Know When to Hold ‘Em – Know When to Fold ‘Em. Deprescribing in BPH.

“You no longer need to take this medication” is music to a patient’s ears.  How often do clinicians have the opportunity to tell patients that stopping a medication is possible for a chronic condition?  A recently published study explores the possible benefits to discontinuing an alpha-1 blocker after receiving combination therapy with a 5-alpha reductase inhibitor for the treatment of benign prostatic hyperplasia (BPH).¹

Although the etiology of BPH is unknown, the hyperproliferation of smooth muscle and endothelial cells within the prostate likely contribute to lower urinary tract symptoms (LUTS) such as nocturia, urinary frequency, urgency, hesitancy, straining, dribbling, and incomplete bladder emptying.²  The complex relationship between BPH and LUTS are believed to be related to two pathways: direct bladder outlet obstruction and increased smooth muscle tone, decreasing urine flow.  In more symptomatic patients, or patients with confirmed, enlarged prostates, it is recommended to use both medication classes (alpha-1 blocker and 5-alpha reductase inhibitor) to minimize symptoms by relaxing the prostatic smooth muscle and reducing the size of the prostate – producing a potentially synergistic effect.²  The Combination of Avodart and Tamsulosin (CombAT) study demonstrated that combination therapy with dutasteride and tamsulosin was superior to monotherapy with dutasteride or tamsulosin alone in treatment-naïve men over a 4-year follow-up period.^3,4  After 12 months of treatment, the dutasteride group had continued improvement in subjective symptoms that paralleled the combination group; whereas, the tamsulosin group slowly worsened.³  This suggests that the symptom improvement was driven by the 5-alpha-reductase inhibitor and begs the question if indefinite combination therapy is needed.

Matsukawa and colleagues conducted a single Japanese center, randomized, prospective study to evaluate the withdrawal of alpha 1-blockers from combination therapy.¹  The study outcomes included both BPH symptoms and urodynamic measures.  Subjects with LUTS who presented between May 2010 and December 2012 and met the inclusion criteria (Table 1) were enrolled in the study.

Table 1: Study Inclusion and Exclusion Criteria

^{*International Prostate Symptom Score (8-19 [moderate], 20-35 [severe]), **I-PSS Quality of Life (score 0-6; higher scores indicate worse QOL rating)}

All subjects were treated with 12 months of combination therapy (dutasteride 0.5 mg/day and silodosin 8 mg/day) then randomized, in an unblinded manner, to either continued combination therapy or dutasteride as monotherapy for an additional 12 months (See Figure 1).  The primary outcome was change in International Prostate Symptom Score (I-PSS).  The trial was powered for non-inferiority between combination and monotherapy; if no difference was found between groups, then superiority would be analyzed. Secondary outcomes included both subjective measures (I-PSS-QOL, Overactive Bladder Symptom Score [OABSS]) and objective measures (urodynamic studies [UDS]) to evaluate bladder storage and voiding function.  Subjects were also categorized into two dicotinous outcome groups — “I-PSS improved/neutral” or “I-PSS worsened” — and charateristics that were associated with these outcomes were examined.

A total of 150 men were screened for the study, 132 were randomized, and 117 completed the 24-month trial, 57 in the combination therapy group and 60 in the monotherapy group.  Baseline age was similar in the two groups (approximately 70 years).  The authors did not report any other baseline demographic information other than age.  After 12 months of combination therapy, all outcomes significantly (p < 0.001) improved from baseline.  At 24 months, no differences were found between combination therapy and monotherapy groups (Table 2).  The primary outcome demonstrated non-inferiority but not superiority.

Table 2: Select Study Results

^{CT = Combination therapy; MT = Monotherapy; *CT vs. MT at 24 months; QOL = Quality of life; PVR = Post-void residual}

After randomization, the I-PSS worsened in 38.3% (n=23) of the subjects in the monotherapy group and in 26.3% (n=15) of the subjects in the combination group, p = 0.11.  In the monotherapy “I-PSS improved/neutral” group vs “I-PSS worsened” group analysis, the only significant differences were observed in those with an elevated body mass index (BMI) and worsening of symptoms appeared to be related to body weight (Table 3).

Table 3: Characteristics of patients based on I-PSS change after switch to monotherapy

Withdrawal due to drug-related adverse reactions was low with 3 patients dropping out during the first 12 months and 5 patients dropping out after randomization: 3 (4.5%) in the combination group and 2 (3.0%) in the monotherapy group.  Withdrawal from the trial due to urinary retention was also low (n=3).

The trial has several strengths including a low attrition rate, longer follow-up (than previously published withdrawal trials), and the use of both subjective and objective assessments of urinary function.  The I-PSS was appropriate for both research and clinical practice purposes; it is a validated tool to assess BPH-related symptoms.⁵  The I-PSS is similar to the American Urological Association Symptom Index (AUA-SI) questionnaire and but includes a question regarding how BPH symptoms affect quality of life (QOL).  After conversion to monotherapy, grouping patients into cohorts who experienced worsening of symptoms and those who did not enabled the investigators to identify patient characteristics associated with worse outcomes.

Despite these strengths, there are several limitations.  First, this was an open-label study – not a placebo controlled.  Being aware of the treatment withdrawn could impact the reporting of symptoms.  An independent investigator evaluated the UDS using de-identified data and this improves the validity of the objective findings.  Second, adherence to the treatment was not reported; therefore it is unclear how adherent the subjects were to the regimen both before and after randomization.  This is especially relevant given that a retrospective study found adherence rates to BPH medications at 12 months was very low (only 29%) and decreased with each subsequent year.⁶

Per the AUA BPH guidelines, the use of any alpha-1 blocker is considered equally efficacious with minor differences in adverse effect profile.²  However, there are few peer-reviewed studies directly comparing alpha-1 blocker agents head-to-head.   Silodosin is approved in the U.S. but is not commonly prescribed and may affect the general recommendation compared to the other alpha-1 blocker agents. Given that the study was conducted at a single Japanese center, it reduces the generalizability and the results might not apply to a more diverse patient population.  More studies are needed that evaluate the impact of weight and obesity on symptoms and the effectiveness of BPH treatment.

This study found that withdrawal of alpha 1-blockers after a year of combination therapy did not worsen urinary symptoms, QOL, and voiding or storage function.  This provides evidence that combination therapy may not be needed indefinitely for all patients.  The results could be of significant value in reducing drug cost and exposure to adverse effects.  Are the results convincing enough?  Would you considering recommending a trial off alpha-1 blocker therapy after 1 year of combination therapy?  Tell us what you think.