | 1271 | 40.9 |
| Tobacco use | ||
| Never | 980 | 31.5 |
| Quit | 1547 | 49.8 |
| Yes | 168 | 5.4 |
| Unknown | 412 | 13.3 |
| BPH stage | ||
| Uncomplicated | 2834 | 91.2 |
| Complicated* | 273 | 8.8 |
| Presence of hematuria | ||
| No | 2859 | 92.0 |
| Yes | 248 | 8.0 |
| Presence of bladder stone | ||
| No | 3004 | 96.7 |
| Yes | 103 | 3.3 |
| Type of 5ARIs | ||
| Dutasteride | 339 | 10.9 |
| Finasteride | 2768 | 89.1 |
| Combined therapy | ||
| No | 2855 | 91.9 |
| Yes | 252 | 8.1 |
| Comorbidity | ||
| Diabetes | 283 | 9.1 |
| Hypertension | 729 | 23.5 |
| Mental Disorder | 110 | 3.5 |
| Erectile dysfunction | 96 | 3.1 |
PDC = Proportion of days covered
acute urinary retention, renal failure, hydronephrosis or sepsis
As shown in the Kaplan-Meier curve in Figure 3, low level of adherence to 5ARIs was significantly associated with shorter time to BPH related surgery (log-rank test p = 0.0372). The results of sensitivity analyses conducted using adherence measured for two years and three years were similar. When adjusted for age, BPH stage, presence of hematuria, bladder stone, and type of 5ARIs, Multivariate Cox proportional hazard regression analysis revealed the hazard ratio (HR) was 1.29 (95% confidence interval [CI]: 1.04 to 1.62, p = 0.023) (Table 2). Moreover, we found that the presence of bladder stones (HR = 1.71, 95% CI: 1.02 to 2.87, p = 0.042) and finasteride use (HR = 1.42, 95% CI: 1.01 to 1.98, p = 0.044) were significant risk factors for BPH related surgery. Other factors including high BPH stage and presence of hematuria were related to poor outcomes however, they were not significant in the adjusted model.
Figure 3:
Time to 5ARI failure by level of medication adherence. Log rank test p=0.0372.
Table 2:
Cox model measured hazard ratio and 95% confidence intervals of BPH related surgery
| Characteristics | Crude | Adjusted | ||||||
|---|---|---|---|---|---|---|---|---|
| HR | CI | p value | HR | CI | p value | |||
| Medication adherence (first year) | ||||||||
| High (PDC>=0.8) | 1 | Ref | 1 | Ref | ||||
| Low (PDC<0.8) | 1.26 | 1.01 | 1.58 | 0.038 | 1.29 | 1.04 | 1.62 | 0.023 |
| Age | ||||||||
| <70 | 1 | Ref | 1 | Ref | ||||
| 70–79 | 1.01 | 0.77 | 1.34 | 0.925 | 0.97 | 0.73 | 1.29 | 0.851 |
| ≥80 | 1.17 | 0.87 | 1.58 | 0.290 | 1.14 | 0.85 | 1.54 | 0.390 |
| Race | ||||||||
| White | 1 | Ref | ||||||
| Others | 0.91 | 0.61 | 1.36 | 0.640 | ||||
| Marital Status | ||||||||
| Single | 1 | Ref | ||||||
| Married | 0.97 | 0.76 | 1.23 | 0.810 | ||||
| Education Level | ||||||||
| High school or below | 1 | Ref | ||||||
| College or above | 0.82 | 0.64 | 1.05 | 0.117 | ||||
| Tobacco use | ||||||||
| Never | 1 | Ref | ||||||
| Quit | 0.94 | 0.75 | 1.18 | 0.600 | ||||
| Yes | 0.93 | 0.59 | 1.48 | 0.770 | ||||
| Alcohol use | ||||||||
| No | 1 | Ref | ||||||
| Yes | 0.89 | 0.68 | 1.17 | 0.406 | ||||
| Veteran Status | ||||||||
| No | 1 | Ref | ||||||
| Yes | 0.89 | 0.70 | 1.13 | 0.333 | ||||
| BPH stage | ||||||||
| Uncomplicated | 1 | Ref | 1 | Ref | ||||
| Complicated * | 1.57 | 1.10 | 2.25 | 0.012 | 1.38 | 0.95 | 1.98 | 0.090 |
| Diabetes | ||||||||
| No | 1 | Ref | ||||||
| Yes | 1.03 | 0.70 | 1.54 | 0.849 | ||||
| Hypertension | ||||||||
| No | 1 | Ref | ||||||
| Yes | 0.88 | 0.68 | 1.14 | 0.334 | ||||
| Mental Disorder | ||||||||
| No | 1 | Ref | ||||||
| Yes | 1.33 | 0.75 | 2.36 | 0.960 | ||||
| Erectile dysfunction | ||||||||
| No | 1 | Ref | ||||||
| Yes | 1.13 | 0.64 | 2.02 | 0.669 | ||||
| Presence of hematuria | ||||||||
| No | 1 | Ref | 1 | Ref | ||||
| Yes | 1.42 | 0.98 | 2.05 | 0.065 | 1.24 | 0.85 | 1.83 | 0.264 |
| Presence of bladder stone | ||||||||
| No | 1 | Ref | 1 | Ref | ||||
| Yes | 1.86 | 1.12 | 3.07 | 0.015 | 1.71 | 1.02 | 2.87 | 0.042 |
| Type of 5ARIs | ||||||||
| Dutasteride | 1 | Ref | 1 | Ref | ||||
| Finasteride | 1.41 | 1.01 | 1.97 | 0.045 | 1.42 | 1.01 | 1.98 | 0.044 |
| Combined Therapy | ||||||||
| No | 1 | Ref | ||||||
| Yes | 1.08 | 0.78 | 1.49 | 0.635 | ||||
PDC = Proportion of days covered
acute urinary retention, renal failure, hydronephrosis or sepsis
Discussion
This study aimed to evaluate the impact of 5ARI drug adherence on long-term clinical outcomes among a cohort of patients diagnosed with BPH. Among patients initiating their first 5ARI regimen, we found that patients with low level of adherence are 27% more likely to need a BPH related surgery compared to those with high level of adherence. An association between adherence to 5ARI treatment and better clinical outcome is expected and has been reported4. However, long-term studies using longitudinal claims data are warranted.
5α-reductase is an enzyme that catalyzes the conversion of testosterone to 5α-dihydrotestosterone (DHT), which is involved in the pathogenesis of prostatic hyperplasia. 5ARIs including finasteride and dutasteride act as competitive and specific inhibitors of 5α-reductase to prevent conversion of testosterone to DHT, which ultimately reduces prostate size6,19,20 to relieve patients of bladder outlet obstruction. Multiple studies21–23 suggest that larger prostate volumes are associated with higher risk of BPH progression. Clinical trials such as the Proscar Long-Term Efficacy and Safety Study (PLESS) and the Medical Therapy of Prostatic Symptoms (MTOPS) study have demonstrated that 5ARIs have the potential for long-term reduction in prostate volume and need for prostate surgery4,24. Nevertheless, other observational studies have failed to demonstrate the effectiveness of 5ARI therapy in treating men with BPH25,26. One possible explanation is that findings from clinical trials cannot be generalized to men outside the study’s inclusion criteria. Moreover, patients undergoing long-term treatment in a real-world setting may exhibit lower adherence to the prescribed course of treatment compared to those in a clinical trial setting27.
Our results are consistent with those of a previous study from Cindolo et al4. They reported that, among men aged 40 years old, one year adherence to 5ARI treatment for BPH was 29% and discontinuation was an independent risk factor for hospitalization for BPH and BPH surgery (HR 1.65 and 2.80; p < 0.0001). Nonetheless, adherence and discontinuation are different. Some patients who failed to show improvement early in the treatment and discontinued may later restart the original treatment, and thus may have been inappropriately classified as non-adherent. Thus, discontinuation can only represent adherence when the level of adherence is very low28. In our study, we measured adherence by PDC instead of discontinuation, which is supported by the International Society for Pharmaceutical Outcomes Research14.
We also found several factors that could influence the probability of surgical intervention. These factors included higher BPH stage, the presence of bladder stones, and whether or not the initiating treatment was finasteride. BPH stage defined by Thomson Medstat Disease Staging Criteria18 was used to measure BPH severity. The presence with hematuria and/or bladder stones was also included to capture additional severity risks18. In our multivariable analysis, once the presence of hematuria and/or bladder stones was included, the information gained from BPH stage was no longer statistically significant in predicting outcomes. Bladder stones are commonly associated with bladder outlet obstruction, chronic urinary tract infection and neurogenic bladder29. We demonstrated that the presence of bladder stones was strongly associated with poor outcomes. We also found that patients using finasteride were 41% more likely to require surgical intervention compared to dutasteride. Currently, there are two 5ARIs approved in the United States: finasteride and dutasteride. Dutasteride, a dual 5ARI, results in a significantly greater decrease in dihydrotestosterone compared to finasteride, which is a selective inhibitor of the type 2 isoenzyme30,31. Our findings are inconsistent with previous studies, which showed no overall differences in clinical outcomes between the two treatments14. These inconsistent results may be due to the longer follow-up in our study or the imbalance between regimens (only 10.9% of patients in our study received dutasteride while 89.1% received finasteride).
We acknowledge that there are limitations to our analysis. Firstly, when we measured medication adherence with claims data, we assumed that patients consumed all medication as prescribed. Thus, it may be possible to overestimate the percentage of patients who are adherent to their medication. Secondly, there was selection bias since patients in our study were Medicare beneficiaries (i.e.: ≥ 65 years of age). The results could be different among younger patients. Finally, although we adjusted our results using BPH stage generated by diagnosis information, diagnostic tests and biochemical results were missing. It would be useful to link prostate size or PSA levels to each individual as variations in BPH severity between different adherent groups are likely. Despite these limitations, this is one of the few studies providing insight into drug adherence and the impact on clinical outcome for 5ARIs treatment for BPH.
Conclusion
In conclusion, low levels of adherence to 5ARI treatment in patients with BPH are associated with higher probability of BPH related surgery and poor outcomes. Therefore, intervention strategies are needed to increase adherence to 5ARIs treatment after patients are diagnosed.
Acknowledgements:
We appreciate and acknowledge Dr. Christine Vogeli and Partners Population Health’s support of this project.
Reference
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