Risk factors for failure of long-term dutasteride add-on treatment to alpha-adrenergic antagonist for patients with lower urinary tract symptoms and benign prostatic enlargement.

PURPOSE: To identify the clinical factors resulting in the failure of dutasteride add-on treatment to alpha-adrenergic antagonist for patients with lower urinary tract symptoms and benign prostatic enlargement (BPE). METHODS: We retrospectively surveyed the patient cohort who had been enrolled in the study of dutasteride add-on treatment to alpha-adrenergic antagonist from December 2009 to November 2011. Treatment failure was defined as receiving surgery for BPE or requiring intermittent catheterization or permanent bladder catheter for urinary retention or huge postvoid residual urine. Clinical parameters before dutasteride treatment were compared between the successful and failed group. RESULTS: Of 92 patients, 23 (25%) were defined as treatment failure at 7-109 months (mean: 38 months) after dutasteride add-on treatment. In the failed group, the patient' age was younger (71.6 ± 6.8 vs 75.4 ± 8.4, p = 0.033), prostatic volume (PV) was larger (76 ± 41 vs 49 ± 26 ml, p = 0.005), voiding efficiency was lower (54 ± 27 vs 68 ± 24%, p = 0.045) and bladder outlet obstruction index was higher (73 ± 30 vs 48 ± 30, p = 0.015). The cox proportional-hazards model indicated that only intravesical prostatic protrusion (IPP) was associated with treatment failure. Non-failure rate at 3 years after dutasteride add-on treatment was 89% with patients of IPP < 13 mm versus 51% with those of IPP ≥ 13 mm (p < 0.001). CONCLUSION: IPP ≥ 13 mm is the risk factor resulting in the failure of dutasteride add-on treatment to alpha-adrenergic antagonist. This kind of information should be provided to the patients early in the clinical practice so that they could consider the necessity of BPE surgery in the long run.

Pharmacotherapy of patients with benign prostate enlargement and storage symptoms in everyday clinical practice.

OBJECTIVE: Storage symptoms significantly deteriorate the quality of life in men with benign prostate enlargement (BPE). Muscarinic receptor antagonists (MRAs) and ß3-adrenergic receptors agonists alone, or in combination with selective α1-alpha-antagonists, are considered the most effective medicines relieving storage symptoms. The aim of this study was to analyze the pharmacotherapy of storage symptoms in men with BPE, and their compliance with the European Association of Urology (EAU) guidelines. PATIENTS AND METHODS: The survey was conducted in 2018 by 261 urologists among 24,613 men with lower urinary tract symptoms (LUTS) and BPE treated pharmacologically. Data concerning recent severity of non-neurological LUTS, storage symptoms and pharmacotherapy were collected. RESULTS: Storage symptoms were reported by 12,356 patients (50.2%) with BPE, more frequently nocturia (75.8%), than urinary urgency (57.8%) and frequency (44.3%). Patients with storage symptoms were more frequently prescribed with MRAs and mirabegron (43.1% vs. 5.0% and 2.4% vs. 0.3%, respectively; p<0.001). Of note, 54.5% of patients with storage symptoms were treated neither with MRAs, nor ß3-adrenergic receptors agonists. In the subgroup with storage symptoms, the increasing severity of LUTS accounted for more frequent prescription of MRA (2.1% vs.  29.1% vs. 42.8% in patients with mild, moderate, and severe LUTS, respectively). Decision tree analysis revealed that patients with urinary urgency and urinary frequency, as well as younger ones with urinary urgency but without urinary frequency, were more frequently prescribed with MRAs. CONCLUSIONS: Urinary urgency and frequency are associated with increased utilization of MRAs in men with BPE in everyday clinical practice. The attitude of Polish urologists toward management of persistent storage symptoms in BPE patients is in line with the EAU guidelines.

The use of mono- and combination drug therapy in men and women with lower urinary tract symptoms (LUTS) in the UK: a retrospective observational study.

BACKGROUND: Combination drug therapy for lower urinary tract symptoms (LUTS) is beneficial to selected patients and recommended by guidelines. Patterns of real-world LUTS drug use, especially combination drug therapy, have not been studied extensively. Moreover, further understanding of the recent landscape is required following the introduction of the beta-3-adrenoceptor agonist mirabegron in the UK in 2013 for overactive bladder (OAB). The objective was to describe mono- and combination drug therapy use for LUTS in patients in UK clinical practice. METHODS: This was a retrospective, descriptive, observational database study using UK Clinical Practice Research Datalink GOLD and linked databases. Men and women ≥ 18 years with a first prescription for any LUTS drug from 2014 to 2016 with ≥ 12 months continuous enrollment pre- and post-index date were included. Primary endpoints were mono- or combination drug therapy use for LUTS in male and female cohorts. Secondary endpoints were description of treatment prescribed, treatment persistence and patient demographics. Data were analyzed descriptively. Sub-cohorts were defined by drugs prescribed at index date. RESULTS: 79,472 patients (61.3% male) were included, based on index treatments. Of all men, 82.5% received any benign prostatic obstruction (BPO) drug, 25.4% any OAB drug, and 7.9% any BPO drug plus any OAB drug. As either mono- or combination drug therapy, 77.1% received an alpha-blocker, 18.9% a 5-alpha reductase inhibitor, 23.9% an antimuscarinic agent, and 2.1% mirabegron. Of all women, 94.5% received any OAB drug, 6.0% duloxetine, and 0.5% any OAB drug plus duloxetine. As either mono- or combination drug therapy, 87.7% received an antimuscarinic, and 9.7% mirabegron. In men or women receiving OAB treatment, approximately 2.5% received combination drug therapy with an antimuscarinic agent and mirabegron. For OAB drug monotherapies, mirabegron had the highest persistence in both male and female cohorts. CONCLUSIONS: This study provides a better understanding of the recent landscape of LUTS drug use in UK clinical practice. It highlights potential undertreatment of storage symptoms in men with LUTS and the low use of combination OAB treatments.

Vasodilators for primary Raynaud's phenomenon.

BACKGROUND: Numerous agents have been suggested for the symptomatic treatment of primary Raynaud's phenomenon. Apart from calcium channel blockers, which are considered to be the drugs of choice, evidence of the effects of alternative pharmacological treatments is limited. This is an update of a review first published in 2008. OBJECTIVES: To assess the effects of drugs with vasodilator effects on primary Raynaud's phenomenon as determined by frequency, severity, and duration of vasospastic attacks; quality of life; adverse events; and Raynauds Condition Score. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases, and the World Health Organization International Clinical Trials Registry Platform and the ClinicalTrials.gov trial register to November 16, 2020. SELECTION CRITERIA: We included randomized controlled trials evaluating effects of oral, intravenous, and topical formulations of any drug with vasodilator effects on subjective symptoms, severity scores, and radiological outcomes in primary Raynaud's phenomenon. Treatment with calcium channel blockers was not assessed in this review, nor were these agents compared. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, assessed studies using the Cochrane "Risk of bias" tool, and extracted study data. Outcomes of interest included frequency, severity, and duration of attacks; quality of life (QoL); adverse events (AEs); and the Raynaud Condition Score (RCS). We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We identified seven new studies for this update. In total, we included 15 studies involving 635 participants. These studies compared different vasodilators to placebo. Individual studies used different methods and measures to report different outcomes. Angiotensin-converting enzyme (ACE) inhibitors Combining data from three studies revealed a possible small increase in the frequency of attacks per week after treatment (captopril or enalapril) compared to placebo (mean difference [MD] 0.79, 95% confidence interval [CI] 0.43 to 1.17; low-certainty evidence). There was no evidence of a difference between groups in severity of attacks (MD -0.17, 95% CI -4.66 to 4.31; 34 participants, 2 studies; low-certainty evidence); duration of attacks (MD 0.54, 95% CI -2.42 to 1.34; 14 participants, 1 study; low-certainty evidence); or AEs (risk ratio [RR] 1.35, 95% CI 0.67 to 2.73; 46 participants, 3 studies; low-certainty evidence). QoL and RCS were not reported. Alpha blockers Two studies used alpha blockers (buflomedil or moxisylyte). We were unable to combine data due to the way results were presented. Buflomedil probably reduced the frequency of attacks compared to placebo (MD -8.82, 95% CI -11.04 to -6.60; 31 participants, 1 study; moderate-certainty evidence) and may improve severity scores (MD -0.41, 95% CI -0.62 to -0.30; moderate-certainty evidence). With moxisylyte, investigators reported fewer attacks (P < 0.02), less severe symptoms (P < 0.01), and shorter duration of attacks, but the clinical relevance of these results is unclear. No evidence of a difference in AEs between buflomedil and placebo groups was noted (RR 1.41, 95% CI 0.27 to 7.28; 31 participants, 1 study; moderate-certainty evidence). More AEs were observed in participants in the moxisylyte group than in the placebo group. Prostaglandin/prostacyclin analogues One study compared beraprost versus placebo. There was no evidence of benefit for frequency (MD 2.00, 95% CI -0.35 to 4.35; 118 participants, low-certainty evidence) or severity (MD -0.06, 95% CI -0.34 to 0.22; 118 participants, low-certainty evidence) of attacks. Overall, more AEs were noted in the beraprost group (RR 1.59, 95% CI 1.05 to 2.42; 125 participants; low-certainty evidence). This study did not report on duration of attacks, QoL, or RCS. Thromboxane synthase inhibitors One study compared a thromboxane synthase inhibitor (dazoxiben) versus placebo. There was no evidence of benefit for frequency of attacks (MD 0.8, 95% CI -1.81 to 3.41; 6 participants; very low-certainty evidence). Adverse events were not reported in subgroup analyses of participants with primary Raynaud's phenomenon, and the study did not report on duration of attacks, severity of symptoms, QoL, or RCS. Selective serotonin reuptake inhibitors One study compared ketanserin with placebo. There may be a slight reduction in the number of attacks per week with ketanserin compared to placebo (MD -14.0, 95% CI -27.72 to -0.28; 41 participants; very low-certainty evidence) and reduced severity score (MD -133.00, 95% CI -162.40 to -103.60; 41 participants; very low-certainty evidence). There was no evidence that ketanserin reduced the duration of attacks (MD -4.00, 95% CI -14.82 to 6.82; 41 participants; very low-certainty evidence), or that AEs were increased in either group (RR 1.54, 95% CI 0.89 to 2.65; 41 participants; very low-certainty evidence). This study did not report on QoL or RCS. Nitrate/nitrate derivatives Four studies compared topical treatments of nitroglycerin or glyceryl trinitrate versus placebo, each reporting on limited outcomes. Meta-analysis demonstrated no evidence of effect on frequency of attacks per week (MD -1.57, 95% CI -4.31 to 1.17; 86 participants, 2 studies; very low-certainty evidence). We were unable to pool any data for the remaining outcomes. Phosphodiesterase inhibitors Three studies compared phosphodiesterase inhibitors (vardenafil, cilostazol or PF-00489791) to an equivalent placebo. Results showed no evidence of a difference in frequency of attacks (standardized MD [SMD] -0.05, 95% CI -6.71 to 6.61; 111 participants, 2 studies; low-certainty evidence), severity of attacks (MD -0.03, 95% CI -1.04 to 0.97; 111 participants, 2 studies; very low-certainty evidence), duration of attacks (MD -1.60, 95% CI -7.51 to 4.31; 73 participants, 1 study; low-certainty evidence), or RCS (SMD -0.8, 95% CI -1.74 to 0.13; 79 participants, 2 studies; low-certainty evidence). Study authors reported that 35% of participants on cilostazol complained of headaches, which were not reported in the placebo group. PF-00489791 caused 34 of 54 participants to experience AEs versus 43 of 102 participants receiving placebo (RR 1.49). Headache was most common, affecting 14 participants (PF-00489791) versus nine participants (placebo). AUTHORS' CONCLUSIONS: The included studies investigated several different vasodilators (topical and oral) for treatment of primary Raynaud's phenomenon. Small sample sizes, limited data, and variability in outcome reporting yielded evidence of very low to moderate certainty. Evidence is insufficient to support the use of vasodilators and suggests that vasodilator use may even worsen disease.

Selective vs non-selective alpha-blockade prior to adrenalectomy for pheochromocytoma: systematic review and meta-analysis.

OBJECTIVE: Alpha-adrenergic blockade is currently the first choice of preoperative treatment in patients with functional pheochromocytoma and sympathetic paraganglioma. Nevertheless, there is no consensus whether selective or non-selective alpha-blockade is superior for preventing both perioperative hemodynamic instability and complications. DESIGN: Our study aimed to compare selective and non-selective alpha-blockade through a systematic review with meta-analysis. METHODS: MEDLINE, Embase, Web of Science and Cochrane Library were searched for eligible studies. Randomized and observational studies comparing selective and non-selective alpha-blockade in pheochromocytoma and sympathetic paraganglioma surgery in adults were included. Data on perioperative hemodynamic parameters and postoperative outcomes were extracted. RESULTS: Eleven studies with 1344 patients were enrolled. Patients receiving selective alpha-blockade had higher maximum intraoperative systolic blood pressure (WMD: 12.14 mmHg, 95% CI: 6.06-18.21, P < 0.0001) compared to those treated with non-selective alpha-blockade. Additionally, in the group pretreated with selective alpha-blockers, intraoperative vasodilators were used more frequently (OR: 2.46, 95% CI 1.44-4.20, P = 0.001). Patients treated with selective alpha-blockers had lower minimum intraoperative systolic blood pressure (WMD: -2.03 mmHg, 95% CI: -4.06 to -0.01, P = 0.05) and shorter length of hospital stay (WMD: -0.58 days, 95% CI: -1.12 to -0.04, P = 0.04). Operative time, overall morbidity and mortality did not differ between the groups. CONCLUSIONS: This meta-analysis shows non-selective alpha-blockade was more effective in preventing intraoperative blood pressure fluctuations while maintaining comparable risk of both intraoperative and postoperative hypotension and overall morbidity.

Nonselective Compared With Selective α-Blockade Is Associated With Less Intraoperative Hypertension in Patients With Pheochromocytomas and Paragangliomas: A Retrospective Cohort Study With Propensity Score Matching.

BACKGROUND: Both selective and nonselective α-blockade are used for preoperative preparation in patients with pheochromocytomas and paragangliomas (PPGLs). However, the effects of different types of α-blockade on perioperative outcomes remain inconclusive. This study was designed to assess the association between the choice of α-blockade and the amount of intraoperative hypertension in patients undergoing surgery for PPGLs. METHODS: In this propensity-matched retrospective cohort study, data of patients who received either selective or nonselective α-blockade preoperatively and underwent surgery for PPGLs were collected. The primary end point was the time-weighted average above the systolic blood pressure (SBP) of 160 mm Hg (TWA-SBP >160 mm Hg), which was calculated as the total area of the SBP-time curve above the SBP of 160 mm Hg and divided by anesthesia duration. RESULTS: A total of 286 patients were included in analysis; of them, 156 received selective α-blockade and 130 nonselective α-blockade. After propensity score matching, 89 patients remained in each group. Patients who received nonselective α-blockade had a lower TWA-SBP >160 (median 0.472 mm Hg, interquartile range [IQR], 0.081-1.300) versus those who received selective α-blockade (median 1.114 mm Hg, IQR, 0.162-2.853; median difference -0.391, 95% confidence interval [CI], -0.828 to -0.032; P = .016); they also had a lower highest SBP during surgery (193 ± 24 mm Hg versus 205 ± 34 mm Hg; mean difference -12, 95% CI, -20 to -3; P = .008). Postoperative outcomes did not differ significantly between the 2 groups. CONCLUSIONS: For patients undergoing surgery for PPGLs, preoperative nonselective α-blockade was associated with less intraoperative hypertension when compared with selective α-blockade.

Neural signatures of α2-Adrenergic agonist-induced unconsciousness and awakening by antagonist.

How the brain dynamics change during anesthetic-induced altered states of consciousness is not completely understood. The α2-adrenergic agonists are unique. They generate unconsciousness selectively through α2-adrenergic receptors and related circuits. We studied intracortical neuronal dynamics during transitions of loss of consciousness (LOC) with the α2-adrenergic agonist dexmedetomidine and return of consciousness (ROC) in a functionally interconnecting somatosensory and ventral premotor network in non-human primates. LOC, ROC and full task performance recovery were all associated with distinct neural changes. The early recovery demonstrated characteristic intermediate dynamics distinguished by sustained high spindle activities. Awakening by the α2-adrenergic antagonist completely eliminated this intermediate state and instantaneously restored awake dynamics and the top task performance while the anesthetic was still being infused. The results suggest that instantaneous functional recovery is possible following anesthetic-induced unconsciousness and the intermediate recovery state is not a necessary path for the brain recovery.

Efficacy of adding mirabegron to alpha-adrenoreceptor blocker in patients with benign prostatic hyperplasia with persistent overactive bladder symptoms: A prospective study.

Purpose: To compare the efficacies of mirabegron 50 mg addition after alpha-adrenoreceptor blocker in terms of reducing storage symptoms in patients with BPH. Materials and Methods: Fifty-eight patients that had been taking alpha-adrenoreceptor blocker for more than 8 weeks, but had an OABSS of greater than 3 points, were initially enrolled. One group added any alpha-adrenoreceptor blocker with mirabegron 50 mg (n=39; the mirabegron group) and the other group received alpha-adrenoreceptor blocker only (n=19; the control group) for 8 weeks. Results: In the control group, mean total IPSS decreased from 15.7 to 13.1 (p=0.298) and in mirabegron group, mean total IPSS decreased from 19.4 to 16.5 (p=0.024). Mean storage symptom scores reduced in the control and mirabegron groups from 8.5 to 7.9 (p=0.584) and from 9.1 to 7.6 (p=0.015), respectively, and mean QoL scores from 3.7 to 3.1 (p=0.052) and 3.6 to 3.2 (p=0.027), respectively. Mean overall OABSS in the control and mirabegron groups reduced from 8.4 to 7.2 (p=0.173) and from 8.8 to 7.3, respectively (p=0.005); mean OABSS Q3 from 3.6 to 2.9 (p=0.073) and from 3.5 to 2.7 (p=0.002), respectively; and mean OABSS Q4 from 2.4 to 2.0 (p=0.306) and from 2.7 to 2.0 (p=0.016), respectively. The change of mean Qmax and PVR was insignificant in 2 groups. Conclusions: IPSS total scores, storage symptom scores, QoL, overall OABSS, OABSS Q3 and Q4 were more improved significantly by alpha-adrenoreceptor blocker with mirabegron 50 mg in BPH patients with persistent overactive symptoms. Mirabegron 50 mg addition is considered to patients with persistent storage symptoms after alpha-adrenoreceptor blocker.

Pooled analysis of the efficacy and safety of adjunctive alpha-blocker therapy before ureteroscopy in the management of ureteral stones.

OBJECTIVE: To evaluate the efficacy and safety of adjunctive alpha-blocker therapy before ureteroscopy in the management of ureteral stones. METHODS: The databases MEDLINE®, EMBASE and The Cochrane Controlled Trail Register of Controlled Trials were searched between January 1980 and June 2019 to identify randomized controlled trials (RCTs) that referred to the use of alpha-blockers as adjunctive therapy before ureteroscopy for the treatment of ureteral stones. Odds ratios (ORs) with 95% confidence intervals (CIs) were used for dichotomous outcomes; and mean difference (MD) with 95% CIs were used to report continuous outcomes. RESULTS: The analysis included five RCTs with a total of 557 patients. Compared with placebo, patients that received adjunctive alpha-blockers had significantly higher successful access to the stone (OR 5.44; 95% CI 2.99, 9.88), a significantly higher stone-free rate at the end of week 4 (OR 3.75; 95% CI 2.20, 6.39), significantly less requirement for balloon dilatation (OR 0.26; 95% CI 0.15, 0.44) and a significantly lower risk of complications (OR 0.25; 95% CI 0.15, 0.42). There was no significant difference in the operation time between the two groups (MD -3.33; 95% CI -7.03, 0.37). CONCLUSIONS: Adjunctive alpha-blocker therapy administered before ureteroscopy was effective in the management of ureteral stones with a lower risk of complications than placebo treatment.

Modulation of nose-to-brain delivery of a P-glycoprotein (MDR1) substrate model drug (quinidine) in rats.

During the last decades several new drug formulations were developed to target the central nervous system (CNS) from the nasal cavity. However, in these studies less attention was paid to the possible drug-drug interactions in case of multi-drug therapy. In our pilot study first we compared a nasal solution and a nasal gel to demonstrate their distribution in the nasal cavity (3D printed rat skull model and histology). Due to the aspiration induced high mortality at administration of nasal solution the study was continued only with the gel formulation of quinidine. The aim of our experiments was to identify the possible functional role of P-glycoprotein (P-gp) in the drug absorption in nasal cavity and to test drug-drug interactions at nose-to-brain delivery. Therefore, a P-gp substrate model drug, quinidine was tested by intranasal (IN) administration in presence of PSC-833 (specific P-gp inhibitor) given intravenously (IV) or IN and adrenaline (IN) at low (50 ng) or high (20 µg) dose. In control animals the brain penetration of quinidine was at the level of detection limit, but in combination therapy with IV PSC-833 the brain levels increased dramatically, similarly to high dose IN adrenalin, where due to vasoconstriction peripheral distribution was blocked. These results indicate that P-gp has an important role in drug absorption and efflux at nasal cavity, while adrenaline is also able to modify the penetration profile of the P-gp substrate model drug at nasal application as it decreases nose-to-blood absorption, letting more quinidine to reach the brain along with the nasal nerves.

The hemodynamic interactions of combination therapy with α-blockers and phosphodiesterase-5 inhibitors compared to monotherapy with α-blockers: a systematic review and meta-analysis.

OBJECTIVE: The present study systematically reviewed the safety of combined treatment with an alpha blocker and phosphodiesterase-5 inhibitor. MATERIALS AND METHODS: The study was performed according to the PRISMA statement. The included studies were randomized controlled trials that included at least one group on alpha-blocker monotherapy and one group on a combined treatment with an alpha blocker and phosphodiesterase-5 inhibitor. The primary endpoints were the hemodynamic effects of the two groups, specifically the clinically significant changes and a positive orthostatic test. The secondary endpoints were the adverse events of the two treatment modalities. RESULTS: A total of 6687 studies were screened, and 19 randomized controlled trials were eligible for the meta-analysis. The combined treatment more often produced a clinically significant hemodynamic change with an MD of 4.73 (CI 1.25, 17.94; I2 = 0%; p = 0.02), but the positive orthostatic test was similar between the groups with an MD of 1.64 (CI 0.36, 7.47; I2 = 50%; p = 0.52). The meta-analysis of adverse events favored alpha-blocker monotherapy with an OD of 0.5 (CI 0.32, 0.78; I2 = 44%; p = 0.002). However, if we consider only the adverse events due to hypotension, the result was similar between the two groups with an OD of 0.97 (CI 0.58, 1.64; I2 = 0%; p = 0.92). CONCLUSION: The combined treatment may produce a clinically significant hemodynamic change. The combination of alpha blocker and phosphodiesterase-5 inhibitor was safe because it did not increase the rate of adverse events due to hypotension.

The effect of alpha blocker treatment prior to prostate biopsy on voiding functions, pain scores and health-related quality-of-life outcomes: A prospective randomized trial.

PURPOSE: To evaluate the effect of alpha-blocker treatment prior to transrectal ultrasound-guided prostate biopsy (TRUS-Bx) on voiding functions, pain scores and health-related quality-of-life outcomes. MATERIALS AND METHODS: From January 2018 to April 2019, a total of 112 patients underwent TRUS-Bx due to elevated prostate-specific antigen (PSA) or abnormal digital rectal examination findings. Patients were divided into 2 groups depending on whether they received pharmacological treatment before biopsy. Group 1 consisted of patients with no alpha-blocker treatment prior to biopsy and Group 2 consisted of patients who received Tamsulosin for one week before biopsy continuing for one week after biopsy. Voiding function was evaluated three times using the validated International Prostate Symptom Score (IPSS) and uroflowmetry (maximal flow rate (Qmax) and residual volume (PVR)). The Turkish version of the Medical Outcomes Study Short Form 36-item Questionnaire (SF-36) was used to assess health-related quality of life. Pain scores were rated according to the Visual Analogue Scale (VAS) just after the biopsy procedure. RESULTS: Mean IPSS and Qmax on the post-biopsy 7 day were significantly in favor of Group 2 (P<0.001, P=0.004). Although post-biopsy day 7 PVR was similar between the groups, Δ1 PVR was significantly in favor of Group 2 (P=0.004). Mean VAS score was 2.7±2.3 for the Tamsulosin group and 4.2±2.2 for the control group (P=0.001). There was no significant difference between two groups according to baseline and postoperative 1st month SF-36 scores. CONCLUSION: Alpha-blocker therapy prior to TRUS-Bx is effective in preventing voiding dysfunction and biopsy-related pain in patients undergoing TRUS-Bx. LEVEL OF EVIDENCE: 2.

Efficacy of α-Blockers on Hemodynamic Control during Pheochromocytoma Resection: A Randomized Controlled Trial.

CONTEXT: Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL). OBJECTIVE: To determine which type of α-adrenergic receptor blocker provides the best efficacy. DESIGN: Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898). SETTING: Multicenter study including 9 centers in The Netherlands. PATIENTS: 134 patients with nonmetastatic PPGL. INTERVENTION: Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized. MAIN OUTCOME MEASURES: Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score. RESULTS: Median cumulative time outside blood pressure targets was 11.1% (interquartile range [IQR]: 4.3-20.6] in the phenoxybenzamine group compared to 12.2% (5.3-20.2)] in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8-58.0) and 50.0 (35.3-63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days. CONCLUSIONS: The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome.

Extracorporeal Shockwave Therapy Combined with Drug Therapy in Chronic Pelvic Pain Syndrome : A Randomized Clinical Trial.

PURPOSE: Chronic prostatitis/ chronic pelvic pain syndrome (CP/CPPS) is a nonspecific pelvic pain in the absence of signs of infection or other obvious local pathology for at least three of the last 6 months. Evidence for treatment approach is limited. So the aim of this study is to investigate the effect of extracorporeal shock wave therapy (ESWT) combined with pharmacotherapy in the treatment of CP/CPPS. MATERIALS AND METHODS: In this randomized clinical  trial, 31 patients with CP/CPPS were investigated in two groups: the intervention group (n=16) was treated with a combination of an alpha-blocker, an anti-inflammatory agent, a muscle relaxant and a short course of antibiotic in combination with 4 sessions of focused ESWT (a protocol of 3000 impulses, 0.25 mJ/mm2  and 3 Hz of frequency). The control group (n=15) received the aforementioned pharmacotherapy with 4 sessions of sham-ESWT . Follow-up was performed 4 and 12 weeks following ESWT by using the Visual Analogue Scale (VAS), International index of Erectile function (IIEF) 5, National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) and International Prostate Symptom Score (IPSS) questionnaires. Post void residual (PVR) urine and maximum flow rate (Qmax) were also assessed in both groups. RESULTS: The patients mean age was 43.7 ±12.6 years. In both groups, the mean scores of NIH-CPSI (total and sub-domains) and VAS showed statistically significant improvements after 4 and 12 weeks compared to the baseline (P < .001). In the intervention group, IPSS (mean difference: 4.25) and Qmax (mean difference: 2.22) were also significantly improved (P < .001).  There was a significant improvement in NIH-CPSI (mean difference: 1.1) and VAS scores (mean difference: 1.1) in the intervention group as compared to the control group (P < .01). Qmax, PVR and IIEF score were not statistically different in the two groups. CONCLUSION: ESWT in combination with pharmacotherapy could improve the treatment outcome in patients with CP/CPPS.

Combination Therapy with Alpha-blocker and Phosphodiesterase-5 Inhibitor for Improving Lower Urinary Tract Symptoms and Erectile Dysfunction in Comparison with Monotherapy: A Systematic Review and Meta-analysis.

CONTEXT: The effects of combination therapy consisted of an α-blocker and a phosphodiesterase-5 inhibitor (PDE5I) for the treatment of lower urinary tract symptoms (LUTS) and erectile dysfunction (ED). OBJECTIVE: To systematically investigate the efficacy and safety of combination therapy in comparison with monotherapy. EVIDENCE ACQUISITION: The study complied with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement and the recommendations of the European Association of Urology Guidelines office. The study was registered in the PROSPERO database with ID CRD42018086619. Only comparative prospective studies, randomized or quasirandomized, with at least one control group with monotherapy were selected for the meta-analysis. The primary endpoint was the quality of life related to LUTS and ED, measured with the International Prostate System Score (IPSS), maximum flow rate (Qmax), postvoid residual (PVR), and International Index of Erectile Function (IIEF). Secondary endpoints included the adverse events rate. In the subgroup analysis of the influence of adding a PDE5I to the treatment of LUTS, the use of different PDE5Is was considered. EVIDENCE SYNTHESIS: After the screening of 6687 publications, 25 randomized controlled trials were considered eligible to be included in the meta-analysis. In the combination group, IPSS was lower and Qmax was higher than in the α-blocker group, with mean differences (MDs) of 1.41 (95% confidence interval [CI]: 0.42, 2.41; I2 = 71%, p = 0.005) and -1.01 ml/s (95% CI: -1.58, -0.43; I2 = 58%, p = 0.0006), respectively. The mean change of the IPSS was bigger in the combination group, with an MD of -1.72 (95% CI: -2.55, -0.89; I2 = 37%, p < 0.0001). The mean change of Qmax was insignificant, with an MD of -0.61 (95% CI: -1.57, 0.34; I2 = 63%, p = 0.21), as well as PVR and the mean change of PVR, with MDs of 0.65 (95% CI: -5.37, 6.66; I2 = 76%, p = 0.83) and -20.79 (95% CI: -48.94, 7.37; I2 = 75%, p = 0.15), respectively. The IIEF and the mean change of the IIEF had no difference between the combination group and the PDE5I-monotherapy group, with MDs of 1.82 (95% CI: -0.91, 4.54; I2 = 40%, p = 0.19) and 0.25 (95% CI: -1.11, 1.62; I2 = 47%, p = 0.72), respectively. Regarding the adverse events, the meta-analysis was in favor of monotherapy. None of the studies reported any serious or severe adverse event. CONCLUSIONS: Treatment with combination therapy is more effective for the improvement of the IPSS. Less significant improvement was shown in Qmax. The beneficial effect of combination therapy regarding ED remains equivocal. The combination therapy seemed to be safe and well tolerated. PATIENT SUMMARY: In this study, we review the effects of the combination therapy consisting of an α-blocker and a phosphodiesterase-5 inhibitor for the treatment of lower urinary tract symptoms (LUTS) and erectile dysfunction (ED). We found strong evidence to suggest the combination therapy for the improvement of LUTS. Benefits regarding the treatment of ED are less clear.

Preoperative Alpha-Blockers for Ureteroscopy for Ureteral Stones: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Introduction: Preoperative alpha-blockers have been proposed to improve intraoperative outcomes and patient stone-free status after ureteroscopy for ureteral stones. Materials and Methods: We searched six databases, including Medline, Embase, and Web of Science, for randomized controlled trials (RCTs) evaluating alpha-blocker use before planned ureteroscopy for the management of ureteral calculi. Meta-analysis was performed using DerSimonian and Laird method with inverse variance weighting. Quality of evidence was summarized using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. Results: Of 3338 records, 26 were screened as full text and 12 RCTs were included totaling 1352 patients. Meta-analysis demonstrated a 61% risk reduction in need for intraoperative ureteral dilatation in patients administered preoperative alpha-blockers (relative risk [RR]: 0.39 [95% confidence interval, CI: 0.31-0.48], p < 0.00001), as well as increased stone-free status for patients at 4 weeks postoperatively (RR: 1.17 [95% CI: 1.08-1.26], p < 0.0001), and at final follow-up (RR: 1.18 [95% CI: 1.11-1.24], p < 0.00001; median final follow-up 4 weeks [range: 2-8 weeks]). Urologists were more likely to reach the stone with the ureteroscope in patients administered alpha-blockers (RR: 1.16 [95% CI: 1.10-1.23], p < 0.00001). A statistically significant reduction in operative time (mean difference [MD]: -6.05 [95% CI: -10.17 to -1.93] minutes, p = 0.004) and length of hospital stay (weighted MD: -0.34 [95% CI: -0.55 to -0.13] days, p = 0.001) was also demonstrated. Main reported side effects of treatments were abnormal ejaculation, postural hypotension, and dizziness. Outcomes were robust to sensitivity analyses. Results were rated moderate quality evidence using the GRADE framework. Conclusions: Among patients scheduled for semirigid ureteroscopy of ureteral stones, use of preoperative alpha-blockers demonstrated a significant reduction in the need for ureteral orifice dilation and an increase in patient stone-free status at follow-up, and facilitates higher rate of ureteroscopic access to stones, although reducing operative time. An adequately powered trial is needed to definitively address the safety and efficacy of preoperative alpha-blockers for ureteroscopy of ureteral stones.

Determining the minimal important differences in the International Prostate Symptom Score and Overactive Bladder Questionnaire: results from an observational cohort study in Dutch primary care.

OBJECTIVES: To determine the minimal important difference (MID) of the International Prostate Symptom Score (IPSS) and the Overactive Bladder Questionnaire short form (OAB-q SF) assessed in primary care among patients treated for lower urinary tract symptoms (LUTS). DESIGN: Single-arm, open-label observational cohort study with a 6-week follow-up. SETTING: Twenty-two pharmacies in the Netherlands. PARTICIPANTS: We enrolled Dutch men with uncomplicated LUTS who received a new alpha-blocker prescription from their general practitioner or urologist. PRIMARY AND SECONDARY OUTCOMES: The IPSS and OAB-q SF were completed before and after 6 weeks of therapy. At 6 weeks, men also completed the Patient Global Impression of Improvement (PGI-I). The mean change scores of the IPSS and OAB-q SF were calculated for each PGI-I outcome category, with the category 'a little better' used to determine the MID. The SE of measurement (SEM) was calculated for each questionnaire. RESULTS: In total, 165 men completed follow-up. The MID was 5.2 points (95% CI 3.9 to 6.4; SEM 3.6) for the IPSS and 11.0 points (95% CI 7.1 to 14.9; SEM 9.7) for the OAB-q SF. For both questionnaires, CIs showed an overlap with the no-change categories. However, the MID for the IPSS was higher in men with severe baseline symptoms (7.1; 95% CI 5.3 to 9.0) than in men with moderate baseline symptoms (3.2; 95% CI 1.7 to 4.8). CONCLUSION: In this study, the MID for the IPSS was considerably higher than the MID of 3.1 reported in the only other study on this topic, but may be due to methodological differences. Interpretation of the MID for the OAB-q SF is hampered by the overlap with the SEM. Future studies are needed to confirm our results because correlations between the PGI-I and symptom questionnaires were suboptimal.

Trends in the use of antimuscarinics and alpha-adrenergic blockers in women with lower urinary tract symptoms in Taiwan: A nationwide, population-based study, 2007-2012.

BACKGROUND: We aim to examine the trend in the use of antimuscarinics and off-label alpha-adrenergic blockers for treatment of lower urinary tract symptoms (LUTS) in a Taiwanese Women Cohort between 2007 and 2012. METHODS: This population-based National Health Insurance Research Database (NHIRD) was used to examine the trends in the use of antimuscarinics or off-label alpha-adrenergic blockers in Taiwan. A sample of 1,000,000 individuals randomly drawn from the whole population of 23 million individuals who were registered in the NHI in 2005. From 2007 through 2012, women aged over 18 years whose claim record contained prescriptions of either of the two drugs for treatment of any of the LUTS-related diagnoses were identified and analyzed. The annual usage of the two drug classes were calculated by defined daily dose (DDD). RESULTS: From 2007-2012, there was a 0.80 fold (69676.8 to 125104.3) increase in DDD of antimuscarinics in our cohort. The overall healthcare seeking prevalence of LUTS was 7.33% in 2007 and 12.38% in 2012, in a rising trend. The prevalence of antimuscarinics-treated LUTS in our cohort increased from 2.53 in 2007 to 3.41 per 1000 women in 2012. The prevalence of LUTS treated by antimuscarinics increased especially for those older than 60 years during the study period. CONCLUSIONS: This 6-year observational study provided the epidemiologic information of clinically significant LUTS of Asian female population. Moreover, there was a rising trend in the use of antimuscarinics and off-label alpha-adrenergic blockers in the population-based cohort.