Major adverse cardiovascular events related to phosphodiesterase 5 inhibitors: analysis of real-life data from Eudra-Vigilance database.

BACKGROUND: Phosphodiesterase 5 inhibitors (PDE5i) are the standard medical treatment for erectile dysfunction. Aim of our study was to evaluate the rate of major adverse cardiovascular events (MACE) reported during PDE5i treatment based on Eudra-Vigilance (EV) reports. METHODS: EV database is the system for managing and analyzing data on suspected adverse reactions to medicines which have been authorized or being studied in clinical trials in the European Economic Area. MACE are defined as non-fatal stroke, non-fatal myocardial infarction, non-fatal congestive heart failure, revascularization after aorto-coronary graft bypass and cardiovascular death. We recorded the number of MACE for sildenafil, tadalafil, vardenafil, avanafil per category and severity until 1st July 2023. Pooled Relative Risk (PRR) was used to compare data between drugs. RESULTS: Overall, 951 MACE events were reported. Most of them were observed in younger patients <65 years old (452/951 events, 48%). Overall, 377/8939 (4%) MACE events were observed for sildenafil, 221/5213 (4%) for tadalafil, 50/1029 (4%) for vardenafil and no events for avanafil. No significative differences were reported comparing sildenafil and tadalafil (PRR 0.71-0.99, IQR 0.61-1.35, P>0.05), neither sildenafil vs. vardenafil (PRR 0.68-0.79, IQR 0.43-1.55, P>0.05), neither tadalafil vs. vardenafil (PRR 0.77-0.95, IQR 0.64-1.30. P>0.05) even when compared for age. Comparison between different classes of age showed MACE were more frequent in patients younger than 65 years old taking sildenafil and tadalafil when compared to patients older than 85 years old (PRR 0.02-0.11. IQR 0.01-0.40. P<0.01) and when compared to patients in 65-85 class of age (PRR 0.02-0.12, IQR 0.01-0.95, P<0.01). CONCLUSIONS: Real life data is consistent with MACE related to PDE5i. PDE5is are infrequently (<5%) associated with MACE. However, risk seems higher in younger patients, particularly for sildenafil (452/951 events, 48%). Clinicians should consider these data when prescribing PDE5i especially in young patients.

Adverse events related to alpha-blockers: analysis of real-life data from Eudra-Vigilance.

BACKGROUND: Patients on alpha-blockers (ABs) treatment may have an increased risk of adverse events (AEs). Aim of our study was to compare real-life data on neuro-vascular and sexual AEs associated with ABs based on Eudra-Vigilance reported AEs. METHODS: Eudra-Vigilance (EV) database is the system for managing and analyzing information on suspected adverse reactions to medicines which have been authorized or being studied in clinical trials in the European Economic Area (EEA). We recorded the number of sexual and neuro-vascular AEs for tamsulosin, alfuzosin, silodosin, prazosin and doxazosin per category and severity until July 30th, 2022. Pooled Relative Risk (PRR) was used to compare data between drugs. RESULTS: Overall the number of AEs were 2842 for Alfuzosin, 11,086 for tamsulosin, 792 for terazosin, 572 for prazosin and 4641 for doxazosin. Different percentages of AEs were obtained for each drug and in different age groups according to EV sub-groups (≤65, 65-85, ≥85). On PRR analysis, the risk of ejaculatory disorders for Silodosin (11%) is 18.5 times higher (PRR 18.5 95%CI; 10.7-31.8; P<0.05) when compared to alfuzosin and the risk of orthostatic hypotension is 2 times lower (PRR=1,84 95%CI 1.32-2.57; P<0.05). CONCLUSIONS: Real life data is consistent with registry studies regarding side effects related to alpha-blockers. Alfuzosin is safer in terms of ejaculatory disorders while silodosin and tamsulosin in terms of orthostatic hypotension. Clinicians should consider these data when prescribing ABs especially in younger and older patients.

Effect of vacation on urinary symptoms in health care workers: an Italian multicenter study.

BACKGROUND: Aim of our study was to assess the impact of vacation on urinary symptoms in health care workers. METHODS: Between March 2018 to October 2019 a survey was carried out by enrolling health care system workers in three centers. Demographic and clinical characteristics of health care workers (i.e. age, smoking status, medical history) were collected. Lower urinary tract symptoms (LUTS) and work related quality of life were assessed before and after vacation with validated questionnaires: Overactive Bladder Questionnaire Short Form (OABq-sf), International Prostate Symptom Score (IPSS), Work-related Quality of Life (WRQOL) and SF-36 questionnaires. As well, night shift workers (NSWs), defined as working at least one time a week from 8 pm to 8 am, were compared to traditional workers (TWs). RESULTS: A total of 236 participants (118 males and 118 females) with a median of 41 (32/49 IQR) years old were included in the survey. Healthcare workers presented after vacation an improvement in LUTS, in work related quality of life and overall health. Overall, 89 (37%) were NSWs and 147 (62%) subjects were TWs. NSWs reported a significant higher median OABq Total Score and IPSS than TWs: respectively, 27 (IQR 23-34) vs. 20 (IQR 19-24) P=0.01, 2 (0/6) vs. 0 (0/2) (P<0.01). No significative differences were found for WRQOL and SF36, respectively 66 (IQR 59/77) vs. 67 (IQR 61/82) (P<0.29) and 98 (97/101) vs. 98 (97/100) (P<0.79). CONCLUSIONS: NSWs present worst urinary symptoms when compared to TWs. Vacation has a beneficial effect, particularly in NSWs, on urinary symptoms and work-related quality of life.

Development of a nomogram predicting the probability of stone free rate in patients with ureteral stones eligible for semi-rigid primary laser uretero-litothripsy.

PURPOSE: Few tools are available to predict uretero-lithotripsy outcomes in patients with ureteral stones. Aim of our study was to develop a nomogram predicting the probability of stone free rate in patients undergoing semi-rigid uretero-lithotripsy (ULT) for ureteral stones. METHODS: From January 2014 onwards, patients undergoing semi-rigid Ho: YAG laser uretero-lithotripsy for ureteral stones were prospectively enrolled in two centers. Patients were preoperatively evaluated with accurate clinical history, urinalysis and renal function. Non-contrast CT was used to define number, location and length of the stones and eventually the presence of hydronephrosis. A nomogram was generated based on the logistic regression model used to predict ULT success. RESULTS: Overall, 356 patients with mean age of 54 years (IQR 44/65) were enrolled. 285/356 (80%) patients were stone free at 1 month. On multivariate analysis single stone (OR 1.93, 95% CI 1.05-3.53, p = 0.034), stone size (OR 0.92, 95% CI 0.87-0.97, p = 0.005), distal position (OR 2.12, 95% CI 1.29-3.48, p = 0.003) and the absence of hydronephrosis (OR 2.02, 95% CI 1.08-3.78, p = 0.029) were predictors of success and these were used to develop a nomogram. The nomogram based on the model presented good discrimination (area under the curve [AUC]: 0.75), good calibration (Hosmer-Lemeshow test, p > 0.5) and a net benefit in the range of probabilities between 15 and 65%. Internal validation resulted in an AUC of 0.74. CONCLUSIONS: The implementation of our nomogram could better council patients before treatment and could be used to identify patients at risk of failure. External validation is warranted before its clinical implementation.

Rotterdam mobile phone app including MRI data for the prediction of prostate cancer: A multicenter external validation.

OBJECTIVES: The Rotterdam Prostate Cancer Risk calculator (RPCRC) has been validated in the past years. Recently a new version including multiparametric magnetic resonance imaging (mpMRI) data has been released. The aim of our study was to analyze the performance of the mpMRI RPCRC app. METHODS: A series of men undergoing prostate biopsies were enrolled in eleven Italian centers. Indications for prostate biopsy included: abnormal Prostate specific antigen levels (PSA>4 ng/ml), abnormal DRE and abnormal mpMRI. Patients' characteristics were recorded. Prostate cancer (PCa) risk and high-grade PCa risk were assessed using the RPCRC app. The performance of the mpMRI RPCRC in the prediction of cancer and high-grade PCa was evaluated using receiver operator characteristics, calibration plots and decision curve analysis. RESULTS: Overall, 580 patients were enrolled: 404/580 (70%) presented PCa and out of them 224/404 (55%) presented high-grade PCa. In the prediction of cancer, the RC presented good discrimination (AUC = 0.74), poor calibration (p = 0.01) and a clinical net benefit in the range of probabilities between 50 and 90% for the prediction of PCa (Fig. 1). In the prediction of high-grade PCa, the RC presented good discrimination (AUC = 0.79), good calibration (p = 0.48) and a clinical net benefit in the range of probabilities between 20 and 80% (Fig. 1). CONCLUSIONS: The Rotterdam prostate cancer risk App accurately predicts the risk of PCa and particularly high-grade cancer. The clinical net benefit is wide for high-grade cancer and therefore its implementation in clinical practice should be encouraged. Further studies should assess its definitive role in clinical practice.

Phamacological treatment of persistant lower urinary tract symptoms after a transurethral resection of the prostate is predictive of a new surgical treatment: 10 years follow-up study.

AIM: To evaluate possible risk factors of re intervention in patients with benign prostatic enlargement (BPE) undergoing transurethral resection of the prostate (TURP). MATERIALS AND METHODS: A consecutive series of patients with LUTS and BPE underwent TURP in our center in 2004 and 2005 and they were then followed up to September 2016. Patients were assessed at baseline, 3-, 6-month postoperatively and yearly thereafter with medical history, international prostate symptom score, prostate specific antigen, maximal urinary flow rate, post void residual urine. Reoperation was defined as the requirement of a new TURP to relieve bothersome LUTS. Cox regression was used to determine covariates associated with reoperation rate and the Kaplan-Meier curve assessed the time to reoperation. RESULTS: Overall, 92 patients were enrolled. Median follow up was 142 months. 13 patients underwent a second TURP during the follow-up period (reoperation rate was 14%); out of them 9/13 (69%) received medical treatment for persistent LUTS (p = .001). The need of LUTS/BPE pharmacological treatment after TURP is an independent risk factor for a second surgical procedure (odds ratio 9,3; p = .001). Out of the 13 patients treated with a re-TURP, 12 (92%) underwent surgery within 5 years of follow-up. CONCLUSION: In our single center study, the need of LUTS/BPE pharmacological treatment was a predictive factor of a re-TURP. Considering that more than 90% of re-TURP were performed during the first 5 years of follow-up, it is assumable that a follow-up longer than 5 years is not needed in these patients.

Night shift workers refer higher urinary symptoms with an impairment quality of life: a single cohort study.

BACKGROUND: The aim of the present study is to assess the impact of night shift work (NSW) on urinary symptoms. METHODS: Between March 2018 to October 2018, we evaluated a group of National Health care system workers. Urinary symptoms and quality of life were measured by Overactive Bladder Questionnaire Short Form (OABq-sf). Clinical variables (i.e. age, smoking status, medical history) were collected and analyzed according to be NS workers (NSWs) from subjects working at least one time from 8 pm to 8 am or from traditional workers (TWs). Univariate and multivariate analysis was performed to identify predictive variables of worse OAB outcomes (OABq-sf>30, OABq-SB≥12, OABq HRQL≥18). RESULTS: A total of 136 participants (68 males and 68 females) were included in the study. On OABq-sf, total score, symptoms bother (OABq-SB) and health related quality of life (OABq-HRQL) domains were significantly (P<0.05) higher in NSWs group, respectively: 31 (IQR 26-35) vs. 19 (IQR 19-20); 11 (IQR 10-13) vs. 6 (IQR 6-7); 19 (IQR 16-22) vs. 13 (13-14). Finally, seven NSWs (10.6%) referred nocturia respect to only one (1%) TWs, (P=0.02). On multivariate analysis NSW was an independent predictor of OABq-sf>30 units (OR:30; CI: 9-111, P=0.001), OABq-SB ≥12 units (OR:16, CI: 6-43, P=0.001) and OABq HRQL≥18 units (OR:20, CI: 6-70, P=0.001). CONCLUSIONS: Night shift workers presented worst OAB Score and poor QL when compared to similar traditional workers. Long-term data on NSWs patients are also needed to further clarify this relationship.

Adverse events related to radium-223 treatment: "real-life" data from the Eudra-Vigilance database.

BACKGROUND: The aim of our study was to analyze adverse events (AEs) associated with radium-223 using real life data from Eudra-Vigilance (EV) database. METHODS: EV database is the system for managing and analyzing information on suspected adverse reactions to medicines which have been authorized or being studied in clinical trials in the European economic area (EEA). We recorded number of AEs for radium-223 per category and severity from 2013 to May 2019. We recorded AEs per age group (<65 years old; between 65 and 85 years; >85 years old) pooled relative risk (PRR) were used to compare groups. The number of individual cases identified in EV database was 4339. RESULTS: According to the registry study the most frequent AEs in patients treated with radium-223 were hematological, general and gastrointestinal disorders and they were confirmed as the most frequent AEs in the EV database. In the EV database over 90% of the reported AEs were defined as serious and 8% were fatal. Older patients (>85 years) treated with radium-223 were at increased risk of cardiac, infectious, and metabolism disorders when compared to younger patients (<65). However, we have no information on the number of patients under treatment in the EV database. CONCLUSIONS: EV database highlights several AEs which are not reported in registry studies as well as different AEs profiles according to age. Clinicians should consider these data when treating patients with radium-223.

Urinary and sexual function after treatment with temporary implantable nitinol device (iTind) in men with LUTS: 6-month interim results of the MT-06-study.

PURPOSE: To evaluate the functional outcomes as they relate to the preservation of urinary continence and sexual function after treatment with the temporarily implanted nitinol device (iTind; Medi-Tate Ltd, Israel); a novel minimally invasive treatment for lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). METHODS: Men with symptomatic BPH (IPSS ≥ 10, Qmax < 12 ml/s, and prostate volume (PV) < 120 ml) were invited to participate in this single-arm, prospective multicenter study (MT06). Patients were not washed out of BPH medications before the procedure. The iTind was implanted through a 22F rigid cystoscope under intravenous sedation and was removed 5-7 days later through a 22F Foley catheter under local anesthesia. Post-operative VAS and complications (Clavien Dindo-Grading System) were recorded. Preservation of urinary continence and erectile and ejaculatory function were assessed according to ISI, MSHQ-EjD and SHIM questionnaires. Post-operative IPSS, QoL, Qmax and PVR were also assessed at 1, 3, and 6 months post-operatively. RESULTS: This interim report includes data out to 6 months on the first 70 patients enrolled in the study. The median age was 62.31 years, and the mean prostate volume was 37.68 ml (15-80 ml). Baseline and follow-up data are reported in Table 1. No intraoperative complications were observed, the average post-operative VAS score was 3.24 ± 2.56. On average patients returned to daily life after 4.3 days following the retrieval procedure. Sexual function and urinary continence were preserved in all subjects according to the ISI, SHIM and MSHQ-EjD questionnaires and significant improvements (p < 0.0001) from baseline levels were recorded in IPSS, QoL and peak flow. CONCLUSION: iTind is a well-tolerated, minimally invasive treatment for BPH-related LUTS which preserves sexual function and urinary continence, offers a rapid recovery and return to daily life, and a significant improvement of symptoms and urinary flow at 6-month follow-up.

Impairment of autophagy may represent the molecular mechanism behind the relationship between obesity and inflammation in patients with BPH and LUTS.

BACKGROUND: Aim of this study was to evaluate the roles of inflammation and autophagy in obese patients with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). METHODS: We analyzed 150 surgical specimens from patients underwent transurethral resection of the prostate (TURP) for LUTS/BPH (Median age 70.3±8.1 years, median BMI 25.7±4.0 kg/m2 and median PSA 6.0±5.4 ng/mL). All surgical specimens were investigated for the presence inflammatory infiltrates, according to the standardized classification of chronic prostatitis of the National Institute of Health. The inflammatory score (IS Score) was calculated. High IS score was defined as ≥7. Each sample was stained for anti-LC3B (cell signaling) and for anti-P62/SQSTM1 (MBL) according to manufacturer's suggestions and scored as follow: 0 (no dots); 1 (detectable dots in 5-25% of cells); 2 (readily detectable dots in 25-75% of cells); 3 (dots in >75% of cells). High percentage of p62 or LC3B was defined as >25%, whereas low percentage of p62 or LC3B was defined as <25% of cells with dots. RESULTS: Overall 74/150 (49.3%) patients were overweight or obese (BMI >25 kg/m2). Obese patients presented a higher inflammatory score. Obese/overweight patients presented a lower percentage of LC3B (58/74; 78.4%) and higher of p62 (49/74; 66.2%) compared to those of normal weight, which it means a deactivated autophagy (P<0.05). At multivariate analysis LC3B (OR=0.22; CI: 0.069-0.70; P=0.01) percentage and BMI (OR=1.118; CI: 1.001-1.250; P=0.04) were independent risk factors of prostatic inflammation (IS≥7). CONCLUSIONS: Here we confirm the association between obesity and prostatic inflammatory infiltrates and present the first evidence of autophagy deregulation in obese patients with LUTS/BPH. Further studies should better investigate this relationship and provide new possible therapeutic targets.

Laparoscopic simple prostatectomy vs bipolar plasma enucleation of the prostate in large benign prostatic hyperplasia: a two-center 3-year comparison.

PURPOSE: To compare surgery outcomes and safety of button bipolar enucleation of the prostate vs laparoscopic simple prostatectomy in patients with large prostates (> 80 g) in a two-center cohort study. METHODS: All patients with lower urinary tract symptoms due to benign prostatic enlargement (Prostate volume > 80 cc) undergoing button bipolar enucleation of the prostate (BTUEP) or laparoscopic simple prostatectomy (LSP) in two centers were enrolled. Data on clinical history, physical examination, urinary symptoms, uroflowmetry and prostate volume were collected at 0, 1, 3 6, 12, 24 and 36 months. Early and long-term complications were recorded. RESULTS: Overall, 296 patients were enrolled. Out of them, 167/296 (56%) performed a LSP and 129/296 (44%) performed a BTUEP. In terms of efficacy both procedures showed durable results at three years with a reintervention rate of 8% in the LSP group and of 5% in the BTUEP group. In terms of safety, BTUEP and LSP presented similar safety profiles with a 9% of transfusion rate and no major complications. CONCLUSION: LSP and BTUEP are safe and effective in treating large-volume adenomas with durable results at three years when performed in experienced centers.

Adverse events related to abiraterone and enzalutamide treatment: analysis of the EudraVigilance database and meta-analysis of registrational phase III studies.

BACKGROUND: Data from clinical trials do not always provide adequate information to judge the impact of new treatments when used in a real-world setting. The aim of our study was to analyze adverse events (AEs) associated with enzalutamide (ENZ) and abiraterone (ABI) using real-life data from the EudraVigilance (EV) database. METHODS: The EV database is the system for managing and analyzing information on suspected adverse reactions to medicines, which have been authorized or are being studied in clinical trials in the European Economic Area. We recorded the number of AEs for ABI and ENZ per category and severity from January 2013 to January 2019. In addition, we recorded AEs per age group. A meta-analysis of AEs reported in registrational phase III studies (AFFIRM, PREVAIL, COU-AA) was performed. RESULTS: The number of individual cases identified in EV database was 13,562 for ABI and 40,599 for ENZ. Over 90% of the reported AEs were defined as serious for both drugs. Older patients (>85 years and 65-85 years) treated with ABI or ENZ are at increased risk of cardiac, infectious, metabolic, and respiratory disorders when compared with younger patients (<65). According to registrational phase III studies, the most frequent AEs in patients treated with ABI are hepatobiliary disorders, while the most frequent AEs in patients treated with ENZ are psychiatric and vascular disorders. Several AEs present in the EV database are not reported in the registrational phase III studies. It is important to note that we have no information on the number of patients under treatment in the EV database. CONCLUSIONS: The EV database highlights several AEs that are not reported in registrational phase III studies as well as different AEs profiles according to age. Clinicians should consider these data when treating patients with castration-resistant prostate cancer with ABI or ENZ.

External validation of Imamura nomogram as a tool to predict preoperatively laser semi-rigid ureterolithotripsy outcomes.

BACKGROUND: We aimed to validate Imamura nomogram for prediction of stone free rate in patients undergoing ureterolithotripsy (ULT). METHODS: From January 2013 to June 2016, patients undergoing laser semi-rigid ULT were prospectively enrolled at our center. All patients were preoperatively assessed with clinical history, blood samples, uranalysis and non-contrast enhanced computed tomography (CT). Treatment efficacy was assessed 1 month later by non-contrast enhanced CT. ROC curve was used to evaluate the performance characteristics of Imamura nomogram. RESULTS: Overall, we enrolled 275 patients. Median age was 55 years (IQR: 46/64), median length of stone was 9.8 mm (IQR: 7.5/12). Pyuria was detected in 6/275 (2.1%) patients. Stones were located at ureteropelvic junction in 55/275 (19%) patients, proximal ureter in 74/275 (26%) patients, middle and distal ureter in 66/275 (24%) patients and 82/275 (30%) patients, respectively. At 1-month follow-up, 209/275 (76%) patients were stone free. Imamura nomogram presented an AUC of 0.67 (95% CI: 0.580-0.761) for the prediction of stone free rate. At the best cut-off value of 75%, sensitivity was 76%, specificity was 55%, positive predictive value (PPV) was 83% and negative predictive value was 45%. CONCLUSIONS: We firstly validated Imamura nomogram in a European cohort study. It proved a reasonable accuracy (area under curve: 0.67) and a good PPV (83%). Further studies should confirm our results to support the routine clinical use of Imamura nomogram as a tool to predict ULT outcomes.