5. Treatment of Voiding LUTS
KeywordsConservative treatmentBehavioral modificationAlpha-adrenergic antagonist5-alpha-reductase inhibitorPhosphodiesterase type 5 inhibitorPhytotherapyBeta-3 agonistAntimuscarinicCombination therapyAquablationProstatic artery embolizationTransurethral resection of the prostateLaser prostatectomyOpen prostatectomy
Many different conservative treatments could be evaluated for both men and women suffering from lower urinary tract symptoms (LUTS); however, the treatment should be tailored and personalized according to the personal characteristics and the clinical history. Several drug therapies are available for male patients with bothersome lower urinary tract symptoms. α-Blockers (ABs) are the most widely prescribed drugs, used as monotherapy or in combination with 5-alpha-reductase inhibitors to manage patients with LUTS and benign prostatic enlargement (BPE). ABs are relatively quick in onset. The main differences among the different ABs are in the profile of adverse events, notably cardiovascular and ejaculatory dysfunction. The long-term effect (up to 5 years) and the possibility to co-administer ABs with other drugs, especially to manage persistent storage symptoms or to prevent BPE progression (5-alpha-reductase inhibitors), make this drug group particularly important. Medical management of voiding LUTS is advised when watchful waiting is deemed too risky and behavioral and dietary modifications may not suffice.
Voiding LUTS and the underactive bladder (UAB) syndrome may arise from anatomical or functional bladder outlet obstruction (BOO), as well as neurologic, iatrogenic, myogenic, and idiopathic factors [1, 2]. In brief, these factors cover microtrauma, fibrosis and/or thinning of the detrusor muscle, and consequent detrusor underactivity (DUA) . To date, there are no approved urinary bladder-targeted pharmacotherapies that address UAB syndrome . In this chapter, novel medical treatments of voiding LUTS, including UAB , will be addressed. Theoretically, depending on urodynamic findings, such drugs should increase detrusor contractility (directly or by boosting afferent activity) and/or reduce BOO. However, to our knowledge, very few have passed the preclinical phase.
The minimally invasive treatment options aim to achieve shorter hospital stay, lighter anesthesia, and a more favorable safety profile than existing gold standard techniques, like transurethral resection or open adenomectomy. This is an expanding field, with developments that are starting to deliver greater success.
Surgical treatment of benign prostatic obstruction (BPO) is performed in men with enlarged prostate and bothersome moderate-to-severe lower urinary tract symptoms (LUTS) secondary to BPO. Transurethral resection of the prostate (TURP) is the surgical standard procedure for men with prostate sizes of 30–80 mL. Holmium laser enucleation of the prostate (HoLEP) and 532-nm laser vaporization of the prostate are alternatives to TURP that result in immediate, objective, and subjective improvements that are comparable with TURP. Transurethral incision of the prostate (TUIP) is the surgical treatment of choice for men with prostate sizes <30 mL. Open prostatectomy (OP) or HoLEP are the first choice of surgical treatment in men with prostate sizes >80 mL. OP achieves good treatment efficacy in patients with large prostate, but it is the most invasive surgical method and has significant morbidity. The long-term functional results of HoLEP are comparable with those of TURP or OP. Prostatectomy or enucleation using Thulium:yttrium-aluminum-garnet (Tm:YAG) laser demonstrated symptom improvement and intraoperative safety in patients with BPO in a study with a relatively short-term follow-up, and thus, additional studies on long-term efficacy and safety are required.
Persistent voiding and postmicturition LUTS after prostate surgery may be due to incomplete surgical treatment, DUA, or a postoperative complication. Confirming BOO urodynamically is therefore crucial before offering further prostate surgery. Residual benign prostatic obstruction due to incomplete surgical treatment can be effectively managed by medical therapy or reoperation. Patients with DUA are less likely to have favorable outcomes after prostate surgery. There are no effective medical or surgical therapies for DUA.
5.2 “Watchful Waiting” and Behavioral Treatment for Men
Many men with LUTS do not complain of high levels of bother  and are therefore suitable for nonmedical and nonsurgical management—a policy of care known as watchful waiting (WW) . It is customary for this type of management to include the following components: education, reassurance, periodic monitoring, and lifestyle advice. In many patients, it is regarded as the first tier in the therapeutic cascade, and most men will have been offered WW at some point. Watchful waiting is a viable option for many men, as relatively few, even if left untreated, will progress to acute urinary retention and complications such as renal insufficiency and stones [4, 5]. Similarly, some symptoms may improve spontaneously, while other symptoms remain stable for many years .
All men with LUTS should be formally assessed prior to starting any form of management in order to identify those with complications that may benefit from intervention therapy. Men with mild to moderate uncomplicated LUTS (causing no serious health threat), and who are not too bothered by their symptoms, are suitable for a trial of WW. A large study comparing WW and TURP in men with moderate symptoms showed that those who had undergone surgery had improved bladder function over the WW group (flow rates and post-void residual (PVR) volumes), with the best results being in those with high levels of bother. Thirty-six percent of patients crossed over to surgery in 5 years, leaving 64% doing well in the WW group . Approximately 85% of men will be stable on WW at 1 year, deteriorating progressively to 65% at 5 years [8, 9]. The reason why some men deteriorate with WW and others do not is not well understood; increasing symptom bother and PVR volumes appeared to be the strongest predictors of failure.
education about the patient’s condition;
justified reassurance that cancer is not a cause of the urinary symptoms;
delivery in a framework of periodic monitoring .
Reduction of fluid intake at specific times aimed at reducing urinary frequency when most inconvenient, e.g., at night or going out in public. The recommended total daily fluid intake of 1500 mL should not be reduced, but higher volumes are really unnecessary unless there is excessive fluid loss (e.g., sweating or diarrhea), or a sense of thirst indicates dehydration.
Avoidance or moderation of caffeine and alcohol which may have a diuretic and irritant effect, thereby increasing fluid output and enhancing frequency, urgency, and nocturia.
Use of relaxed and double-voiding techniques.
Urethral compression and expression, notably in the region of the urethral bulb, to prevent postmicturition dribble.
Distraction techniques, such as penile squeeze, breathing exercises, perineal pressure, and mental “tricks” to take the mind off the bladder and toilet, to help control storage symptoms.
Bladder retraining, by which men are encouraged to “hold on” when they have sensory urgency, to increase their bladder capacity (to around 400 mL) and the time between voids.
Reviewing a man’s medication and optimizing the time of administration, or substituting drugs for others that have fewer urinary effects.
Providing necessary assistance when there is impairment of dexterity, mobility, or mental state.
Treatment of constipation .
5.3 Conservative Measures in Women
In women, LUTS o ccur at any age, but transition through the menopause adds co mplexity . Postmenopausal estrogen withdrawal is contributory, since the hormonal dependence of genital tract tissues can mean important physiological changes at the menopause. Notably there are changes in the vagina and external genitalia that are collectively known as vulvovaginal atrophy (VVA) . Menopause also carries significant changes in the lower urinary tract and the pelvic floor. The urethra and surrounding tissues, the bladder muscle and mucosa, and the pelvic floor muscles, all express estrogen receptors and become to some extent dysfunctional in the absence of estrogens. Nearly 50% of postmenopausal women have clinical symptoms related to VVA, alongside increase in symptoms of overactive bladder (OAB) and urgency urinary incontinence (UUI). All these symptoms and signs may be grouped as the so-called genitourinary syndrome of menopause (GSM) .
In postmenopausal women, urinary tract infections (UTIs) often accompany the symptoms and signs of the GSM . In particular, UTIs are the most common bacterial infections in women, and increase in incidence during the climacteric. for this reason, it is important to uncover underlying abnormalities or modifiable risk factors; however, several risk factors for recurrent UTIs have been identified, including the frequency of sexual intercourse, spermicide use , and abnormal pelvic anatomy .
Any use of estrogens, either orally, transdermally, or vaginally, may be helpful in improving VVA. However, patients may be wary of estrogen treatment. Forty-one percent of women have long-term safety concerns; 30% are apprehensive about breast cancer. Nine percent of menopausal women receiving a vaginal estrogen prescription never fill it, and those who do fill prescriptions for estrogen creams typically discontinue therapy after just 3 months. Reluctance of patients to continue vaginal estrogens or physician disinclination to recommend therapy suggests either that vaginal estrogen might have minimal effectiveness in the management of pelvic floor disorders or that its utility might be underappreciated [14, 15].
While vaginal estrogen therapy provides symptomatic relief for urogenital atrophy, there is no evidence that it is beneficial in preventing or limiting the progression of Pelvic Organ Prolapse (POP) .
5.4 Medications for Male Voiding LUTS
5.4.1 α-Adrenergic Receptor Blockers
Alpha-adrenergic receptors (ARs) are G-protein-coupled transmembrane receptors that mediate cathecholaminergic actions in the sympathetic nervous system and they bind the neurotransmitter norepinephrine . To date, three different AR subfamilies (α1a, α1b, and α1d) have been identified with a different distribution in selected human tissues. In human prostatic stroma, α1aARs are predominant, with α1dARs less expressed. α1dARs are predominant in human bladder and in sacral ventral motor neurons and parasympathetic pathways. α1bARs are mostly expressed in human central nervous system, spleen, lungs, and human vascular smooth muscle—though in younger patients, α1aARs may predominate . In 1975, Caine et al.  demonstrated that strips of human prostate contracted in response to norepinephrine are inhibited by pretreatment with phenoxybenzamine, a nonselective α-receptor blocker (AB). Since then, ARs have been investigated as the mediators of prostate smooth muscle contractions and as a target for LUTS treatment.
α1-Blockers are the main medication used worldwide for the management of LUTS in patients with BPE . α1-Blockers inhibit the effect of endogenously released noradrenaline on prostate smooth muscle cells, thereby reducing prostate tone and bladder outlet obstruction [17, 20]. Five different long-acting ABs are in mainstream use and are approved by the Food and Drug Administration (FDA) for the treatment of BPE/LUTS: alfuzosin, doxazosin, silodosin, tamsulosin, and terazosin . Alfuzosin, doxazosin, and terazosin are usually considered nonselective drugs, inhibiting all the different α1-receptor subtypes; conversely, tamsulosin and silodosin have higher selectivity for α1A receptors . Particularly, terazosin and doxazosin were the first ABs investigated for the treatment of LUTS/BPE. Both of them included an initial dose titration study design in order to avoid the first dose effect . Tamsulosin was introduced into the market as the first subtype-selective AB, considering that binding studies showed that it was less than tenfold more selective for the α1a vs. α1b subtype ; subsequently, the lack of need for dose titration mostly increased the prescription of tamsulosin over terazosin and prazosin in clinical practice. Alfuzosin 10 mg once day was the fourth AB approved by the FDA. It is nonselective for any α1 subtypes, but its slow release formulation increases its tolerance . Recently, silodosin, a novel AB with specific α1a subtype selectivity, was approved. Compared to tamsulosin, silodosin is 162 times more selective for α1a than for α1b and is 55 times more selective for α1a than for α1d [21, 24]. All the α-blockers available on the market for several years (alfuzosin, doxazosin, tamsulosin, and terazosin) have been extensively studied, and although head-to-head comparative studies are rare, they are currently regarded as equally effective drugs in improving symptoms (often stated as an IPSS improvement of about 35–40%, mostly in the voiding subscore), patient quality of life due to LUTS, and maximum flow rate (Q max improvements of 20–25%), as demonstrated by systematic reviews performed by the Cochrane Collaboration and AUA guidelines panel [25–28]. Long-term (up to 5 years) efficacy has been reported . The more recent randomized controlled trials and meta-analysis evaluating the novel AB silodosin confirmed that silodosin reduces the IPSS score about 3 points more than placebo and improves Q max about 1 mL/s more than placebo. Silodosin and tamsulosin 0.4 mg were at least as effective in all the efficacy analyses [22, 30, 31]. A recent meta-analysis  also showed that ABs improve bladder outlet obstruction (BOO) in patients with LUTS/BPE, mainly by reducing P detQ max—especially in patients presenting with urodynamic obstruction at baseline. The overall pooled data showed a mean BOO Index change of −14.2 (p < 0.0001), and a mean P detQ max change of −11. 4 cm H2O (p < 0.0001).
ABs have also been used to manage patients with acute urinary retention due to benign prostatic obstruction (see Chap. 4). A meta-analysis confirmed that AB treatment significantly increases the probability of a successful trial without catheter (56.8% vs. 38.9%) and a successful micturition (RR: 1.45 (1.2–1.75), I 2 = 34%, p = 0.0001) .
Although all the ABs had similar efficacy for treating LUTS/BPE, tolerability appeared to differ; alfuzosin and tamsulosin may be tolerated better than terazosin or doxazosin, particularly for cardiovascular adverse events and for blood pressure regulation, specifically in the elderly population taking concomitant cardiovascular medications . Silodosin also presents a tolerable cardiac and blood pressure-related safety profile, and data have shown that it does not promote QT interval prolongation . Another common adverse event associated with ABs treatment is ejaculatory dysfunction (retrograde, absent, or reduced ejaculation), mostly evident with tamsulosin and silodosin [21, 33]. This effect is probably related to the blockade of α1a and/or α1d in the vas deferens, bladder neck, and/or seminal vesicles.
Possible interactions between ABs and phosphodiesterases-5 inhibitors may have some vasodilatation effect; combined administration can induce significant hypotension events. Sildenafil should be used with caution in patients taking an α-blocker (especially doxazosin). Concomitant treatment using vardenafil or tadalafil with tamsulosin reportedly was well tolerated and less associated with clinically significant hypotension. Stable AB dosing is indicated prior to initiating avanafil treatment [33, 34].
The intraoperative floppy iris syndrome, which can impair removal of cataract during ophthalmic surgery and can induce the rupture of the posterior capsule, is observed in patients treated with ABs—mostly tamsulosin and sporadic cases for alfuzosin, doxazosin, or silodo sin .
5.4.2 5α-Reductase Inhibitors
Dihydrotestosterone (DHT) is derived fro m testosterone by the enzyme 5α-reductase, a nuclear-bound steroid enzyme. The main type in the prostate is 5α-reductase type II —the type I isoform is expressed a little in the prostate but much more elsewhere, notably skin and liver. Inhibition of the enzyme blocks the generation of DHT and thereby prevents the key androgen driver at its target site. The two drugs within this class, finasteride and dutasteride, differ in their extent in blocking the 5-alpha-reductase conversion of testosterone to DHT. Finasteride selectively inhibits the 5-alpha-reductase type II enzyme, while dutasteride inhibits both 5-alpha-reductase type I and type II isoenzymes, preventing 95% conversion of testosterone to DHT at 6 months .
Both serum and intraprostatic DHT concentrations are lowered, leading to androgen suppression effects, such as cessation of prostate cell proliferation, prostate cell apoptosis, and reduction of rate of angiogenesis within the prostate. Prostate DHT concentration is reduced to a similar extent (85–90%) by the 5-ARIs, and this may explain why the two drugs are similarly effective clinically, even though dutasteride reduces circulating DHT rather more than finasteride does. Their effect is to reduce the overall size of the prostate by up to a quarter, and they also decrease circulating PSA levels by approximately 50%. Because of their indirect mechanism of action, they take several months to have an evident effect. After 2–4 years, IPSS may be reduced by a fifth, and the free flow rate test shows a slight improvement, the extent of reduction being greater for prostate glands with a larger size at start of therapy. For smaller glands, they may not be better than placebo, with a threshold volume of 40 mL prostate size for finasteride and 30 mL for dutasteride. For prostate volumes >30 mL in men with increased risk for disease progression, dutasteride appears to be more effective than tamsulosin, and this translates into a reported reduction in the risk of emergency acute urinary retention, or likelihood of undergoing TURP, both falling by about a half at four years in the proscar (finasteride) long-term efficacy and safety study (PLESS). In the medical treatment of prostate symptoms (MTOPS) study, the reduction in risk of AUR and surgery was closer to two thirds. Finasteride reduces risk of AUR and surgical intervention in men with moderately severe LUTS. Where surgery is undertaken, finasteride apparently improves blood loss, probably due to reduction of prostatic vascularization. Dutasteride likewise improves AUR or surgery risk and also urodynamic function.
Side effects potentially include erectile dysfunction (ED), ejaculatory disorders, and reduced libido. Breast enlargement (gynecomastia) and breast tenderness occur in 1–2% of patients. A higher rate of detection of high-grade cancers has been reported. There may be adverse cardiovascular effects of 5-ARIs, but this is not certain.
Considering treatment with 5-ARIs in men with moderate-to-severe LUTS and an enlarged prostate (>40 mL) and/or elevated PSA concentration (>1.4–1.6 ng/mL).
They are suitable only for long-term treatment (years).
The reduction of serum PSA concentration needs to be factored in when considering prostate cancer screening using PSA lev els.
5.4.3 Phosphodiesterase Type 5 Inhibitors
Phosphodiesterase type 5 (PDE5) inhibitors are established as the first-line drugs for treatment of erectile dysfunction (ED). More recent evidence indicates the role of PDE5 inhibitors in the treatment of LUTS , using tadalafil 5 mg in LUTS patients with or without ED. They increase cyclic GMP, which reduces muscle tone in the lower urinary tract, including the vasculature. They may also counteract chronic inflammation in the prostate. Clinically they improve both storage and voiding LUTS, and QoL, but their effect on flow rate appears to be minimal. Dosing differs from PDE5 inhibitor treatment of ED (used on demand, with dose titration against response); in LUTS, the licensed therapeutic approach is tadalafil 5 mg taken daily. This reduces IPSS by about a quarter. LUTS appear to improve regardless of baseline severity or prostate volume. The use of tadalafil improves both LUTS and erectile dysfunction; LUTS improvement can be seen in men who do not have ED. Another analysis showed a small but significant increase in Q max without any effect on PVR. A recent integrated analysis of RCTs showed that tadalfil was not superior to placebo for IPSS improvement at 12 weeks in men ≥75 years (with varied effect size between studies) but was for men <75 years. An open-label urodynamic study reported a lower BOO index and improved flow rate. Long-term experience with tadalafil in men with LUTS is very limited. Adverse effects include flushing, gastroesophageal reflux, headache, and nasal congestion. PDE5 inhibitors are contraindicated in patients using nitrates, nicorandil, doxazosin, or terazosin. They are also contraindicated in unstable angina pectoris or recent myocardial infarction.
Herbal drug preparations have been derived from saw palmetto (Serenoa repens), African plum tree (Pygeum africanum), pumpkin seeds, South African star grass (Hypoxis rooperi), rye pollen (Secale cereale), and stinging nettle root. These may contain active compounds, such as phytosterols, ß-sitosterol, and lectins, which may act by antiandrogenic and estrogenic effects, or by reducing inflammation. As things stand, however, underlying mechanisms are not known. Despite not being specifically recommended in international guidelines, phytotherapeutics are commonly prescribed [39, 40]. A consideration when evaluating efficacy is that the marketed products may not be consistent in their ultimate composition, since they are derived by extraction from biological sources rather than chemical manufacture. Thus, comparisons between manufacturers or batches need to factor in potential biological or clinical variation. This may be a contributor in the failure to derive clinical evidence of reduction in prostate size, BOO, or disease progression. The latest Cochrane review concluded that Serenoa repens extract as phytotherapeutic monotherapy does not improve LUTS or Q max compared with placebo in men with LUTS/BPH, even at double or triple the usual dose . Cochrane reviews on Pygeum africanum and Secale cereale suggested improved LUTS, but the evidence base was limited. Generally, the phytotherapeutic agents are well tolerated, but they can be associated with gastrointestinal side effects. They are popular, perhaps due to dissatisfaction with conventional therapy, and personal opinion. The heterogeneity of pharmacologically active plant extract contents means high-level quality evidence is lack ing.
5.4.5 Combinations of Drugs for Male LUTS
To date, there are six pharmacological classes available for treatment of LUTS in men, including alpha-adrenoceptor blockers [ABs], 5alpha-reductase inhibitors [5ARIs], antimuscarinics [AMs], beta-3-adrenoceptor agonists, phosphodiesterase type 5 inhibitors [PDE5Is], and phytotherapeutics (plant extracts). They can be used alone or in combination for the treatment of male LUTS.
5.4.6 Alpha-Adrenoceptor Blockers + 5-Alpha-Reductase Inhibitors (AB + 5ARI)
The combination of AB + 5ARI was f irst as sessed by Lep or and coworkers in 1996 to provide rapid relief of LUTS and delay LUTS/BPH clinical progression . It was the first multicenter, prospective, randomized, double-blind, placebo-controlled trial, comparing finasteride, terazosin, and combination therapy (finasteride and terazosin) in 1229 U.S. veterans with LUTS/BPH. Since its introduction, AB + 5ARI has become the most commonly prescribed combination treatment [43, 44].
The addition of dutasteride in patients already on AB monotherapy improves both symptoms and urodynamic parameters, including decrease of P detQ max from 71.5 ± 30.1 to 59.1 ± 24.9 cm H2O, BOO Index from 55.2 ± 31.9 to 42.3 ± 27.9, and improvement of obstruction grade assessed by the Schafer nomogram.
Six randomized controlled trials (RCTs) have looked into the efficacy of AB + 5ARI as combination treatment. Finasteride has been tested in RCTs with alfuzosin (Alfuzosin, Finasteride, and Combination in the Treatment of Benign Prostatic Hyperplasia [ALFIN] study), terazosin (Veteran Affairs Cooperative [VA-COOP] study), and doxazosin (Prospective European Doxazosin and Combination Therapy [PREDICT] and Medical Therapy of Prostatic Symptoms [MTOPS] studies), and dutasteride has been studied in combination with tamsulosin (Combination of Avodart and Tamsulosin [CombAT] and CONDUCT studies). In addition, two studies assessed whether the AB can be omitted after initial successful combination therapy . Long-term data (up to 4 years) from the MTOPS and CombAT studies showed that combination treatment is superior to monotherapy for symptom relief and Q max, and superior to AB plus placebo in reducing prostatic volume, risk of AUR, and need for surgery .
The Medical Therapy of Prostatic Symptoms (MTOPS) trial enrolled 3047 LUTS/BPH patients across 18 academic centers in the United States who were treated with doxazosin or finasteride, alone or in combination, vs. placebo for 4–6 years. The primary outcome of this study was overall clinical progression defined by an IPSS increase of at least four points in AUA symptom score, acute urinary retention (AUR), incontinence, urinary tract infection, or renal function impairment (an increase in creatinine >50%) [45–48]. The study suggests that the combination of doxazosin and finasteride exerts a clinically relevant positive effect on rates of disease progression. The risk of progression was reduced by 39% for doxazosin, 34% for finasteride, and 67% for combination therapy compared with placebo. The risk reduction comparing both single and combination therapy with placebo was statistically significant (p < 0.01); the risk reduction comparing combination therapy with either monotherapy was also significant (p < 0.001) [43, 45]. The number needed to treat (NNT) to prevent a case of LUTS or BPH progression as defined in MTOPS was 8.4 with combination therapy, 13.7 with doxazosin, and 15.0 with finasteride. For those men treated with combination therapy with a baseline PSA ≥4.0 ng/mL, the NNT was 4.7; for those with baseline prostate volume >40 mL, the NNT was 4.9. The NNT for those treated with finasteride was 7.2 for both subgroups [43, 45].
Crawford et al. further looked into the placebo arm in MTOPS and found that the risk of progression was higher in those with median prostate volume of 31 mL or greater, baseline median serum PSA 1.6 ng/dL or greater, Q max of less than 10.6 mL per second, post-void residual of 39 mL or greater, and age 62 years or older .
Roehrborn et al. reported the 2-year and 4-year results of the Combination of Avodart and Tamsulosin (CombAT) study where 4500 patients were randomized to treatment with tamsulosin, dutasteride, or their combination. The 4-year data revealed that combination therapy significantly reduced the relative risk of AUR or BPH-related surgery with tamsulosin monotherapy by 65.9% and dutasteride monotherapy by 19.6%. Combination therapy with dutasteride plus tamsulosin provided better long-term control (up to 4 years) of moderate-to-severe LUTS compared with monotherapy for men with prostate volume of 30 mL or greater [43, 48, 50].
Although MTOPS and CombAT studies showed comparable findings, the baseline characteristics were significantly different in terms of mean prostate volume (36.3 mL vs. 55.0 mL) and serum PSA 2.4 ng/mL vs. 4.0 ng/mL for MTOPS vs. CombAT, respectively .
The impact upon withholding AB after 6 months of combination therapy (dutasteride and tamsulosin) was evaluated in an RCT of 327 men with symptomatic BPH. The Symptom Management After Reducing Therapy (SMART-1) study conducted by Barkin et al. concluded that 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 75% of patients after the AB is removed after 24 weeks of the combination therapy. Patients with severe symptoms may benefit from longer-term combination therapy . This concurs with another trial where control of LUTS associated with BPH was maintained for at least 9 months with AB discontinuation, following a 9-month course of combination therapy with finasteride and an alpha blocker .
The CONDUCT study randomized 742 patients over a 2-year period into a combination of dutasteride and tamsulosin vs. watchful waiting (with a protocol defined), and initiation of tamsulosin if symptoms did not improve. Both arms were given lifestyle advice. The improvement in IPSS at 24 months was significantly greater for fixed-dose combination group than watching waiting (−5.4 vs. −3.6 points, p < 0.001). Fixed-dose combination therapy with dutasteride and tamsulosin, plus lifestyle advice, resulted in a rapid and sustained improvement in patients with moderate LUTS, reducing relative risk of disease progression by 43.1% (p < 0.001) and absolute risk of 11.3% compared with watchful waiting plus protocol-driven initiation of tamsulosin. .
In the ALFIN trial, 1051 patients were randomized into alfuzosin, finasteride, or a combination of both over a 6 month period. Symptomatic improvement was significantly higher from the first month of treatment with alfuzosin, alone or in combination; mean changes in IPSS vs. baseline at end point were −6.3 and −6.1, respectively, compared with −5.2 with finasteride alone .
In the PREDICT trial, 1095 men aged 50–80 years were randomized into doxazosin, finasteride, or a combination of both, or placebo over 1 year. The analysis showed that doxazosin and combination therapy produced statistically significant improvements in total IPSS and Q max compared with placebo and finasteride alone (p < 0.05). Finasteride alone was not significantly different from placebo with respect to total IPSS and Q max .
The VA-COOP trial concluded that at 1 year, terazosin was an effective therapy, whereas finasteride was not, and the combination of terazosin and finasteride was no more effective than terazosin alone .
The ALFIN, PREDICT, and VA-COOP trials concluded there was no additional benefit in combining 5ARI with AB. AB monotherapy was consistently more effective in symptom reduction and Q max improvement than placebo, but 5ARI was not. However, these 3 RCTs had short follow-up periods of 6–12 months, by which time, the effect of 5ARI may not be fully express ed [54, 55].
5.4.7 Alpha-Adrenoceptor Blockers + Antimuscarinic Agents (AB + AM)
Many patients with LUTS/BPH have coe xisting OAB. The combinat ion of alpha blocker and antimuscarinic is suitable in patient s with storage LUTS and those without the potential of AUR. It is advised by EAU guidelines to prescribe with caution due to the presumed inhibitory effect of AMs on detrusor contraction.
Most RCTs were add-on studies where they investigate the efficacy of AB + AM vs. AB, AM, or placebo. In all studies, patients at risk of AUR, e.g., post-void residual urine (PVR) >200 mL and Q max < 5 mL/s, were excluded [56–67].
In the TIMES study, Kaplan et al. conducted a randomized, double-blind, placebo-controlled trial across 95 urology clinics in the United States involving 879 men with LUTS and a bladder diary documenting micturition frequency (≥8 micturitions per 24 h) and urgency (≥3 episodes per 24 h), with or without urgency urinary incontinence. The patients were randomized among four treatment arms: tolterodine, tamsulosin, a combination of both, and placebo over a 12-week period. Patients reported treatment-significant benefit by week 12 in the combination group, compared with placebo, group (80% vs. 62%, p < 0.001). The combination group compared with placebo experienced significant reductions in urgency urinary incontinence (−0.88 vs. −0.31, p = 0.005), urgency episodes without incontinence (−3.33 vs. −2.54, p = 0.03), micturitions per 24 h (−2.54 vs. −1.41, p < 0.001), and micturitions per night (−0.59 vs. −0.39, P.02). The incidence of AUR was low across all groups (0–0.5%). These results suggest that treatment with tolterodine extended release plus tamsulosin for 12 weeks provides benefit for men with moderate-to-severe lower urinary tract symptoms including overactive bladder with an NNT of 5 . Similarly, the RCT conducted by Rovner et al. also concluded treatment with tolterodine extended release plus tamsulosin significantly improved urgency variables and patient-reported outcomes in men, meeting entry criteria for overactive bladder and prostatic enlargement trials .
The ADAM study employed a different design investigating the efficacy of alpha-blocker/antimuscarinic combination therapy. The study included 652 men with persistent OAB symptoms who were already on stable α-blocker therapy and randomized them to placebo or tolterodine SR. At 12 weeks, subjects receiving the combination therapy had significantly greater improvements vs. placebo plus alpha blocker in 24-h micturitions, daytime micturitions, 24-h urgency episodes, daytime urgency episodes, nocturnal urgency episodes, frequency-urgency sum, IPSS storage subscale, OAB-q symptom bother scale, and OAB-q coping domain. The urinary retention rates were the same (1.8%) in both the combination and alpha-blocker monotherapy arms, where there were no clinically significant differences in post-void residual volume or maximum urinary flow rate .
MacDiarmid et al. reported a multicenter, double-blind trial on 420 men aged 45 years or older with a total IPSS of 13 or more and IPSS storage subscore of eight or more. Patients were randomized to receive tamsulosin with either extended-release oxybutynin or placebo for 12 weeks. The primary end point was change from baseline in total IPSS after 12 weeks of treatment. Tamsulosin combined with extended-release oxybutynin resulted in significantly greater improvement in total IPSS compared with tamsulosin and placebo after 8 (p = 0.03) and 12 (p = 0.006) weeks of treatment, and improved IPSS for storage and quality of life at all assessment points (p < 0.01). This evidence is in favor of combination therapy in men with substantial storage symptoms .
The combination of solifenacin plus tamsulosin vs. placebo plus tamsulosin was investigated extensively, such as in the VICTOR, ASSIST, and NEPTUNE studies [66, 68, 69]. The VICTOR trial demonstrated statistically significant reductions in urgency (−2.18 vs. −1.10, p < 0.001). However, the larger reductions in frequency in the combination arm did not reach statistical significance (−1.05 vs. −0.67, p = 0.135). Overall, there was a low incidence of urinary retention requiring catheterization .
The NEPTUNE II study is the first to shed light onto long-term (up to 52 weeks) safety and efficacy of combining these drug classes (solifenacin and tamsulosin oral controlled absorption system (OCAS)). Those who completed the 12-week, double-blind NEPTUNE study could continue in the 40-week, open-label NEPTUNE II study. Reductions in total IPSS and Total Urgency and Frequency Score (TUFS) during NEPTUNE were maintained for up to 52 weeks throughout the study . Risk of urinary retention was extremely low over this time frame .
The benefits from the treatment combination can be experienced as early as during the first week into treatment, irrespective of PSA level and prostate size, while AM monotherapy was more efficacious in men who had lower PSA levels (<1.3 ng/mL) and a smaller pro state [58–60, 62].
5.4.8 α-Blocker + β3 Agonist
Evidence on combination of α-blocker and beta-3 agonist is slowly accumulating. In 2015, Ichihara reported t he first 8-week open-label RCT on 94 men with benign prostatic obstruction with urinary urgency at least once per week and a total OABSS of three or more points. The patients were randomized to tamsulosin monotherapy or combination of tamsulosin plus mirabegron. The change from baseline OABSS was significantly greater in the combination group than in the monotherapy group (−2.21 vs. −0.87, p = 0.012), and so were the changes in scores for urinary urgency, daytime frequency, IPSS storage symptom subscore, and quality of life index at 8 weeks. Only one patient experienced urinary retention. The authors concluded that this combination is more effective and safer than monotherapy in treating OAB symptoms. However, six patients experienced adverse effects—constipation 1, acute urinary retention 1, increased urgency 1, dizziness 1, heartburn 1, and increase in hepatic enzymes 1 .
While previous studies of combination therapy using an α-blocker and anticholinergic agent (TIMES , ADAM , and TAABO ) did not show significant improvement in the QOL index vs. α-blocker monotherapy, this first RCT on combination of AB and beta-3 agonist showed significant change in QOL index 8 weeks into treatment. Combination therapy using an α-blocker and β3-adrenoceptor agonist may be a promising option for patients with BPO and OAB in terms of quality of life. The EAU guideline since 2016 has included β3 agonist into the algorithm as a therapeutic add-on option in patients on AB treatment with persistent OAB sympt oms.
5.4.9 α-Blocker + PDE5I
The systematic review and meta-analysis in 2015 by Wang et al. looked into the effic acy and safety of PDE5I together with AB for the treatment of LUTS, compared to monotherapy and placebo. In the comparison of PDE5I pl us AB vs. AB alone, as well as the comparison of PDE5I plus AB vs. PDE5I alone, the pooled analysis for assessment of IPSS, Q max, PVR, QoL, and erectile function (IIEF) all favored combination therapy. There was no significant difference in rates of adverse effects across all group s .
5.4.10 PDE5I + 5ARI
The efficacy of finasterid e plu s tadalafil 5 mg vs. finasteride plus placebo was looked i nto by Casabe et al. A total of 695 patients were randomized and received 26 weeks of double-blind therapy. The finasteride/tadalafil coadminstration group show ed significant change in IPSS subscores (storage and voiding), quality of life index, and IIEF scores at 4, 12, and 26 weeks. Treatment satisfaction at week 26 was also significantly greater with finasteride/tadalafil coadministration vs. the finasteride/placebo gro up [73, 74].
5.4.11 β3 Agonist + Antimuscarinic
Combining the beta-3-adrenoceptor agonist mirabegron and an AM agent may improve efficacy in th e treatment of OAB, while reducing the A M side effects. The SYMPHONY trial (1306 patients)—a Phase II, placebo- and monotherapy-controlled, dose-ranging, 12-week trial by Abrams et al. evaluated the efficacy of combinations of solifenacin/ mirabegron compared with solife nacin monotherapy, as well as the dose–response relationship and safety/tolerability. Adult patients with OAB for ≥3 months were randomized to 1 of 12 groups: 6 combination (solifenacin 2.5/5/10 mg + mirabegron 25/50 mg), 5 monotherapy (solifenacin 2.5/5/10 mg or mirabegron 25/50 mg), or placebo. Combination therapy with solifenacin/mirabegron significantly improved mean volume voided per micturition, micturition frequency, and urgency compared with solifenacin 5 mg monotherapy. All combinations were well tolerated, with no important additional safety findings compared with monotherapy or placebo. The incidence of constipation was slightly increased with combination therapy [75, 76].
A randomized double-blind multicenter Phase 3B Study (BESIDE) particularly evaluated the efficacy and safety of mirabegron add-on therapy to solifenacin in “wet” (incontinent) overactive bladder patients. Drake et al. concluded that the addition of mirabegron 50 mg to solifenacin 5 mg further improved OAB symptoms vs. solifenacin 5 or 10 mg, and it was well tolerated, studying OAB patients remaining incontinent after initial 4 weeks of solifenacin 5 mg treatment . Likewise, the SYNERGY studies supported the efficacy of this combination therapy in the longer ter m .
5.4.12 α-Blocker + Phytotherapeutic Agents
Serenoa repens is on e of t he most investigated phytotherapeutic extracts. The efficacy of the combination of Serenoa repens plus tamsulosin has been investigated but met with conflicting results. The OCAS trial by Glemain et al. randomized patients into 2 treatment groups: tamsulosin + placebo vs. tamsulosin + Serenoa repens over 52 weeks. It did not show any statistically significant difference between the two groups in both primary and secondary endpoints (change in total IPSS from baseline; change in voiding scores, filling scores, and improvement of QoL) . On the other hand, higher efficacy is seen in the combination therapy of Serenoa repens plus tamsulosin than tamsulosin monotherapy in reducing storage symptoms .
5.5 Novel Treatment Targets for Voiding LUTS
A range of theoretical and experimental approaches has been considered, though the prospects of their reaching actual clinical use are obviously subject to a development pathway comprising a whole series of substantial challenges. Alongside efficacy in the lower urinary tract, these compounds need to avoid unwanted influence in other organ systems. They need to work with sustained benefit in a defined clinical context and without long-term risks. The challenges are huge and culminate in the scrupulous regulatory scrutiny and the health economic reality of requiring demonstrable cost effectiveness in health-care systems with limited funding. Thus, the earlier compounds may make claims of being potential targets or promising therapies but that has to be regarded realistically. The list below includes some compounds which have not made progress into clinical practice, but whose early research gave signals which warrant including them in the hope that future developments might identify where they potentially could contribute in research or clinical practice.
5.5.1 Voiding LUTS
Naftopidil is a selective alpha blocker that appears to have similar effects to tamsulosin and silodosin .
Serotonin has been shown to control prostate growth through androgen receptor downregulation . Dapoxetin, by increasing serotonin levels, may protect against testosterone-induced prostate enlargement, through antiproliferative and anti-inflammatory effects .
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