The current treatments for benign prostatic hyperplasia (BPH) include pharmacotherapy with alpha1-selective adrenergic receptor (a1-AR) antagonists, 5-alpha-reductase inhibitors (5-aRIs), and a range of invasive and minimally invasive interventions, each of which is effective in the amelioration of lower urinary tract symptoms (LUTS) and the prevention of symptom progression and BPH-related complications. Pharmacotherapy is considered the mainstay of treatment for LUTS caused by BPH. The available a1-AR antagonists have comparable efficacy for the relief of LUTS and to enhance patients' quality of life. The use of nonsubtype-selective drugs in this class may precipitate vasodilatory adverse events such as dizziness, somnolence, and orthostatic hypotension. Based on current studies, a1-AR antagonists are more cost effective (particularly the subtype-selective a1-AR antagonist, tamsulosin) than the 5-aRIs (eg, finasteride) and comparable in cost to transurethral resection of the prostate and minimally invasive therapies. There are few cost-effectiveness studies comparing the various pharmacologic interventions for BPH. Only 1 cost-analysis model has addressed the impact of adverse events on the cost effectiveness of pharmacotherapy for BPH. The publication of additional analyses would contribute to the appropriate selection of therapy in patients with BPH.
(Am J Manag Care. 2006;12:S141-S148)
Recently published data suggest that clinical benign prostatic hyperplasia (BPH), which is hallmarked by the occurrence of moderate-to-severe lower urinary tract symptoms (LUTS), increases in prevalence from the fifth to the eighth decade of life.1 Postmortem histological evidence has shown that nearly all men eventually develop BPH by the ninth decade of life.2 Moderate-to-severe LUTS, defined clinically by an American Urological Association (AUA) Symptom Index (SI) score of >7 points, is associated with significant costs, healthcare resource utilization, and impact on quality of life (QOL).1 It has been estimated that the direct cost of medical services for BPH and its associated morbidity is approximately 1.1 billion annually; this amount is exclusive of outpatient drug therapy costs and indirect costs.1 Outpatient pharmacotherapy for BPH from 1996 to 1998 was estimated to cost $194 million, with the majority of the prescriptions having been written for terazosin, doxazosin, and finasteride; tamsulosin is the newest to the market.1
LUTS caused by BPH include those symptoms associated with voiding (urinary hesitancy or intermittency, weak urine stream) and storage (frequency, urgency, nocturia, incontinence), with the latter group of symptoms regarded by many to be the most bothersome.3 Although most LUTS associated with BPH are not considered life-threatening, if left untreated they can have a profound impact on QOL. Nocturia, which occurs in 75% of men in their 60s and as many as 83% of men in their 70s, can severely disrupt sleep patterns.1 Frequency and urgency in the daytime can disrupt work and social activities.3 More serious complications of BPH can include acute urinary retention (AUR), defined as the sudden inability to urinate that requires catheterization; recurrent urinary tract infections (UTIs); gross hematuria; and bladder stones.4,5 Data from the population-based Olmsted County study suggest that in men aged 70 years or older with moderate-to-severe LUTS, the incidence of AUR is 34.7 per 1000 patient-years of follow-up.1,6 In another retrospective cohort study of men aged 45 years and older with newly diagnosed LUTS, the incidence of AUR was 18.3 per 1000 patient-years of follow-up, and AUR was the first presenting symptom of BPH in 50% of AUR cases.7
The goals of therapy for BPH are to ameliorate LUTS, prevent related complications, and achieve measurable improvement in the patient's QOL.3 In addition to drug and resource utilization costs, additional information that is useful for health economic analyses includes symptom severity, associated morbidities (eg, AUR), and patient satisfaction or QOL as part of the overall impact of treatment for BPH. This article will review some of the recent data regarding BPH treatment-associated costs and outcomes.
Pharmacologic Treatment Outcomes
Patients with mild LUTS and without bothersome symptoms may be managed with watchful waiting and periodic reevaluation. 4,8 Pharmacologic treatment of BPH is currently indicated for the treatment of men with moderate-to-severe LUTS who prefer to avoid invasive treatment. Medical therapy is also recommended for patients who are not candidates for invasive procedures, or for those whose symptoms are not considered bothersome enough to warrant surgical intervention.4 The 2 classes of pharmacologic therapies for LUTS caused by BPH, alpha1-selective adrenergic receptor (a1-AR) antagonists and 5-alpha-reductase inhibitors (5-aRIs), differ in the amount of time required to achieve efficacy as well as in their adverse event profiles.9,10 Medical therapy reduces the risk of progression to prostatic surgery; the incidence of prostatic surgery is 40.2 per 1000 patient-years in patients receiving medical treatment, versus 83.3 in those not receiving medical therapy. 11 However, it is important to periodically reassess patients with severe symptoms who are receiving medical therapy to ensure an optimal treatment outcome.12 In a recent study, the probability of surgery after failed pharmacologic treatment for BPH with doxazosin was significantly higher in those patients who subjectively rated their drug treatment as "ineffective" (Table 1).12
Outcomes and Cost-effectiveness of a1-AR
LUTS affect the patient's vitality and ability to work and perform daily tasks.13,14 An increase in the severity of LUTS is associated with depressed mood and anxiety.15 The pharmacologic treatment of LUTS with a1-AR antagonists is associated with improvements in QOL and sexual function.16-19
Although therapy with a1-AR antagonists is effective in the treatment of LUTS, the use of nonsubtype-selective agents is most likely to precipitate vasodilatory adverse events such as dizziness, hypotension, and falls. Within 4 months of the initiation of therapy with a nonsubtype-selective agent (ie, doxazosin or terazosin), an increase in hypotension- related adverse events related to a1-AR antagonism is seen (Table 2).20 These adverse events may increase costs associated with falls, as well as negatively impact the patient's QOL. The use of agents less prone to cause hypotension-related adverse events is therefore highly desirable and will likely reduce associated costs.
Alfuzosin, a nonsubtype-selective agent, appears to show greater selectivity for the lower urinary tract compared with vascular tissues in preclinical studies.21 The efficacy of alfuzosin in patients with LUTS has been demonstrated in double-blind, placebo-controlled trials and an open-label extension up to 1 year in duration, and improvements in QOL have also been noted (<.001).21
Outcomes data demonstrate that the subtype- selective a1-AR antagonist tamsulosin is effective in alleviating LUTS caused by BPH. The principal adverse event associated with tamsulosin, when compared with placebo, was abnormal (mainly retrograde) ejaculation; however, this event was not associated with a higher incidence of discontinuation of treatment.22 In a recent study, the amelioration of LUTS afforded by treatment with tamsulosin was accompanied by a significant improvement in QOL (<.001).16 Improvement in symptom scores and sexual function, without the addition of bothersome sexual side effects such as impotence or decreased libido, may improve overall QOL for men with BPH treated with tamsulosin. Further studies are required to determine whether the improvements in sexual functioning and QOL are associated with reduced costs.
Effective control over LUTS with tamsulosin may also reduce treatment failure rates and the need for re-treatment. An analysis of data from the General Research Practice Database has shown that the risk of treatment failure (defined as the need for catheterization assuming AUR or a switch to other therapy or surgery) is lower with tamsulosin than with alfuzosin, doxazosin, or terazosin when using finasteride as a reference therapy. 11 Another retrospective review with a 3- year follow-up demonstrated a significantly lower rate of re-treatment with tamsulosin compared with either alfuzosin or terazosin (Table 3).23 The cost effectiveness of terazosin and placebo has been compared in a multicenter, randomized, double-blind trial of 2084 patients with moderate-to-severe BPH. Healthcare resource utilization costs, based on 1000 patients per treatment arm, were approximately equivalent ($3.8 million for placebo and $3.6 million for terazosin).24 All 3 AUA disease-specific functional status scores (symptom, bother, and QOL) were improved with terazosin compared with placebo, whereas no difference was seen for disease nonspecific functional status. The lower cost of terazosin may be explained by the reduced risk of progression of LUTS afforded to patients who receive treatment.
Few cost-efficacy analyses are available that compare the different a1-AR antagonist therapies for BPH. A recent study used a decision analytic model to project the treatment course at 6-month intervals (up to 3 years) after the initiation of therapy using tamsulosin, terazosin, or doxazosin.25 Efficacy was defined as successful medical treatment over 3 years without surgery; treatment failure was defined as failure to attain and maintain a 25% improvement in the AUA SI. Results of this analysis are shown in Table 4. Although total direct medical costs were slightly higher with tamsulosin, the medical success rate (ie, no transurethral resection of the prostate [TURP]) was higher for tamsulosin than for either doxazosin or terazosin (Table 4). The incremental cost over 3 years for tamsulosin versus terazosin was $610, and the incremental cost-effectiveness ratio was $14 609 per success.25 Patients who discontinued either doxazosin or terazosin because of hypotensive adverse events and were switched to tamsulosin had costs for doxazosin and terazosin that were lower than those in the base-case scenario.25
Treatment Outcomes: 5-
aRIs. 5-a-reductase is a prostatic enzyme required for the conversion of testosterone to 5-a-dihydrotestosterone, an important androgen mediator of prostatic enlargement in BPH.10 Currently prescribed inhibitors of 5-a-reductase include finasteride and dutasteride.4 Because these drugs act to reduce prostate size, they are usually recommended for patients who have prostatic volumes =40 mL.4,8,26 The 5-aRIs effectively reduce the risk of developing AUR and the need for BPH-related surgery, particularly in patients with the highest risk for developing these complications (eg, large prostate gland size).27 The principal drawback associated with the use of 5-aRIs is the occurrence of sexual side effects such as erectile dysfunction (4.9%-15.8% of patients),19 decreased libido, and ejaculatory dysfunction (1%-2% of patients for each).28
In a 36-month decision-tree cost-efficacy analysis assessing initial therapies for BPH after an unsuccessful watch-and-wait period, finasteride was less favored over therapy with the nonselective a1-AR antagonist prazosin (mean savings per successfully treated patient, ~$382).29 Another study showed that finasteride was suitable for use in patients with moderate BPH when the treatment period was 3 years or less, but not for those patients with severe symptoms requiring 4 or more years of treatment.30 These early studies did not take into account the recent data showing the long-term risk reduction provided by finasteride therapy that occurs after 1 year of therapy.27,31 Data from the Proscar Long-Term Efficacy and Safety Study27 and the Medical Therapy of Prostatic Symptoms (MTOPS) trial31 have been used to assess costs and cost-utility for finasteride in a semi-Markov decision analytic model.32 Results showed finasteride to be less favored than doxazosin but more favored than watchful waiting among patients who failed doxazosin and did not opt for surgery (cost utility, $44 336 per quality-adjusted life-year [QALY] among all patients and $35 016 per QALY among patients with a prostate-specific antigen level of >3.2 ng/mL).32
Treatment Outcomes: Combination Therapy.
The distinct mechanisms of action of 5-aRIs and a1-AR antagonists on the respective static and dynamic components of BPH lend themselves to use as combination therapy. The efficacy and safety of combination therapy versus treatment with either agent alone has been investigated in 3 large multicenter trials.
The Veterans Affairs Cooperative Study compared the safety and efficacy of placebo, terazosin (10 mg/day), finasteride (5 mg/day), or their combination over a 1-year period. AUA SI scores were significantly lower at all follow-up visits for the terazosin and combination therapy arms compared with those from subjects in the placebo (<.001 vs placebo) and finasteride (<.001 vs finasteride) treatment groups. However, there was no significant advantage observed for combination therapy over terazosin alone.33
Similarly, the Prospective European Doxazosin and Combination Therapy (PREDICT) trial (N = 1095) compared the effects of combination therapy on symptomatic relief, but not on disease progression, of placebo, doxazosin, finasteride, or both in a prospective, 52-week study.34 Treatment with doxazosin alone or combination therapy significantly improved both the International Prostate Symptom Score (IPSS) and maximum flow rate (Qmax) compared with placebo or finasteride alone (<.05).34 As was observed in the Veterans Affairs study, no significant difference was observed between patients treated with combination therapy and patients treated with doxazosin alone. AUR and TURP occurred at a low frequency in the trial but were more frequent in patients taking placebo or finasteride alone. Patients treated with combination therapy had no incidence of AUR or TURP.
The MTOPS trial investigated the efficacy and safety of the same 4 treatment arms as the PREDICT trial in a population of men (N = 3047) with moderate-to-severe BPH symptoms over a 4.5-year follow-up.31 As was the case with the PREDICT and the Veterans Affairs studies, no significant differences in AUA SI scores were observed in MTOPS between subjects treated with combination therapy and those treated with doxazosin alone at the end of 1 year. However, by the end of the MTOPS study, results showed a significant reduction in the rate of overall clinical progression (defined as first occurrence of increase in AUA SI score of =4 points, AUR, renal insufficiency, recurrent UTI, or urinary incontinence) with combination therapy compared with either agent alone (rate/100 person-years: 1.5 vs 2.7 for doxazosin, 2.9 for finasteride, and 4.5 for placebo).31 The rate of AUR was reduced by 81% and the need for invasive therapy was reduced by 67% with combination therapy versus placebo (<.001 for both outcomes), whereas neither of these 2 outcomes was significantly reduced with doxazosin.31 These results suggest that combination therapy may be most effective when given over the course of more than 1 year.
All 3 studies demonstrated a higher incidence of impotence in the combination therapy arms compared with that of the a1-AR antagonist arms, in addition to the expected higher incidence of a1-AR antagonist-mediated dizziness and hypotension.31,33,34 Impotence and other sexual side effects, such as decreased libido, are associated with combination therapy and may significantly affect QOL and compromise long-term tolerability in patients who wish to remain sexually active; however, the impact of this treatment regimen on QOL has not yet been studied. In a recently reported semi-Markov decision analytic model, combination therapy was found to be cost effective versus treatment with doxazosin alone in men with moderate- to-severe LUTS, with cost-utility ratios less than $40 000 (Canadian)/QALY over a range of scenarios.32 At present, it appears that combination therapy is best suited to those men at high risk for BPH progression (ie, those with high symptom scores, large prostate volume, and low Q max values) who are able to tolerate the increased side effects.
Outcomes of Invasive and Minimally Invasive Treatments
Despite the improvement in BPH symptoms and QOL that can be achieved with current pharmacologic therapies, especially those with more tolerable adverse event profiles, a proportion of patients will not want lifetime medication, will not be able to tolerate medication, or will ultimately fail pharmacotherapy and require more invasive therapies. Appropriate candidates for surgical and/or invasive BPH interventions are generally those with the previously mentioned outcomes or those with large prostates and moderate-to-severe symptoms in whom progression to complications such as AUR and recurrent UTIs are likely.4,8 There is a wide range of invasive and minimally invasive therapies for BPH, including the gold standard of TURP. The different methodologies will not be described in detail here. The AUA has recommended the use of minimally invasive therapies such as transurethral microwave thermotherapy (TUMT) and transurethral needle ablation (TUNA) for men with obstructive BPH symptoms, lateral lobe enlargement, and prostates of 60 g or less.4 Recent outcomes data from several trials comparing these and other procedures with TURP or pharmacologic interventions will be reviewed in the following section.
Nearly 90% of patients have symptom improvement at 1 year after TURP, with improvement in both symptom scores (average, 82%) and Qmax (125%).35 Refinements in the TURP procedure over the years have led to treatment failure rates of 10% or less after 3 years of follow-up35; however, complications such as stricture and bladder neck contraction may occur in approximately 4% of patients. Furthermore, this intervention is not recommended for men concerned about maintaining potency and fertility, because about 20% of men report a decline in sexual function after TURP.35 The cost effectiveness of medical therapy compared with TURP was analyzed in a hypothetical cohort of 65-year-old men with moderate-to-severe BPH.36 The 5-year estimated costs (1999 US dollars) were lower with a1-AR antagonist therapy ($6294) compared with those for TURP ($7334).
Although there have been wide variations observed between studies, TUMT has generally been associated with a 50% reduction in symptom scores and a 45% increase in Qmax, with minor bleeding (for which intervention is generally not necessary) as the primary early adverse event.35 Outpatient TUMT has significantly lower costs than TURP ($2629 vs $4557, 1999 US dollars), because no hospital stay is required.37,38 One analysis of TUMT versus TURP reported efficacy for at least 36 months for TUMT, with a 3.2% rate of retreatment at 1-year follow-up.39 AUR (up to 13.5%) and voiding discomfort were the most common adverse events occurring after TUMT, whereas bleeding, retrograde ejaculation (up to 80%), and urethral strictures (up to about 7%) occurred after TURP.39 Although TUMT was found to be effective and safe for the treatment of LUTS, improvement in most variables was better with TURP. Similar results have been reported in a recent meta-analysis of 6 studies comparing TUMT with TURP.40 Mean symptom scores decreased 65% with TUMT and 77% with TURP, and Qmax increased 70% with TUMT and 119% with TURP. The need for re-treatment was more common for TUMT than for TURP (relative hazard, 10.0). However, TURP was found to be associated with a greater incidence of retrograde ejaculation (58% vs 22%), need for transfusion (6% vs 0%), and re-treatment for strictures (relative hazard 9.8) than TUMT.40 In addition, cost-effectiveness data have favored the use of TUMT over TURP.39
Compared with TURP in the previously discussed hypothetical cohort study, TUMT had a higher 5-year utility value (53.52 quality-adjusted life-months), and the cost was lower (difference of $299).36 A more recent, randomized 1-year comparative trial of the newer technology TUMT versus TURP reported similar symptomatic and bother scores, and lower costs for TUMT.41 The results of this trial suggest that further refinements in TUMT technology may lead to better efficacy and fewer complications.
Overall, TUMT appears to be a safe, effective, and cost-effective alternative therapy to TURP. TUMT may also be a cost-effective option for patients failing pharmacotherapy with a1-AR antagonists.
Transurethral Vaporization of the
TUVP is a modification of the TURP procedure, comparable in efficacy to TURP (at least in the short term) and allowing for better control over hemostasis.35 A recent comparative analysis defined a satisfactory outcome as a reduction in the IPSS score of =5.42 Results of this multicenter, randomized, controlled trial showed TUVP and TURP to be comparably effective, with success rates of 74% and 85%, respectively. Improvement was sustained for up to 2 years in both groups. Both treatments were equivalent in terms of overall National Health Service (United Kingdom) resource usage, although the incidence of prolonged bleeding was less with TUVP.42
Thermoablation of the prostate using TUNA (n = 65 patients) was compared with TURP (n = 56 patients) in a 5-year efficacy and safety study.43 Both treatments improved IPSS, QOL scores, and Qmax; however, TURP was associated with a higher incidence of erectile dysfunction, incontinence, and stricture formation. Similar efficacy and safety results were seen in another randomized trial with an 18-month follow-up; however, TURP-treated patients had superior improvements in Qmax compared with patients in the TUNA arm.44
The cost of BPH management using TUNA has been compared with that of medical management with tamsulosin, finasteride, combination therapy, or a mixed treatment regimen using single-agent and combination medical therapy in a cost-analysis model.45 Overall, tamsulosin was less expensive over a 5-year treatment period compared with TUNA ($3485 vs $4811, respectively), whereas finasteride reached a break-even point with TUNA after 5 years ($4867).45 TUNA was also less expensive than combination therapy after 5 years, with a break-even point of about 2.6 years ($4515 for combination therapy vs $4572 for TUNA). A mixed regimen using monotherapy and combination therapy had a break-even point with TUNA at about 4 years ($4696 for medical managenent vs $4645 for TUNA).45 Outcomes thus far with TUNA suggest it is a safe alternative to TURP, with approximately equivalent efficacy. TUNA may be preferable to TURP in men wishing to preserve sexual function.4 Further study is needed to determine whether the intervention will be cost effective and improve QOL over the long term.
Effective treatment of BPH involves not only a reduction of symptom scores and the prevention of serious and costly complications such as AUR but also an improvement in overall QOL and cost effectiveness. Selection of therapy for LUTS caused by BPH should take existing comorbidities, baseline BPH parameters (eg, symptom severity, size of prostate), cost, and most important, patient preference, into consideration. Accordingly, treatments for BPH, whether pharmacologic or surgical, should reduce symptoms and prevent progression without worsening any preexistent medical conditions such as erectile dysfunction, or putting the patient at risk for injury and falls from adverse events such as dizziness and/or hypotension. Data suggest that medical therapy, particularly with subtype-selective a1-AR antagonists (eg, tamsulosin), can effectively alleviate BPH symptoms and improve QOL measures, without causing adverse events such as dizziness, hypotension, or impotence, and in a cost-effective manner. However, there is a paucity of data that collectively integrate improvement in symptoms, reduction in adverse events, improvement in QOL, reduction in complications, and cost effectiveness into a comparison among pharmacologic and/or surgical treatments for BPH. Emerging data and shifting economic priorities make a strong case for further research to identify the best and most cost-effective treatments, as well as the most appropriate patient demographics, for each of the therapies available to manage BPH.
Corresponding author: J. Curtis Nickel, MD, 76 Stuart Street, Empire 4, Kingston, ONK7L 2V7. Tel: 613-548-2497; Fax: 613-545-1970; E-mail: firstname.lastname@example.org.
Editorial assistance in the preparation of this manuscript was provided by Insight Medical Communications.