Experience with the combination of dutasteride and tamsulosin in the long-term management of benign prostatic hyperplasia

Abstract

Lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) commonly affect older men. These bothersome symptoms can lead to a decreased quality of life. Currently, two classes of drugs – α-adrenergic blockers and 5α-reductase inhibitors – are prescribed to treat LUTS secondary to BPH. Due to their different mechanisms of action, these medications work in a synergistic manner. Trials of combination therapy have been conducted to assess its effect compared with monotherapy. Current data support combination therapy in men with moderately enlarged prostates and moderate to severe symptoms.

Introduction

Men with lower urinary tract symptoms (LUTS) attributed to benign prostatic hyperplasia (BPH) have impaired health-related quality of life [O’Leary et al. 2003; Wei et al. 2005]. BPH is found in approximately half of all men by the time they reach age 40 [McNaughton-Collins and Barry, 2005; Oishi et al. 1998]. Half of these men will eventually develop bothersome LUTS [Oishi et al. 1998]. The aims of BPH treatments are threefold: improving subjective symptoms, preventing disease progression, and improving quality of life. First-line therapy, after conservative measures, revolves around medical therapy. The two main categories of pharmacological agents used for the treatment of BPH include α-adrenergic antagonists (α blockers) and 5α-reductase inhibitors (5ARIs) [AUA Clinical Practice Guidelines Committee, 2003]. Additional second-line medical therapies include phosphodiesterase type 5 inhibitors and anticholinergics. The focus of this article will be the combination therapy of α blockers and 5ARIs.

All patient assessments should begin with a thorough history and physical examination. This alone will help to identify risk factors that could lead to LUTS secondary to an enlarged prostate [AUA Clinical Practice Guidelines Committee, 2003]. The medical history should include any causes that may lead to bladder dysfunction, including cerebrovascular accidents, previous surgical procedures, and history of prostate disease. It is equally important to review medications, for example diuretics that impact urinary symptoms or α agonists used as decongestants that may increase prostatic muscle tone. Furthermore, urinary symptoms should be assessed with a validated instrument such as the International Prostate Symptom Score (IPSS) [AUA Clinical Practice Guidelines Committee, 2003].

The IPSS is available in several languages and has been validated in multiple subpopulations. Scores of 0–7 are classified as mild, 8–19 as moderate, and 20–35 as severe LUTS [Abrams et al. 2009]. In general, patients with mild symptoms or those with moderate symptoms with little bother should be monitored and periodically reassessed. Those with moderate or severe symptoms should be offered some form of medical therapy. However, the IPSS does not replace a discussion with the patient about their voiding symptoms.

The physical examination should also include a prostate exam to evaluate size and the presence of nodules. The finding of asymmetry, firmness, or nodules should trigger a referral to a urologist for management of a possible prostate cancer. The prostate should also be assessed for tenderness, as this may represent acute prostatitis that may need to be treated with antibiotics. A neurological examination should also be performed. This allows for assessment of a patient’s mental status, lower neuromuscular function, and anal sphincter tone. The AUA guidelines recommend a urinalysis to screen for blood and infection to identify various other etiologies that may also lead to voiding symptoms [AUA Clinical Practice Guidelines Committee, 2003].

Treatment options

Observation

Men with an enlarged prostate and minimal clinical symptoms as per the IPSS (≤7) can often be observed [Berges, 2003]. These men can be advised about behavioral modifications, including fluid restriction, timed voiding, and double voiding. Observation can also be recommended for those with moderate symptoms (8–19 points) with minimal bother. These patients do require periodic reevaluation to avoid recurrent infection, bladder stones, urinary retention, refractory hematuria, or renal dysfunction [McVary, 2006; Thorpe and Neal, 2003].

Phytotherapy

Many natural agents have been used for LUTS. Saw palmetto is a commonly used over-the-counter medication for an enlarged prostate. In a double-blind, placebo-controlled study, 225 men with LUTS were randomized to either saw palmetto or placebo. American Urological Association (AUA) Symptom Index (AUASI), maximal urinary flow rate, changes in prostate size, residual urinary volume after voiding, and quality of life were assessed. There was no benefit in either subjective or objective parameters measured after a 12-month treatment period [Bent et al. 2006]. The AUA and the European Association of Urology do not support the use of saw palmetto.

α Blockers

α Blockers are recommended as first-line agents in patients with an enlarged prostate less than 40 g in size and bothersome LUTS [Berges, 2003; Lepor, 1998b]. α Blockers decrease bladder outlet resistance provided by urethral smooth muscle and possibly striated sphincter tone to alleviate LUTS [Milani and Djavan, 2005]. As a class, α blockers have a side-effect profile that includes orthostatic hypotension and dizziness. The use of α blockers may result in retrograde ejaculation [Milani and Djavan, 2005]. All medications in this class should be stopped prior to cataract surgery for fear of intraoperative floppy iris syndrome, which may make cataract extraction particularly difficult [Chang and Campbell, 2005].

Symptoms of bladder outlet obstruction (BOO) resulting from BPH are attributable to both static and dynamic processes within the prostate. When there is a proliferation of smooth muscle cells within the prostatic stroma, the entire prostate gland increases in size, accounting for the static component of BPH [Barkin, 2011]. However, the size of the prostate does not necessarily correlate to the severity of men’s LUTS. Increases in smooth muscle tone of the bladder neck and prostate also result in bladder outlet constriction [Anderson, 1993]. This dynamic component is mediated by sympathetic nervous stimulation of α1 adrenoreceptors. These receptors have been shown to be in abundance in the prostate, prostatic capsule and urethra, and bladder neck [Anderson, 1993]. Blocking these adrenoreceptors therefore causes bladder outlet relaxation and improves LUTS. There are three α1 adrenoreceptor subtypes: α1A, α1B, and α1D [Gillenwater et al. 1995; Kawabe et al. 2006]. The human prostate has 70% α1A adrenoreceptors [Malloy et al. 1998]. Tamsulosin is an α1A adrenoreceptor antagonist.

The α-adrenergic antagonists used to treat LUTS include doxazosin, alfuzosin, terazosin, and tamsulosin. These medications are all α1 adrenoreceptor subtype selective. α-Adrenergic antagonists have been reported to be efficacious and well tolerated [Kirby, 2003; Lepor et al. 1988; Lepor and Shapiro, 1984]. Few head-to-head trials of these agents exist. Side effects have been limited to 5–9% of patients taking these medications [Lepor and Shapiro, 1984]. Common side effects for this drug class include dizziness, postural hypotension, asthenia, rhinitis, and sexual dysfunction including abnormal ejaculation [Boyle et al. 2001]. According to the AUA Clinical Practice Guidelines Committee, α-adrenergic antagonists are beneficial in BOO [Boyle et al. 2001; AUA Clinical Practice Guidelines Committee, 2003]. Studies indicate that the AUASI is improved by four to six points with these medications.

5α Reductase inhibitors

Prostate growth is an androgen-dependent process [Coffey and Walsh, 1990]. 5-ARIs were developed to block the conversion of testosterone to dihydrotestosterone, thus reducing prostate volume and thereby decreasing BOO [Roehrborn et al. 2002]. The two commonly used medications are finasteride and dutasteride; finasteride competitively inhibits 5α-reductase type 2 and dutasteride inhibits both subtypes [Nickel, 2004; Roehrborn et al. 2002]. Side effects include erectile dysfunction, reduced libido, and decreased ejaculate volume in 5–10% of patients. Breast enlargement and tenderness may occur in 1–2% of patients [Nickel, 2004]. Dutasteride forms a stable enzyme complex with both type 1 and type 2 5α-reductase isoenzymes, acting as both a competitive and specific inhibitor. Patients with larger prostates derive more efficacy from that 5ARIs than those with smaller prostates [Nickel, 2004].

Monotherapy clinical trials

Tamsulosin

Two important double-blind, placebo-controlled, multicenter studies in the USA examining the use of α blockade (US92-03A and US93-01) enrolled 1486 men with symptoms of BPH over a 13-week period [Lepor, 1998a; Narayan and Tewari, 1998]. Patients were randomized to placebo, tamsulosin capsules 0.4 mg once daily, or tamsulosin capsules 0.8 mg once daily. Primary endpoints included AUASI score and peak urine flow rate (Q_max). The AUASI score improved significantly in groups taking tamsulosin compared with placebo when evaluated at week 13, as did Q_max. There were no significant differences in efficacy between the 0.4 mg and 0.8 mg doses of tamsulosin except in US92-03A, in which the 0.8 mg group had significantly improved AUASI score compared with the 0.4 mg group, albeit at the cost of a higher side-effect rate [Boehringer-Ingelheim, 2009; Lepor, 1998a; Narayan and Tewari, 1998].

Dutasteride

There have been several double-blind, placebo-controlled, multicenter trials evaluating dutasteride in men with BPH [O’Leary et al. 2003; Roehrborn et al. 2004]. These studies enrolled a total of 2167 men in the treatment arm and 2158 men in the placebo arm, with a 2-year open-label extension (n = 2340) [GlaxoSmithKline, 2012]. Inclusion criteria included age 50 or over, serum prostate-specific antigen (PSA) at least 1.5 ng/ml and less than 10 ng/ml. Trial subjects had AUA symptom scores in the moderate to severe range. All demonstrated prostate volumes of at least 30 cm³. Patient attrition was relatively low, with over 70% of subjects completing the study. At 12 months, the dutasteride group had a significantly improved AUASI score compared with placebo. The pooled results of the studies showed a mean decrease in AUASI score of −3.3 units compared with −2.0 units in the placebo group (range of mean difference between both groups: −1.1 to −1.5 units; p < 0.001). At 24 months, the dutasteride group had a mean decrease in AUASI score of −3.8 units compared with −1.7 units for the placebo group (range of mean difference between both groups: −1.9 to −2.2 units; p < 0.001) [GlaxoSmithKline, 2012].

Throughout the additional 2-year open-label extension, the improvements in the dutasteride group were consistent and durable. In a subset analysis, men with prostate volumes at least 40 cm³ demonstrated the greatest improvement in AUASI score at 24 months (−2.2 units; p < 0.001) [Roehrborn et al. 2005]. The primary outcome measure of number of episodes of acute urinary retention (AUR) was significantly lower in the dutasteride group compared with the placebo group (1.8% for dutasteride versus 4.2% for placebo for 57% risk reduction; p < 0.001). The other primary outcome measure of need for BPH-related surgery was also significantly lower in the dutasteride group (2.2% for dutasteride versus 4.1% for placebo for a 48% risk reduction; p < 0.001). While study inclusion for prostate volume was 30 cm³, the mean prostate volume at baseline was 54 cm³. At 12 and 24 months, the mean percentage change in prostate volume was −24.7% and −26.7% respectively compared with placebo (−3.4 and −2.2% respectively). Throughout the 2-year open-label extension, prostate volume reduction was sustained. In addition, differences in Q_max were first noted at 3 months, with mean improvement seen at 12 and 24 months as well (+0.8 ml/s and +1.1 ml/s respectively).

Combination therapy trials

The Combination of Avodart and Tamsulosin (CombAT) trial was the most recent trial investigating dual therapy with an α blocker and a 5ARI [Siami et al. 2007]. The CombAT trial was a multicenter, randomized, double-blind, placebo-controlled trial of 4844 men conducted over 4 years [Siami et al. 2007]. The study examined the efficacy of combination therapy using dutasteride 0.5 mg/day plus tamsulosin 0.4 mg/day (n = 1610) compared with monotherapy (dutasteride alone, n = 1623; tamsulosin alone, n = 1611). The primary outcome measures of the study were reduction in the relative risk of AUR, BPH clinical progression, and need for BPH-related surgery [Roehrborn et al. 2008]. Secondary endpoints included IPSS symptom scores, Q_max, prostate volume, as well as tolerability and safety. Study subjects were predicted to be at increased risk of progression based upon study enrollment parameters of moderate to severe LUTS, prostate volume at least 30 cm³, and PSA at least 1.5 ng/ml. All subjects had a clinical diagnosis of BPH and were at least 50 years of age. Additionally, subjects had an IPSS of 12 or over, PSA between 1.5 and 10 ng/ml, prostate volume of at least 30 cm³, Q_max greater than 5 and up to 15 ml/s, with a minimum voided volume of at least 125 ml.

The trial demonstrated a 65.8% relative risk reduction of AUR and need for BPH-related surgery with combination therapy compared with tamsulosin monotherapy (p < 0.001) [Roehrborn et al. 2011]. There was a 19.6% relative risk reduction in episodes of AUR and BPH-related surgery in the combination group compared with dutasteride alone. Clinical BPH progression was slower in the combination group compared with dutasteride alone (31.2%) and tamsulosin alone (44.1%; p < 0.001) [Roehrborn et al. 2011]. Q_max increased by 2.4 ± 5.26 ml/s in the combination group versus 1.9 ± 5.10 ml/s in the dutasteride group (p = 0.003) versus 0.9 ± 4.57 ml/s in the tamsulosin group (p < 0.0001). Symptom scores were reduced by 35.2% compared with dutasteride alone versus 41.3% compared with tamsulosin alone. Prostate volume decreased by 27.3% and 28% for combination therapy and dutasteride alone, respectively, while increasing by 4.6% for tamsulosin alone.

Conclusion

There are currently multiple treatments available for men with enlarged prostate and LUTS, including α-adrenergic receptor antagonists, 5ARIs, and anticholinergics. It is important to approach each patient individually, focusing on history, physical examination, and laboratory tests. Assessment parameters (AUA symptom score, uroflowmetry, and prostate size) may help in identifying men at greater risk of progression who may benefit from more aggressive medical management using combination therapy. Guidelines are available for the primary care provider to help in the assessment of men with male LUTS and an enlarged prostate, and in choosing from a variety of treatment options. Patients with mild symptoms may be excellent for conservative treatment with behavioral therapy (timed voiding, fluid restriction). As symptom severity increases, patients will be candidates for one, or a combination of currently available treatments.