Alpha-Blocker Therapy Can Be Withdrawn in the Majority of Men Following Initial Combination Therapy with the Dual 5α-Reductase Inhibitor Dutasteride

doi:10.1016/S0302-2838(03)00367-1

European Urology

Volume 44, Issue 4, October 2003, Pages 461-466

https://doi.org/10.1016/S0302-2838(03)00367-1 Get rights and content

Abstract

Objectives: The Symptom Management After Reducing Therapy (SMART-1) study examined the combination of the dual action 5α-reductase inhibitor (5ARI) dutasteride, and α₁-blocker tamsulosin, followed by withdrawal of tamsulosin in men with symptomatic BPH.

Methods: 327 BPH patients were randomised to 0.5 mg dutasteride and 0.4 mg tamsulosin for 36 weeks (DT36) or 0.5 mg dutasteride and 0.4 mg tamsulosin for 24 weeks followed by dutasteride and tamsulosin matched placebo for the remaining 12 weeks (DT24+D12). Patients’ assessment of their symptoms, IPSS at weeks 24, 30, and drug safety were evaluated.

Results: 77% of DT24+D12 patients felt the same/better at week 30 compared with week 24 (changes in IPSS were consistent with this finding). Of those subjects with an IPSS <20 who changed to dutasteride monotherapy at week 24, 84% switched without a noticeable deterioration in their symptoms. In the 27% of men with severe baseline symptoms (IPSS ≥20) who had withdrawal of tamsulosin therapy at week 24, 42.5% reported a worsening of their symptoms compared with 14% in the DT36 group. The regimens were well tolerated.

Conclusions: Dutasteride can be used in a 24-week combination with tamsulosin, to achieve rapid onset of symptom relief in patients at risk of underlying disease progression. This symptom relief is maintained in the majority of patients after the α₁-blocker is removed from the combination. Patients with severe symptoms may benefit from longer-term combination therapy.

Introduction

Data from both longitudinal studies, and the placebo arms of clinical trials, have shown that benign prostatic hyperplasia (BPH) is a progressive disease in many men [1], [2], [3]. Prostate volume increases with advancing age: a change that is associated with decreased urinary flow, increasing symptom severity, increased risks of acute urinary retention (AUR) and the need for BPH-related surgery [1], [2], [3].

Currently, two therapeutic drug classes with differing modes of action provide the mainstay of pharmacotherapy for BPH. 5α-reductase inhibitors (5ARIs) impede the conversion of testosterone to dihydrotestosterone (DHT), which is the primary androgen driving both normal prostate development, and the hyperplasia of the prostatic transitional zone that is responsible for the development of BPH. The dual-action 5ARI dutasteride, which inhibits both the type 1 and 2 isoforms of 5AR, has been shown to achieve ≥90% DHT suppression in >85% of subjects [4]. 5ARIs have been shown to significantly reduce total and transitional zone prostate volume in men with BPH and enlarged prostates (>30 cc) compared with placebo. This reduction in the static component of bladder outlet obstruction (BOO) results in significant improvements in lower urinary tract symptoms (LUTS) and maximum urinary flow rate (Q_max). Furthermore, long-term, placebo-controlled studies have shown that 5ARIs significantly reduce the risk of both AUR and BPH-related surgery in men with BPH [3], [5], [6].

α₁-adrenoceptor blockers target the dynamic component of BOO by decreasing smooth muscle tone in the prostate gland, prostatic capsule, prostatic urethra and bladder [7]. The dynamic component accounts for up to 40% of the obstruction seen in BPH [8]. Although α₁-blocker therapy is associated with a rapid onset of symptom relief and improvement in Q_max in men with BPH, they lack the effect of the 5ARIs on prostate volume. This may explain the finding that α₁-blockers can delay AUR or the need for BPH-related surgery, but they do not lower the long-term risk of these events [6]. Their inability to reduce prostate volume may also account for the finding that rates of treatment failure with α₁-blockers are higher in men with larger (>40 cc), versus smaller prostate volumes [8], [9].

Improvements in symptoms observed with 5ARIs may not be observed until 3–6 months of therapy. This suggests an initial short-term role for α₁-blockers in men for whom a more rapid onset of symptom relief is required, with withdrawal of the α₁-blocker following an initial period of combination therapy. Baseline, long-term therapy with a 5ARI is maintained to reduce prostate volume and positively impact on the long-term risk of BPH progression, reducing the risk of AUR- and BPH-related surgery. This hypothesis has been examined in a study in which 111 men with a prostate mass ≥40 g, and severe symptoms (International Prostate Symptom Score, IPSS ≥20) were initially treated with both finasteride and doxazosin [10]. Of these, 100 responded to treatment, and α₁-blocker-therapy was withdrawn at 3, 6, 9 or 12 months. Success rates (defined as no increase in IPSS and responding ‘no’ to the question ‘Would you like to restart the doxazosin?’) for discontinuation were 20%, 48%, 84% and 84% respectively, suggesting that, for this severe patient population, a period of nine months or more of combination therapy was preferable.

The primary objective of the Symptom Management After Reducing Therapy (SMART-1) study was to investigate whether men with symptomatic BPH, who are at higher risk of progression due to an enlarged prostate, receiving a combination of the dual-action 5ARI dutasteride and the α₁-blocker tamsulosin, would experience deterioration in their symptoms following withdrawal of the α₁-blocker. SMART-1 was designed to provide information that would be of use for clinicians making decisions on how to manage combination therapy in men with BPH.

Section snippets

Subjects

The SMART-1 Phase 3B clinical study was conducted at 32 centres in six countries: Canada, Germany, the Netherlands, Portugal, Russia and the UK. Patients at risk for BPH progression were recruited into the study. Inclusion criteria were: 45 years of age or over with a diagnosis of BPH, including moderate to severe urinary symptoms (IPSS ≥12) and a prostate volume ≥30 cc as determined by digital rectal examination (DRE). Patients with a prostate-specific antigen (PSA) value <1.5 ng/ml or >10 ng/ml

Baseline demographics and study conduct

A total of 327 subjects were included in the two treatment arms. The two study groups were comparable for mean baseline age (67.6±7.1 and 66.9±7.5 years), IPSS (16.4±5.8 and 16.5±5.2) and serum PSA level (4.3±2.2 and 4.3±2.3 ng/ml, for the DT36 and DT24+D12 groups, respectively).

A total of 154 (94%) and 151 (93%) subjects from the DT36 and the DT24+D12 groups completed the first 24 weeks of the study. Ninety-one percent of subjects from both treatment groups completed the 36-week study. The most

Discussion

This study defines a role for the addition of short-term (6 months) α₁-blocker therapy, to a foundation of 5ARI therapy, in providing symptomatic improvement among patients who require rapid symptom relief to cover the lag in onset of symptom relief seen with 5ARI monotherapy. The primary finding from this study is that in men with BPH initially treated with a combination of dutasteride and tamsulosin, the α₁-blocker can be withdrawn in the majority of patients (77%) after 6 months with

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Cited by (191)

The impact of combination therapy of Croton membranaceus and finasteride on benign prostatic hyperplasia (BHP) histo-morphology
2024, Phytomedicine Plus
Benign Prostatic hyperplasia (BPH) is one of the age-related conditions that reduce the quality of life in aging men. Treatment modalities range from surgical, use of allopathic drugs, to phytotherapy. Allopathic drugs such as Finasteride and Tamsulosin are often considered to have adverse side effects such as reduced libido and erectile dysfunction. In some countries finasteride is often recommended for BPH although some prefer the use of Croton membranaceus (CM). However, some indigenes combine the two. The study therefore sought to determine impact of this combination therapy of CM and on BPH histomorphologically.
Thirty-five (35) male Sprague Dawley rats (200–250 g) made up of the following groups were established with 5 rats in each group: Group 1, served as the control group; group 2 (model group); group 3 (0.5 mg/kg.b.wt Finasteride- positive control); group 4 [30 mg/kg b.wt. CM (low dose)]; group 5 [300 mg/kg b.wt. CM (high dose)]; group 6 (30 mg/kg b.wt. CM plus 0.5 mg/kg. b.wt. Finasteride); group 7 (300 mg/kg b.wt. CM plus 0.5 mg/kg b.wt. Finasteride). Groups 2–7 were castrated, allowed to rest for 7 days and BPH-induced by administering 5 mg/kg.b.wt testosterone propionate subcutaneously daily for 28 days. CM and Finasteride were administered for 28 days by oral gavage. The prostate and its accessory organs were weighed and examined histologically.
In the untreated group (model group) fibromuscular stroma showed the typical characteristic of high epithelial folds with apparent typical hyperplasia. The Finasteride group showed increased rate of apoptosis and progressive decrease in epithelial cell size. At the lower dose of CM, not enough apoptotic areas were observed. However, multiple layers of acinar epithelia were noticed. At the higher dose of CM, few apoptotic cells were seen with acini fluid reduction. The combination of Low dose CM and Finasteride led to fluid level reduction in the acini accompanied by fat droplets and reactive cells infiltration. At a higher dose of CM, papillary fronds were not protruded into the acini. However, acini fluid appeared coagulated. The combination treatment did not have any adverse hepatorenal effect, nor did it change PSA significantly.
No overt advantage was seen in this combination therapy, although higher doses of CM in tandem with finasteride may not be advisable. However, there was good tolerability.
Understanding Treatment Response in Individual Profiles of Men with Prostatic Enlargement at Risk of Progression
2023, European Urology Focus
It is unclear how cumulative multivariable effects of clinically relevant covariates impact response to pharmacological treatments for lower urinary tract symptoms (LUTS)/benign prostatic enlargement (BPE).
To develop models to predict treatment response in terms of International Prostate Symptom Score (IPSS) and the risk of acute urinary retention (AUR) or BPE-related surgery, based on large data sets and using as predictors baseline characteristics that commonly define the risk of disease progression.
A total of 9167 patients with LUTS/BPE at risk of progression in three placebo-controlled dutasteride trials and one comparing dutasteride, tamsulosin, and dutasteride + tamsulosin combination therapy (CT) were included in the analysis to predict response to placebo up to 24 mo and active treatment up to 48 mo.
Predictors included age, IPSS, total prostate volume (PV), maximum urinary flow rate (Q_max), prostate-specific antigen, postvoid residual urine (PVR), α-blocker usage within 12 mo, and randomised treatment. A generalised least-squares model was developed for longitudinal IPSS and a Cox proportional-hazards model for time to first AUR/surgery.
The vast majority of patients benefit from dutasteride or CT when compared with tamsulosin alone. The predicted IPSS improvement with dutasteride or CT increased with greater PV and severity of symptoms at baseline. The tamsulosin effect was lower with greater baseline PV and tended to decrease over time. Predicted AUR/surgery risk was greater with tamsulosin versus CT or dutasteride; this risk increased with larger PV, higher PVR, and lower Q_max (all at baseline). An educational interactive web-based tool facilitates visualisation of the results (www.bphtool.com). Limitations include: the placebo and active-treatment predictions are from different studies, the lack of similar studies for external validation, and the focus on a population at risk of progression from the 4-yr CombAT study.
Predictive modelling based on large data sets and visualisation of the risk for individual profiles can improve our understanding of how risk factors for disease progression interact and affect response to different treatments, reinforcing the importance of an individualised approach for LUTS/BPE management.
We used data from previous studies to develop statistical models for predicting how men with lower urinary tract symptoms or benign prostate enlargement and at risk of disease complications respond to certain treatments according to their individual characteristics.
Scoping Review of Randomized Trials With Discontinuation of Medicines in Older Adults
2022, Journal of the American Medical Directors Association
To map the randomized trial evidence describing the feasibility of discontinuing active medications with potential adverse effects in older patients.
Scoping review with systematic search of PubMed, Embase, and Cochrane Library.
Randomized trials investigating discontinuation of a single medicine or medicine class in patients with mean age ≥65 years.
We extracted trial characteristics including study design and assessed bias. As proxies for the “feasibility of discontinuation,” we extracted the “dropout rate” and “disease recurrence rate.”
We identified 40 trials investigating discontinuation of symptomatic (n = 26), preventive (n = 6), or both preventive and symptomatic medicines (n = 8) against psychiatric (n = 10), neurologic (n = 9), musculoskeletal (n = 8), cardiovascular (n = 5), respiratory (n = 4), and urologic diseases (n = 4). Five discontinuation designs were used, 75% (30/40) of trials were placebo-controlled, and 48% (19/40) of trials had bias disfavoring discontinuation. The dropout rate was similar between the discontinuation group and the continuation group in 79% of the trials (30/38), whereas disease recurrence was similar in 72% (23/32) of the trials. In 42% (13/31) of trials reporting both dropout rate and disease recurrence rate, the differences between groups were statistically insignificant and less than 10%; these trials investigated discontinuation of cholinesterase inhibitors for Alzheimer's disease in various settings (n = 3), alendronate for osteoporosis (n = 3), glucosamine for osteoarthritis, lithium as adjunct for unipolar depression, statins for cardiovascular disease in patients with limited life expectancy, droxidopa for neurogenic orthostatic hypotension, tamsulosin for lower urinary tract symptoms, sertraline for major depressive episode, and fentanyl patch for low back or osteoarthritis pain.
We identified 40 randomized trials using a variety of designs investigating discontinuation of both symptomatic and preventive medicines in older patients. Discontinuation of medicines seems feasible for most of the investigated medicines. This scoping review can guide clinical practice and future trials on deprescribing.
Which Drug to Discontinue 3 Months After Combination Therapy of Tadalafil plus Tamsulosin for Men with Lower Urinary Tract Symptom and Erectile Dysfunction? Results of a Prospective Observational Trial
2021, European Urology Focus
Citation Excerpt :
As previously reported for the combination therapy of tamsulosin and dutasteride, the withdrawal of tamsulosin after 24 wk of combination therapy had no significant effect on urinary outcomes. Indeed, LUTS relief was maintained in the majority of patients after tamsulosin was removed from combination, and the authors concluded that only patients with severe symptoms may benefit from longer-term combination therapy [29]. Even if combination therapy with tamsulosin and tadalafil achieved better urinary and sexual outcomes, after a further 12 wk of monotherapy, both drugs were able to preserve a significant recovery of urinary function from baseline.
Safety and efficacy of tamsulosin and tadalafil for men with benign prostatic enlargement (BPE) and/or erectile dysfunction (ED) are defined. However, there are only a few pilot studies on combination therapy with these drugs for men with lower urinary tract symptom (LUTS)/BPE and ED. Moreover, preliminary reports are limited to 12 wk, without any information about subsequent therapies.
To evaluate the impact of discontinuation of tamsulosin versus tadalafil 12 wk after combination therapy.
Fifty consecutive patients with moderate-to-severe LUTS (International Prostate Symptom Score [IPSS] > 7) and mild-to-severe ED (International Index of Erectile Function-5 [IIEF-5] < 22) were treated with combination therapy (tamsulosin 0.4 mg/d plus tadalafil 5 mg/d) for 12 wk. After 12 wk, 25 patients discontinued tamsulosin (Group TAD), while 25 patients discontinued tadalafil (Group TAM).
Efficacy variables were IPSS (total, voiding, storage) and IIEF-5. Paired samples t test and analysis of variance were used.
Groups TAD and TAM presented similar features (age, BMI, metabolic profile) including symptoms scores at baseline. Similar and significant improvements in IPSS (total, voiding, and storage) and IIEF-5 were recorded in both groups after 12 wk of combination therapy (all p < 0.001). Total IPSS was similar between the two groups at the end of the trial. However, we found between-group significant differences from baseline to 24 wk and from 12 to 24 wk in storage-IPSS (Group TAD: –3.32 vs Group TAM: –1.24, p = 0.002; Group TAD: +0.24 vs Group TAM: +1.20, p = 0.040, respectively) and in IIEF-5 (Group TAD: +4.64 vs Group TAM: +0.16, p < 0.001; Group TAD: –1.64 vs Group TAM: –4.40, p = 0.003). No significant treatment-related adverse event was recorded in both groups.
After 12 wk of combination therapy, monotherapy with tadalafil for further 12 wk allows to preserve the improvement of storage IPSS and IIEF-5, in addition to total IPSS.
In this report we evaluated the discontinuation of tamsulosin or tadalafil after 12 wk of combination therapy. We found that tadalafil monotherapy, for a further 12 wk, aids in retaining the improvement of storage symptoms and erectile function.
Commentary RE: “Efficacy and Safety of a Dual Inhibitor of 5-Alpha-Reductase Types 1 and 2 (Dutasteride) in Men With Benign Prostatic Hyperplasia”
2020, Urology
Medical Aspects of the Treatment of LUTS/BPH: Combination Therapies
2018, Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia: From Research to Bedside
Several drugs have been approved for the treatment of nonneurogenic lower urinary tract symptoms (LUTS). 5α-Reductase inhibitors (5ARIs) and α1-blockers (AB) represent the mainstay of medical treatment of male LUTS. These drugs have different modes of actions and the rationale of a combination therapy is to act toward different pathological mechanism of LUTS, to hopefully obtain improved results. In men with moderate-to-severe LUTS and risk of disease progression, a treatment with AB + 5ARI is superior compared to monotherapy in term of symptoms relief, increase of flow max, quality of life, and reduction of risk of progression. Another combination treatment includes AB together with an antimuscarinic agent or a β3-adrenoreceptor agonist. The association of such drugs is indicated in patients with troublesome storage symptoms, excluding those with elevated postvoid residual urine. Combination therapies including plant extracts are common but are not supported by scientific evidence. More recently, a novel combination therapy has been described, 5ARI or AB + tadalafil.
In conclusion, in selected patients a combination therapy with different class of drugs has demonstrated a therapeutical benefit, but this must be balanced with a higher cost and a higher rate of side effects.

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¹: Members of the SMART-1 Investigator Group are listed in the Appendix A.

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Alpha-Blocker Therapy Can Be Withdrawn in the Majority of Men Following Initial Combination Therapy with the Dual 5α-Reductase Inhibitor Dutasteride

Abstract

Introduction

Section snippets

Subjects

Baseline demographics and study conduct

Discussion

Eur. Urol. Suppl.

Urology

J. Urol.

J. Urol.

The progression of benign prostatic hyperplasia: examining the evidence and determining the risk

Eur. Urol.