https://orcid.org/0000-0002-2124-7227
ABSTRACT
The present study aims to analyze the impact of PRO 160/120 prescriptions on the incidence of urinary incontinence, polyuria (including nocturia), urinary retention, and erectile dysfunction in a real-world setting in Germany and to compare these data with data for the 5-ARIs finasteride and dutasteride, and the α1-adrenoceptor antagonists tamsulosin and tamsulosin/dutasteride fixed-dose combination. This retrospective study was based on the IQVIA Disease Analyzer database and included male patients with an initial prescription of PRO 160/120, finasteride, dutasteride, tamsulosin, or tamsulosin/dutasteride fixed-dose combination between January 2010 and September 2020. Multivariable logistic regression analyses adjusted for age, health insurance, specialty, and relevant co-diagnoses were performed to estimate the association between PRO 160/120 prescriptions and incidence of pre-defined outcomes. A total of 77,923 patients were included in the study, 3,035 of whom received PRO 160/120. PRO 160/120 was significantly associated with reduced incidence of urinary incontinence (OR: 1.48; 95% CI: 1.10–1.98) and urinary retention compared to tamsulosin (OR: 3.39; 95% CI: 1.75–6.57 and tamsulosin/dutasteride (OR: 2.81; 95% CI: 1.35–5.82). Furthermore, PRO 160/120 significantly reduced the incidence of erectile dysfunction compared to dutasteride (OR: 2.79; 95% CI: 1.49–5.25). At the same time, patients receiving PRO 160/120 showed the same incidence of the remaining complications as those taking the reference substances. In conclusion, we observed a significant association between PRO 160/120 prescription and reduced incidence of urinary incontinence and urinary retention compared to tamsulosin and tamsulosin/dutasteride, as well as reduced incidence of erectile dysfunction compared to dutasteride.
Introduction
Benign prostatic hyperplasia (BPH) can induce benign prostatic enlargement (BPE) leading to storage or voiding symptoms in the lower urinary tract (lower urinary tract symptoms, LUTS) [Citation1,Citation2]. These symptoms are associated with a reduced quality of life (QoL) [Citation3,Citation4]. Although the pathophysiological mechanisms causing BPH/BPE are not yet fully understood, the role of sexual steroids is well established [Citation5]. There is increasing evidence that chronic inflammation of the prostate is also a risk factor for progression of BPH and triggers irritative LUTS [Citation6].
Previous research has shown that chronic prostate inflammation is associated with a higher risk of disease progression and surgery and a significantly increased risk of urinary retention [Citation7].
The four principal medical therapy classes used to treat LUTS as a result of BPH/BPE are α1-adrenoceptor antagonists, 5α-reductase inhibitors (5ARIs), phosphodiesterase 5 (PDE5) inhibitors, and certain phytopharmaceuticals [Citation8–13]. However, α1-Adrenoceptor antagonists can have negative effects on sexual function [Citation14], and the tolerability of the 5α-reductase inhibitors can be limited by their side effects on sexual function [Citation15]. Both drug classes can also be combined, enhancing the therapeutic effect but also increasing the risk of side effects [Citation16,Citation17].
Phytopharmaceuticals represent another therapy group used to treat LUTS. As mentioned in the current German BPH guidelines, only products with proven efficacy in placebo-controlled clinical trials are recommended [Citation8]. PRO 160/120, a clinically proven combination of specific extracts from saw palmetto fruits (Sabal serrulata or Serenoa repens) and the roots of stinging nettle (Urtica dioica) is prescribed regularly by physicians.
PRO 160/120 targets the conversion of testosterone to dihydrotestosterone and aromatase activity, aiming at balancing the estrogen level. The active ingredients also relax the swollen prostate tissue and thus reduce the pressure on the urethra. Due to the anti-inflammatory effects, PRO 160/120 reduces irritation of the prostate [Citation18].
Recent in vitro and in vivo investigations have confirmed the beneficial effect of the extracts on the inflammation process in the prostate. These experimental data on the pharmacological profile of action offer an explanatory approach for the effects shown in clinical studies [Citation18–22]. The authors concluded that PRO 160/120 was superior to placebo or comparable with tamsulosin or finasteride in all either placebo- or reference-controlled randomized trials. Furthermore, PRO 160/120 demonstrated a better tolerability and safety profile than the reference drugs [Citation22].
In the present study, we aimed to analyze the impact of PRO 160/120 prescription on the incidence of complications of benign prostatic hyperplasia or its therapy (urinary incontinence, polyuria, urinary retention and erectile dysfunction) in a real-world setting in Germany compared to finasteride, dutasteride, tamsulosin, and the tamsulosin/dutasteride fixed-dose combination.
Methods
Data source
We used Disease Analyzer database (IQVIA). This database includes electronic medical records from nearly 3,000 private practices in Germany. The database has been shown to be suitable for pharmaco-epidemiological and pharmaco-economic studies [Citation23,Citation24].
Ethical statement
German law allows the use of anonymous, de-identified electronic medical records for research purposes under certain conditions. In accordance with this legislation, it is not necessary to obtain informed consent from patients or approval from a medical ethics committee for this type of observational study that contains no directly identifiable data. Therefore, no waiver of ethical approval can be obtained from an Institutional Review Board (IRB) or ethics committee. The company and the authors involved had no access to any identifying information at any time during the analysis of the data.
Study population
This retrospective database study included all male patients in GP and urological practices from the IQVIA Disease Analyzer database with an initial prescription of PRO 160/120, dutasteride, finasteride, tamsulosin, or a dutasteride/tamsulosin combination from January 2010 to September 2020. Patients with a diagnosis of urinary incontinence (N39.3, N39.4, R32), polyuria (R35), urinary retention (R33), or erectile dysfunction (N48.4, F52.2) prior to the initial prescription date were excluded. Patients who received a prescription from another substance, hence switched medication within 180 days after the initial prescription were also excluded. Patients had to be observable with at least one other prescription or diagnosis in the database for at least 1 year before and after the initial prescription of PRO 160/120 or the reference substances.
Study outcomes
The outcome of this study was the association between PRO 160/120 prescription and the incidence of urinary incontinence (ICD-10: N39.4, R32), polyuria (ICD-10: R35 – including nocturia), urinary retention (ICD-10: R33), or erectile dysfunction (ICD-10: N48.4, F52.2). Each patient was followed up for up to 12 months after initial prescription. End of follow up was defined as the first occurrence of one of the outcome diagnoses. The follow-up time of 12 months only was considered as the most patients with 5ARI and α1-adrenoceptor antagonists therapy discontinue this therapy within 12 months (low persistence) [Citation25].
The incidences of these study outcomes for PRO 160/120 were compared to those for finasteride and dutasteride (5ARIs), tamsulosin, and tamsulosin/dutasteride fixed-dose combination. Tadalafil was not considered as this drug occupies a special position in the German market. As a 5-phosphodiesterase inhibitor in the higher dosage of 10 mg or 20 mg, the application is erectile dysfunction. In these cases, tadalafil is considered a lifestyle preparation without public insurance reimbursement. After patent expiry in 2017, the active ingredient in a 5 mg dose for BPH treatment as a line extension was introduced. This time period however includes only a part of our study time period. Tamsulosin makes >90% of alpha-blocker prescriptions; finasteride and dutasteride makes >90% of 5α-reductases; other drugs were prescribed only rarely in Germany what is why we only investigated these drugs.
Statistical analyses
The study population was described using patient age as a categorical variable (< 50 years, 50–59 years, 60–69 years, 70–79 years, ≥80 years), insurance status (private or statutory), physician specialty (GP or urology), co-diagnoses documented prior to the index date or during the follow-up time (hypertension (ICD-10: I10), diabetes mellitus (ICD-10: E10–E14), stroke/transient ischemic attack (TIA) (ICD-10: I63, I64, G45), dementia (ICD-10: F01–F03, G30), Parkinson’s disease (ICD-10: G20, G21), obesity (ICD-10: E66), cancer (ICD-10: C00–C97), tobacco addiction (ICD-10: F17), alcohol addiction (ICD-10; F10), use of beta blockers (ATC: C07), use of anticholinergics (ATC: G04BD4). The share of patients diagnosed with BPH (ICD-10: N40) and the distribution of therapy duration for all therapies are also shown.
A multivariable logistic regression analysis was performed to estimate the association between prescription and the incidence of BPH-related complications. The results of the logistic regression analysis were displayed using Odds Ratios (HR) with 95% confidence intervals (CI) adjusted for age, insurance status, physician specialty, and co-diagnoses documented until the end of follow-up. A separate multivariable logistic regression model was used for each defined outcome.
In a sensitivity analysis – yielding very similar results, regression models were calculated separately for patients with a documented BPH diagnosis (ICD-10: N40) within the complete patient history (data not shown).
Finally, as a further sensitivity analysis, patients with prescription of dutasteride, finasteride, tamsulosin, and a dutasteride/tamsulosin combination were each 1:1 matched by age to patients with PRO 160/120 prescription. Regression analyses described previously were repeated for four matched pair cohorts.
Results
Baseline characteristics of study patients
Overall, 77,923 patients were included in the study, 3,035 of whom received PRO 160/120, 3,133 finasteride, 418 dutasteride, 64,962 tamsulosin, and 3,375 tamsulosin/dutasteride fixed-dose combination. The demographic and clinical characteristics of the study sample are displayed in . Of all patients receiving PRO 160/120, 71.3% (2,168 patients) had a documented BPH diagnosis (ICD-10: N40) within their patient history, which is comparable to patients treated with one of the other therapies (finasteride: 68.5%; dutasteride: 81.6%; tamsulosin: 76.8%; tamsulosin/dutasteride: 84.4%). The median age of PRO 160/120 patients was 66.0 years (IQR: 17 years), which was lower than that of the patients receiving one of the other drugs (finasteride 71.0 years; dutasteride: 73.0 years; tamsulosin: 70.0 years; tamsulosin/dutasteride: 74.0 years). Almost half of PRO 160/120 and dutasteride patients, respectively, were covered by private insurance (41.8%, 47.1%), while the proportion of private insurance was lower for the other therapies (finasteride: 17.4%, tamsulosin: 13.8% tamsulosin/dutasteride: 28.7%). PRO 160/120 patients were more likely to receive their prescription from a GP (66.2%). Compared to tamsulosin, patients receiving a PRO 160/120 prescription were less likely to have diabetes mellitus (11.5% vs 16.5%), stroke or TIA (1.7% vs 3.4%), dementia (2.0% vs 3.4%), cancer (7.8% vs 12.4%), and less likely to use beta blockers (16.1% vs 18.1%) or anticholinergics (3.7% vs 6.3%) ().
Table 1. Demographic and clinical characteristics of study patients.
Number of clinical complications
shows the number of new clinical complications that occurred within 12 months after the initial prescription.
Table 2. Number of patients with clinical complications between 1 and 365 days after index date.
Of all PRO 160/120 patients, 47 (1.5%) had a documented diagnosis of urinary incontinence, 33 (1.1%) of polyuria, 9 (0.3%) of urinary retention, and 37 (1.2%) a diagnosis of erectile dysfunction. In total, 126 (4.2%) patients had at least one of these outcomes, which is comparable to the result for finasteride (3.8%) and significantly lower than the result for dutasteride (6.5%), tamsulosin (6.8%), and tamsulosin/dutasteride fixed-dose combination (6.2%).
Association between PRO 160/120 prescription and incidence of LUTS and its therapy-related outcomes
show the results of the multivariable logistic regression models. With the follow-up period starting 1 day after index prescription, PRO 160/120 was significantly associated with a lower incidence of urinary incontinence compared to tamsulosin (OR: 1.48; 95% CI: 1.10–1.98; p = 0.010) (). With regard to the incidence of polyuria including nocturia, finasteride was significantly associated with a lower odds compared to PRO 160/120 (OR: 0.46; 95% CI: 0.28–0.74%; p = 0.002) (). Table 5 shows that PRO 160/120 significantly reduced the incidence of urinary retention compared to tamsulosin (OR: 3.39; 95% CI: 1.75–6.57; p < 0.001) and tamsulosin/dutasteride (OR: 2.81 (95%CI: 1.35–5.82); p = 0.006). Furthermore, PRO 160/120 reduced the risk of erectile dysfunction compared to dutasteride (OR: 2.79; 95%CI: 1.49–5.25; p = 0.001) ().
Table 3. Association between PRO 160/120 prescriptions and the incidence of urinary incontinence, polyuria, incl. nocturia, urinary retention, erectile dysfunction (multivariable logistic regression models).
In the sensitivity analyses done based on age-matched pairs, associations were similar ().
Table 4. Association between PRO 160/120 prescriptions and the incidence of urinary incontinence, polyuria, incl. nocturia, urinary retention, erectile dysfunction (multivariable logistic regression models) in cohorts matched by age.
Discussion
This retrospective study based on real-world data from around 78,000 patients in Germany treated for BPH suggests that treatment with PRO 160/120 is associated with a low incidence of urinary incontinence, retention, and erectile dysfunction. Because of the absence of clinical BPH parameters such as International Prostate Symptom Score (I-PSS), prostate volume, or uroflowmetry in our database and the non-randomized design of the study we cannot exclude differences in disease severity between groups as a potential selection bias.
Nevertheless, this is the first evidence produced which indicates that PRO 160/120 seems to be negatively associated with urinary incontinence and retention compared to tamsulosin. This could clinically support the theory that the suppression of inflammation in the prostate can influence the clinical outcome.
Given the fact that urinary incontinence in this population is most likely due to overactive bladder (OAB) one might speculate that the postulated anti-inflammatory activity might has a beneficial effect regarding the development of OAB.
Bschleipfer and Burkart summarized the evidence concerning the effects of BPH treatment on sexual function and concluded that α1-adrenoceptor antagonist can lead to reversible ejaculation disorders in up to 70% of patients, depending on the substance [Citation14]. It is further concluded that the 5-ARIs finasteride and dutasteride have a negative effect on ejaculation, libido, and erectile function and that treatment with tamsulosin/dutasteride fixed-dose combination therapy significantly worsens sexual function in men. There is evidence that saw palmetto extract can have a favorable effect on sexual function compared to placebo, or at least that it does not worsen it [Citation14]. In the present study, PRO 160/120 had a lower incidence of erectile dysfunction than dutasteride. Our results are in line with those of a literature review of the clinical evidence of PRO 160/120 [Citation22]. Based on four placebo- or reference-controlled clinical trials, it was shown that PRO 160/120 is superior to placebo and comparable with finasteride and tamsulosin in terms of I-PSS total score within a follow-up period of between 24–48 weeks. Compared to finasteride, PRO 160/120 had a better safety profile with fewer reported adverse events such as erectile dysfunction, ejaculation volume, or headache and also showed a better tolerability, with a lower rate of premature withdrawals. Furthermore, another recent meta-analysis concluded that Serenoa repens (one of the compounds of PRO 160/120) had a comparable effect to that of tamsulosin in patients with BPH after at least 6 months of treatment. The meta-analysis also showed that Serenoa repens had fewer side effects, such as ejaculation disorders and decreased libido [Citation26].
Study limitations
Other studies investigating BPH-related symptoms and outcomes often use QoL questionnaires such as the I-PSS, in which patients can give their subjective assessments of their symptoms and general health. As only documented, confirmed diagnoses were analyzed in our study, mild side effects like dizziness or effects on sexual function may not have been documented or insufficiently documented by physicians.
Another limitation of the present study is that the assessments are based on ICD codes entered by GPs and urologists. Diagnosis codes do not allow for the distinction of the severity of BPH or the outcomes. The major limitation of this study is the lack of clinical BPH data such as prostate volume, uroflowmetry, and post-void residual volume. Therefore, it was not possible to grade patients with respect to disease and the possibility of a selection bias relating to the various treatment arms cannot be excluded.
Moreover, PRO 160/120 are drugs which are not covered by public health insurance companies, but 5-ARIs and alpha blockers are covered by them. This may have an effect on the prescription frequency but should not impact the incidence of the outcomes. Furthermore, we have no knowledge of any physician or patient preferences which could have influenced the prescription of PRO 160/120 or a reference therapy. That’s being said, to buy herbal medicines, which are usually out-of-counter drugs, patients mostly do not need a prescription from physicians, but many physicians recommend such medications.
Only around 70% of the patients received a documented BPH diagnosis during their patient history. This can be explained by the fact that, in Germany, the physician does not need to document a diagnosis for each prescription. This effect is known in other therapeutic areas, too. Therefore, it is reasonable to assume that patients receiving PRO 160/120, 5-ARIs, or alpha blockers are mainly being treated for BPH. Nevertheless, we conducted a sensitivity analysis, which yielded very similar results.
Retrospective cohort studies like this are subject to multiple limitations as stated above. Randomized controlled trials are necessary to demonstrate the superiority of one treatment against another. However, where evidence from RCTs is lacking, studies based on real-world data can play an important role in healthcare research.
To date, the only evidence on the effectiveness of PRO 160/120 and the reference therapies has come from either placebo- or reference-controlled clinical trials. This study adds evidence from a real-world setting for the first time.
Conclusion
In conclusion, we observed a significant association between PRO 160/120 prescription and reduced incidence of urinary incontinence and urinary retention compared to tamsulosin and tamsulosin/dutasteride, as well as reduced incidence of erectile dysfunction compared to dutasteride.
Declaration of financial/other relationships
SM and MR report receiving consulting fees from Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany. KR and KK are employees of IQVIA, Frankfurt, Germany.
Declaration of funding
This study was funded by Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany. The pharmaceutical company was not involved in the study design and analysis but only in the correction of the manuscript.
Reviewer disclosures
Peer reviewers on this manuscript have received an honorarium from PGM for their review work but have no other relevant financial relationships to disclose.
Acknowledgments
None stated.
Data availability statement
Derived data supporting the findings of this study are available from the corresponding author on reasonable request.
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