The Effects of Verapamil, Hydralazine, and Doxazosin on Renin, Aldosterone, and the Ratio Thereof.

PURPOSE: Hydralazine, doxazosin, and verapamil are currently recommended by the Endocrine Society as acceptable bridging treatment in those in whom full cessation of antihypertensive medication is infeasible during screening for primary aldosteronism (PA). This is under the assumption that they cause minimal to no effect on the aldosterone-to-renin ratio, the most widely used screening test for PA. However, limited evidence is available regarding the effects of these particular drugs on said ratio. METHODS: In the present study, we retrospectively assessed the changes in aldosterone, renin, and aldosterone-to-renin values in essential hypertensive participants before and after treatment with either hydralazine (n = 26) or doxazosin (n = 20) or verapamil (n = 15). All samples were taken under highly standardized conditions. RESULTS: Hydralazine resulted in a borderline significant rise in active plasma renin concentration (19 vs 25 mIU/L, p = 0.067) and a significant fall in the aldosterone-to-renin ratio (38 vs 24, p = 0.017). Doxazosin caused declines in both plasma aldosterone concentration (470 vs 330 pmol/L, p = 0.028) and the aldosterone-to-renin ratio (30 vs 20, p = 0.020). With respect to verapamil, we found no statistically significant effect on any of these outcome variables. CONCLUSION: We conclude that the assumption that these drugs can be used with little consequence to the aldosterone-to-renin cannot be substantiated. While it is possible that they are indeed the best option when full antihypertensive drug cessation is infeasible, the potential effects of these drugs must still be taken into account when interpreting the aldosterone-to-renin ratio.

The Evidence Paradox of the Effectiveness between the Paediatric and Adult Stone-Forming Population: A Narrative Review.

AIM/OBJECTIVE: To identify trends in the evidence base regarding the effectiveness of using α-blockers in children versus adults and compare outcomes. METHODS: A literature search up using the key words including urolithiasis/renal/ureteric stone in children/paediatric population, medical expulsive treatment (MET), α-blocker/alfuzosin/tamsulosin/doxazosin. Included were randomized or controlled clinical trials in paediatric stone formers (aged ≤18 years). Outcome measures for assessment included the overall stone expulsion rate, expulsion time, the number of pain episodes and adverse drug effects and/or reactions. Further comparison of efficacy levels using respective studies from the adult population was performed in order to identify trends, similarities and differences. RESULTS: A total of 8,259 articles were identified. Full text evaluation was possible for 28 articles. Although the picture is clearer in the paediatric group, the lack of reproducible results in adults certainly poses serious questions about data collection, analysis and interpretation in each individual study. The apparent paradox is due to the methodological differences between studies. CONCLUSION: The effectiveness of α-blockers and other medication as MET needs to be studied in multi-institutional, double-blind, placebo-controlled studies that would aim to prove superiority to placebo in contemporary clinical situations, with realistic end points and standardized outcome measure determination.

Effects of Angiotensin-Converting Enzyme Inhibition and Alpha 1-Adrenergic Receptor Blockade on Inflammation and Hemostasis in Human Hypertension.

Drugs blocking the renin-angiotensin-aldosterone system may offer benefit on endothelial function, inflammation, and hemostasis in addition to the effects of reducing blood pressure. We examined the contribution of the angiotensin-converting enzyme inhibitor ramipril and the alpha 1-adrenergic receptor blocker doxazosin on blood pressure and on markers of inflammation and hemostasis in 59 individuals with mild-to-moderate hypertension randomized to receive double-blind ramipril 10 mg od or doxazosin 8 mg od for 12 weeks. Inflammatory markers (interleukin-6, soluble interleukin-6 receptor, interleukin-8, tumor necrosis factor-α, monocyte chemoattractant protein-1, and C-reactive protein) and hemostasis (plasminogen activator inhibitor-1 activity, tissue plasminogen activator antigen, thrombin-antithrombin complex, and thrombin generation by calibrated automated thrombogram) were assessed. The treatment reduced blood pressure in both groups. Thrombin-antithrombin complex decreased by treatment, and this was dependent on a reduction in thrombin-antithrombin complex in the ramipril group alone. There were no changes in plasminogen activator inhibitor-1 activity, whereas tissue plasminogen activator antigen increased by ramipril and decreased by doxazosin. Only minor changes were observed in systemic inflammation by treatment. Treatment with ramipril seems to reduce thrombin generation beyond effects on reducing blood pressure. Drugs blocking the renin-angiotensin-aldosterone system may reduce atherothrombotic complications beyond their effects to reduce blood pressure.

[Therapeutic effects of α-adrenergic receptor antagonists on benign prostatic hyperplasia: A network meta-analysis].

OBJECTIVE: To investigate the therapeutic effects of commonly used selective α-adrenergic receptor antagonists (α-ARA) on benign prostatic hyperplasia (BPH). METHODS: PubMed, Embase and CNKI databases were searched for the literature about selective α-ARAs for the treatment of BPH and the information was extracted on the common adverse reactions in the course of treatment. Multivariate meta-analysis was conducted to investigate the therapeutic effects of different α-ARAs. RESULTS: The total rates of adverse effects of silodosin and tamsulosin were the highest, 51.9% and 34.0% respectively, with the highest incidences of headache (38.3%), weakness (23.6%) and dizziness (17.5%). Besides, tamsulosin ranked the first in inducing sexual dysfunction of the male patients with BPH (70.4%). CONCLUSIONS: Doxazosin is preferable as the first-choice treatment of BPH for its therapeutic effect and improvement of the patient's quality of life. Silodosin and tamsulosin, however, can be selectively used according to the patient's specific tolerance to different adverse effects.

Effects of the inverse alpha-agonist doxazosin in allergic rhinitis.

BACKGROUND: We examined the paradoxical hypothesis that the alpha-receptor inverse agonist doxazosin might produce beneficial effects in allergic rhinitis. OBJECTIVES: To evaluate single and chronic dosing effects of doxazosin on nasal airflow and symptoms in allergic rhinitis. METHODS: Fifteen patients randomized to receive 3-5 weeks of oral doxazosin 4 mg daily or placebo in crossover fashion. Measurements were taken at baseline and after first and last doses. RESULTS: There was a fall in peak nasal inspiratory flow (PNIF) between baseline vs. first dose of doxazosin: mean difference -19 L/min (95% CI -35 to -2) P = 0.03, with recovery between first and last doses: 21 L/min (95% CI 7-34) P = 0.006. Nasal visual analogue scale (VAS) and blockage scores were worse between baseline vs. first dose of doxazosin: mean difference VAS -10 mm (95% CI -18 to -2) P = 0.02, blockage -0.7 (95% CI -1.3 to -0.1) P = 0.02, with recovery between first and last doses: VAS 15 mm (95% CI 4-25) P = 0.009, blockage 1.1 (95% CI 0.5-1.6) P = 0.001. The oxymetazoline dose-response for PNIF was blunted after single vs chronic dosing with doxazosin: mean difference -17 L/min (95% CI -30 to -4) P = 0.01. Heart rate and diastolic blood pressure showed the same pattern. There was a significant difference between doxazosin and placebo for nasal blockage score and heart rate after single but not chronic dosing. CONCLUSIONS: There was a disconnect between single and chronic dosing effects of doxazosin for nasal symptoms, oxymetazoline response and cardiovascular outcomes, in turn suggesting alpha-1 receptor up-regulation.

Time Course of Incident Adverse Experiences Associated with Doxazosin, Finasteride and Combination Therapy in Men with Benign Prostatic Hyperplasia: The MTOPS Trial.

PURPOSE: We examined first (incident) reports of selected adverse experiences associated with medical therapy in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. MATERIALS AND METHODS: We studied the 6 most common adverse experiences, including nonsexual function related experiences (dizziness, orthostatic hypotension and weakness) and sexual function related experiences (impotence, decreased libido and abnormal ejaculation) reported in the MTOPS (Medical Therapy of Prostatic Symptoms) Study. A total of 3,047 men were randomized to placebo, doxazosin, finasteride or combination therapy and followed for a mean duration of 4.5 years. We compared the incidence rates of adverse experiences at year 1 to the rates thereafter. RESULTS: For each assigned treatment group, the incidence rates were significantly higher for all 6 adverse experiences examined at year 1 compared with the rates thereafter. Men assigned to combination therapy experienced the highest rates at year 1 with rates 3.4-fold to 10.6-fold higher than rates after year 1. The incidence rates for orthostatic hypotension and dizziness were significantly higher in the doxazosin and combination therapy groups compared with the placebo group at year 1. The incidence rates of the 3 examined sexual function related adverse experiences were significantly higher in the finasteride and combination therapy groups than in the placebo group at year 1. CONCLUSIONS: Rates of the first report of sexual function related and other adverse experiences associated with doxazosin, finasteride and combination therapy were greatest during year 1 of treatment. These patterns should be considered by patients and physicians when treatment for lower urinary tract function is initiated with these drugs.

Impact of medical treatments for male lower urinary tract symptoms due to benign prostatic hyperplasia on ejaculatory function: a systematic review and meta-analysis.

INTRODUCTION: Several drugs, currently used to treat lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH), can be associated with bothersome sexual side effects, including ejaculatory dysfunction (EjD). AIM: To provide a systematic review and meta-analysis of the available randomized clinical trials (RCTs) reporting the impact of medical treatments for LUTS due to BPH on ejaculatory function. MAIN OUTCOME MEASURE: EjD related to medical treatments for LUTS. METHODS: A systematic literature search was performed using PubMed, Scopus and Cochrane databases. EjD was identified using both free text ("ejaculat*," "retrograde ejaculation," "anejaculation," "ejaculatory dysfunction") and Mesh ("Ejaculation") searches. RESULTS: Of 101 retrieved articles, 23 were included in the present meta-analysis. EjD was significantly more common with alpha-blockers (ABs) than with placebo (OR:5.88; P < 0.0001), in particular, considering Tamsulosin (OR:8.58; P = 0.006) or Silodosin (OR:32.5; P < 0.0001), with Tamsulosin associated with significantly lower risk of EjD than Silodosin (OR:0.09; P < 0.00001). Conversely, Doxazosin and Terazosin were associated with a risk similar to placebo. Meta-regression showed that EjD was associated with IPSS and with Qmax both before and after treatment with ABs, while multivariate analysis demonstrated that EjD was independently associated with the improvement of IPSS (adj.r:0.2012; P < 0.0001) and Qmax (adj.r:0.522; P < 0.0001). EjD was significantly more common with 5ARIs as compared with placebo (OR:2.73; P < 0.0001). Both Finasteride (OR 2.70; P < 0.0001) and Dutasteride (OR 2.81; P = 0.0002) were associated with significantly higher risk of EjD than placebo. EjD was significantly more common with combination therapy as compared with ABs alone (OR:3.75; P < 0.0001),or with 5ARIs alone (OR:2.76; P = 0.02). CONCLUSIONS: ABs and 5ARI were both associated with significantly higher risk of EjD than placebo. More the AB is effective over time, greater is the incidence of EjD. Finasteride has the same risk of Dutasteride to cause EjD. Combination therapy with ABs and 5ARIs resulted in a 3-fold increased risk of EjD as compared with ABs or 5ARIs alone. These data can be relevant both for drug selection and patients counseling.

Intraoperative floppy iris syndrome (IFIS) in patients receiving tamsulosin or doxazosin-a UK-based comparison of incidence and complication rates.

BACKGROUND: The association between intraoperative floppy iris syndrome (IFIS) and tamsulosin has been well-described. The rate of IFIS in association with other α-1 antagonists needs further clarification. The objective of this study was to determine the incidence of IFIS and associated cataract surgery complications in patients taking tamsulosin or doxazosin. METHODS: Patients receiving tamsulosin or doxazosin, and an equivalent number of controls, were identified using the electronic patient record for cataract surgery performed over 2 years. The presence of IFIS and intraoperative complications were ascertained. Modifications of surgical technique in the form of preoperative 1 % atropine, intraoperative diluted phenylephrine, iris hooks, or highly viscous viscoelastic materials were recorded. RESULTS: Of the 2,785 cataract operations performed in 2,028 patients, 52 cases (1.9 %) were on tamsulosin and 109 were on doxazosin (3.9 %). In the doxazosin group (excluding three cases with incomplete data), significantly more eyes (17 of 106 eyes, 16 %) showed at least one IFIS characteristic than controls, six eyes (6 %) required adjustment of surgical technique, and intraoperative complications occurred in two eyes (1.9 %). In the tamsulosin group, significantly more eyes (25 of 52 eyes, 48 %) demonstrated at least one IFIS feature than control or doxazosin eyes; 18 eyes (35 %) needed adjustment of surgical technique, and seven (13.5 %) suffered intraoperative complications. CONCLUSION: Incidence of IFIS was significantly higher in tamsulosin and doxazosin patients. The presence of IFIS was associated with a significantly higher complication rate. We would advise that all patients receiving α1 antagonists (not only those receiving tamsulosin) should be identified preoperatively, receive appropriate modifications in preparation, and have alternative techniques and a senior surgeon available at the time of surgery.

Comparison of 7 α(1)-adrenoceptor antagonists in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia:a short-term crossover study.

A crossover study was conducted to identify the best α1-adrenoceptor (α1AR) antagonist for individual patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). One hundred thirteen patients (mean age 70.8 years) were enrolled. All patients met BPH clinical study guidelines. Seven agents were utilized:tamsulosin 0.2mg, silodosin 8mg, urapidil 60mg, naftopidil 50mg, prazosin 1mg, terazosin 2mg, and doxazosin 1mg. Patients were initially prescribed tamsulosin or silodosin for a week and then urapidil for a week. Two weeks later, they were prescribed the better of the 2 agents for a week and a new agent for the next week. This cycle was repeated until all 7 agents were tested. Efficacy was evaluated with the International Prostate Symptom Score. The agent rankings were doxazosin (25 [22%]), silodosin (22 [19%]), urapidil (19 [17%]), naftopidil (17 [15%]), terazosin (12 [11%]), tamsulosin (11 [10%]), prazosin (7 [6%]). Only 12 patients (11%) changed agents after the crossover study was completed. The major reason was adverse events (83%). We found that each of the 7 α1AR antagonists has its own supporters. Further, the one-week crossover study was useful in identifying the best agent for the treatment of each individual with LUTS.

[Results of open multicenter study of the safety of doxazosin in combination with indigal in men with stages I-II prostatic adenoma].

The article presents a method of conservative treatment of men with I-II stage prostatic adenoma using a combination of doxazosin and indigal, which has antioxidant, antiproliferative and anti-inflammatory properties, that allowed improving urodynamic parameters and reducing the progression prostate adenoma, minimizing the adverse effects of treatment.

[Experience of the use of silodosin in acute urinary retention caused by benign prostatic hyperplasia].

For the treatment of acute urinary retention (AUR) as one of the most serious complications of adenoma of the prostate (BPH), alpha-adrenoblockers are widely used. The article presents an experience of the use of the new uroselective alpha-adrenoblocker silodosin approved for the treatment of patients with urination disorders caused by BPH. Its pharmacological profile has a number of advantages, including the highest uroselectiveness at the present day, immediate action, the potential for the use of standard dose of 8 mg 1 time a day, which does not require a correction depending on the age, and the possibility of the simultaneous application with antihypertensive drugs.

Gene panels to help identify subgroups at high and low risk of coronary heart disease among those randomized to antihypertensive treatment: the GenHAT study.

OBJECTIVE: To identify panels of genetic variants that predict treatment-related coronary heart disease (CHD) outcomes in hypertensive patients on one of four different classes of initial antihypertensive treatment. The goal was to identify subgroups of individuals on the basis of their genetic profile who benefit most from a particular treatment. METHODS: Candidate genetic variants (n=78) were genotyped in 39 114 participants from Genetics of Hypertension Associated Treatment study, ancillary to Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial. Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial randomized hypertensive participants (≥55 years) to one of four treatments (amlodipine, chlorthalidone, doxazosin, lisinopril). The primary outcome was fatal CHD or nonfatal myocardial infarction (mean follow-up=4.9 years). A pharmacogenetic panel was derived within each of the four treatment groups. Receiver-operating characteristic (ROC) curves estimated the discrimination rate between those with and without a CHD event, on the basis of the addition of the genetic panel risk score. RESULTS: For each treatment group, we identified a panel of genetic variants that collectively improved the prediction of CHD to a small but statistically significant extent. Chlorthalidone (A): NOS3 rs3918226; SELE rs5361; ICAM1 rs1799969; AGT rs5051; GNAS rs7121; ROC comparison, P=0.004; Amlodipine (B): MMP1 rs1799750; Factor5 (F5) rs6025; NPPA rs5065; PDE4D rs6450512; MMP9 rs2274756; ROC comparison, P=0.006; Lisinopril (C): AGT rs5051; PON1 rs705379; MMP12 rs652438; F12 rs1801020; GP1BA rs6065; PDE4D rs27653; ROC comparison, P=0.01; Doxazosin (D): F2 rs1799963; PAI1 rs1799768; MMP7 rs11568818; AGT rs5051; ACE rs4343; MMP2 rs243865; ROC comparison, P=0.007. Each panel was tested for a pharmacogenetic effect; panels A, B, and D showed such evidence (P=0.009, 0.006, and 0.001, respectively) and panel C did not (P=0.09). CONCLUSION: Because each panel was associated with CHD in a specific treatment group but not the others, this research provides evidence that it may be possible to use gene panel scores as a tool to better assess antihypertensive treatment choices to reduce CHD risk in hypertensive individuals.

Risk factors for intraoperative floppy iris syndrome: a meta-analysis.

PURPOSE: To evaluate risk factors (hypertension, diabetes mellitus, and current tamsulosin, alfuzosin, terazosin, or doxazosin use) for intraoperative floppy iris syndrome (IFIS) in patients undergoing phacoemulsification cataract surgery. DESIGN: Systematic review and meta-analysis of the literature. PARTICIPANTS: Seventeen eligible studies (17 588 eyes) examining the association between IFIS and risk factors. METHODS: Pertinent publications were identified through a systematic search of PubMed. All references of relevant reviews and eligible articles were also screened. Language restrictions were not used, and data were extracted from each eligible study by 2 investigators working independently. For medications, 2 separate analyses were performed: an analysis using a dichotomous criterion (use/non-use of the examined agent) and an alternative analysis performing comparisons with patients not receiving any α(1)-blocker. The fixed-effects model (Mantel-Haenszel method) or the random-effects (DerSimonian Laird) model was appropriately used to calculate the pooled odds ratio (OR). Publication bias was appropriately assessed. MAIN OUTCOME MEASURES: Pooled OR for the incidence of IFIS. RESULTS: The pooled OR for IFIS after tamsulosin use was approximately 40-fold greater (or 16.5 at the alternative analysis) than that after alfuzosin use, that is, the second α(1)-blocker in order of effect size. Alfuzosin and terazosin were also associated with IFIS with comparable ORs; the effect of doxazosin reached formal statistical significance at the alternative analysis. Intraoperative floppy iris syndrome was positively associated with hypertension (pooled OR = 2.2, 95% confidence interval [CI], 1.2-4.2, fixed effects) but not with diabetes mellitus (pooled OR = 1.3, 95% CI, 0.7-2.2, fixed effects). CONCLUSIONS: This meta-analysis has highlighted a hierarchy concerning the role of α(1)-blockers in IFIS, indicating an extremely sizeable effect size of tamsulosin; this may entail important physiologic implications. Alfuzosin, terazosin, and doxazosin presented with comparable effect sizes. Hypertension, but not diabetes mellitus, emerged as a risk factor for IFIS.

The safety and efficacy of doxazosin in medical expulsion therapy for distal ureteric calculi: A meta-analysis.

PURPOSE: Alpha-adrenergic receptor blockers can be effectively used in the context of medical expulsion therapy (MET) to treat ureteric stones. This study was designed to evaluate the safety and efficacy of doxazosin in MET relative to placebo or tamsulosin. METHODS: We systematically searched the PubMed, the Cochrane Library, EMBASE, Chinese Academic Database, and Web of Science databases to select randomized controlled trials (RCT) that compared the use of doxazosin with placebo or tamsulosin to treat ureteric stones. All patients we included were limited to those diagnosed with visible stones in the distal ureter. The diameter of ureteric stones does not exceed 10 mm. RESULTS: Eight trials comparing doxazosin with placebo or tamsulosin containing 667 patients were assessed in the final analysis. The meta-analysis showed that doxazosin effectively treated ureteric stones and was better than placebo in terms of efficacy. Relative to the placebo group, the expulsion rate of stones from the distal ureter (OR = 3.00, 95% CI [2.15, 4.19], I2 = 0%, P < 0.00001) was significantly increased, and the expulsion time (days) was shortened (mean difference) (MD) = -4.03, 95% CI [-4.53, -3.53], P < 0.00001). The doxazosin group experienced fewer pain episodes (MD = -0.78, CI = [-0.94, -0.23], I2 = 0%, P < 0.00001) than the placebo group. A subgroup analysis showed that the doxazosin group had a higher expulsion rate (of 5-10 mm stones) compared with the placebo group. Although doxazosin resulted in significantly more adverse effects compared with the placebo, the patient's symptoms were mild and no further medical interventions were required. Moreover, the expulsion time (days) was shorter for patients receiving doxazosin (MD = -0.61, 95% CI [-0.97, -0.24], I2 = 39%, P = 0.001) than those receiving tamsulosin. CONCLUSION: Compared with the placebo group, patients receiving doxazosin had a greater expulsion rate, a reduced expulsion time, and fewer pain episodes. The expulsion time of doxazosin was shorter than that of tamsulosin.

Efficacy and tolerability of doxazosin gastro-intestinal therapeutic system versus tamsulosin in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia: A systematic review and meta-analysis.

BACKGROUND: Alpha1-adrenoceptor antagonists (α1-blockers) are first-line drugs for the treatment of lower urinary tract symptoms associated with benign prostate hyperplasia (BPH). Doxazosin gastrointestinal therapeutic system (GITS) and tamsulosin belong to the 2 most frequently prescribed α1-blockers. This systematic review and meta-analysis was performed to compare the efficacy and tolerability of these 2 α1-blockers. METHODS: A systematic review of published randomized controlled trials in English or Chinese language was performed using the PubMed, EMBASE, Cochrane Library, CNKI, Wanfang, and Vip databases. After data extraction and quality assessment, the meta-analysis was performed to compare clinical parameters (International Prostate Symptom Score [IPSS] total [IPSS-T], storage [IPSS-S], voiding [IPSS-V], maximum urine flow [Qmax], and postvoid residual) and adverse events (AEs) that changed after first drug intake. RESULTS: After the screening, 8 eligible randomized controlled trials with 1316 patients were identified. Doxazosin-GITS showed a significantly higher efficacy compared with tamsulosin (IPSS-T P < .001, IPSS-S P < .001, and IPSS-V P < .001). There were no significant differences between the 2 drugs for changes in Qmax (P = .477) or postvoid residual (P = .739). The overall AEs were significantly lower in the doxazosin-GITS group (risk ratio: 0.77; 95% CI: 0.54-1.08; P = .036). However, dizziness (P = .387), headache (P = .745), asthenia (P = .693), postural hypotension (P = .114), and retrograde ejaculation (P = .187) were similar between the 2 groups. CONCLUSIONS: This meta-analysis indicates that doxazosin-GITS has significantly higher efficacy and lower AEs than tamsulosin in patients with lower urinary tract symptoms/benign prostate hyperplasia.

Assessment of Frailty and Association With Progression of Benign Prostatic Hyperplasia Symptoms and Serious Adverse Events Among Men Using Drug Therapy.

Importance: Benign prostatic hyperplasia (BPH) in older men can cause lower urinary tract symptoms (LUTS), which are increasingly managed with medications. Frailty may contribute to both symptom progression and serious adverse events (SAEs), shifting the balance of benefits and harms of drug therapy. Objective: To assess the association between a deficit accumulation frailty index and clinical BPH progression or SAE. Design, Setting, and Participants: This cohort study used data from the Medical Therapy of Prostatic Symptoms trial, which compared placebo, doxazosin, finasteride, and combination therapy in men with moderate-to-severe LUTS, reduced urinary flow rate, and no prior BPH interventions, hypotension, or elevated prostate-specific antigen. Enrollment was from 1995 to 1998, and follow-up was through 2001. Data were assessed in February 2021. Exposures: A frailty index (score range, 0-1) using 68 potential deficits collected at baseline was used to categorized men as robust (score ≤0.1), prefrail (score 0.1 to <0.25), or frail (score ≥0.25). Main Outcomes and Measures: Primary outcomes were time to clinical BPH progression and time to SAE, as defined in the parent trial. Adjusted hazard ratios (AHRs) were estimated using Cox proportional hazards regressions adjusted for demographic variables, treatment group, measures of obstruction, and comorbidities. Results: Among 3047 men (mean [SD] age, 62.6 [7.3] years; range, 50-89 years) in this analysis, 745 (24%) were robust, 1824 (60%) were prefrail, and 478 (16%) were frail at baseline. Compared with robust men, frail men were older (age ≥75 years, 12 men [2%] vs 62 men [13%]), less likely to be White (646 men [87%] vs 344 men [72%]), less likely to be married (599 men [80%] vs 342 men [72%]), and less likely to have 16 years or more of education (471 men [63%] vs 150 men [31%]). During mean (SD) follow-up of 4.0 (1.5) years, the incidence rate of clinical BPH progression was 2.2 events per 100 person-years among robust men, 2.9 events per 100 person-years among prefrail men (AHR, 1.36; 95% CI, 1.02-1.83), and 4.0 events per 100 person-years among frail men (AHR, 1.82; 95% CI, 1.24-2.67; linear P = .005). Larger point estimates were seen among men who received doxazosin or combination therapy, although the test for interaction between frailty index and treatment group did not reach statistical significance (P for interaction = .06). Risk of SAE was higher among prefrail and frail men (prefrail vs robust AHR, 1.81; 95% CI, 1.48-2.23; frail vs robust AHR, 2.86; 95% CI, 2.21-3.69; linear P < .001); this association was similar across treatment groups (P for interaction = .76). Conclusions and Relevance: These findings suggest that frailty is independently associated with greater risk of both clinical BPH progression and SAEs. Older frail men with BPH considering initiation of drug therapy should be counseled regarding their higher risk of progression despite combination therapy and their likelihood of experiencing SAEs regardless of treatment choice.

Efficacy and Safety of Doxazosin in Medical Expulsive Therapy for Distal Ureteral Stones: A Systematic Review and Meta-analysis.

PURPOSE: Alpha-blockers have been proven as an effective method for increasing the stone expulsion rate of distal ureteral stones. Limited studies have focused on doxazosin; its efficacy remained unclear. We performed this meta-analysis to investigate the efficacy and safety of doxazosin for patients diagnosed with distal ureteral stones less than 10mm. MATERIALS AND METHODS: We systematically searched Ovid MEDLINE®, Cochrane Library, EMBASE, and PubMed for articles comparing doxazosin and conventional care or tamsulosin for distal ureteral stones through October 2019. The outcome measures were stone expulsive rate (SER), stone expulsive time (SET), pain episodes, analgesics consumption, and adverse events. RESULTS: We included 12 studies involving 836 participants with distal ureteral stones less than 10mm in our review. The present meta-analysis showed doxazosin could significantly increase SER [RR=1.64,95%CI (1.32, 2.04), P  < 0.00001], shorten SET [WMD=-3.97,95% CI (-5.68, -2.27), P  < 0.00001] compared with conventional care. In the subgroup analyses, doxazosin showed no benefit in the children subgroup (<16 years old) [RR=1.63,95% CI (0.73,3.64), P  =0.23]. No statistically significant difference was observed regarding the effectiveness of doxazosin and tamsulosin in SER, SET, and safety. 9 in 286 participants reported doxazosin-related adverse events; most were mild to moderate. CONCLUSION: This meta-analysis may suggest that doxazosin is a safe and effective MET for distal ureteral stones less than 10mm. It is not demonstrated to have any significant difference with tamsulosin in SER, SET, and safety. However, it showed no benefits for patients<16 years old.