Phosphodiesterase-5 Inhibitors and Dementia Risk: A Real-World Study.

INTRODUCTION: Biological and scarce epidemiological evidence suggested that phosphodiesterase-5 inhibitors (PDE5i) might reduce dementia risk. We aimed to examine the association between PDE5i and dementia using real-world data. METHODS: Two retrospective cohorts within the database of Clalit, the largest healthcare provider in Israel (2005-2023), were studied. The first cohort included new daily users, older than 50 years of age, of low-dose tadalafil, prescribed for benign prostatic hypertrophy (BPH), propensity-score matched to new-users of alpha-1 blockers, and analyzed using 2-year lag time. The second cohort included patients with erectile dysfunction, with/without any PDE5i treatment, using time-dependent analysis. Individuals in the cohorts were followed through May 2023 for the occurrence of dementia. RESULTS: The first cohort included 5,204 tadalafil initiators propensity-score matched to 18,565 alpha-1 blockers initiators. There was no association between tadalafil use and dementia risk, HR = 0.99 (95% CI: 0.88-1.12), p = 0.927. Similar results were obtained in a competing risk analysis, and in a sensitivity analysis in which we restricted the cohort to patients older than 60 years at cohort entry. The second cohort of 133,336 patients with erectile dysfunction included new users and nonusers of any PDE5i. In a mean follow-up of 7.9 years, 8,631 patients were newly diagnosed with dementia. In a time-dependent multivariable analysis, PDE5i use was not associated with reduced dementia risk, HR = 0.95 (95% CI: 0.86-1.04). Results were not changed in sensitivity analyses (patients older than 60 years or stratification by PDE5i type). CONCLUSION: This study suggests that the use of PDE5 inhibitors is not associated with decreased risk of dementia.

Nutraceutical interventions for erectile dysfunction: a systematic review and network meta-analysis.

BACKGROUND: Although nutraceutical-based treatments are often offered for erectile dysfunction (ED), their efficacy remains doubtful, and the choice of one substance over the other is challenged by the dearth of head-to-head comparative studies. AIM: We aimed to compare the efficacy of available nutraceutical interventions, alone or in combination with phosphodiesterase type 5 inhibitors (PDE5i), in improving erectile function in men with ED through a network meta-analysis (NMA), which incorporates direct and indirect evidence into one model thus generating a hierarchy of effectiveness. METHODS: PubMed, Scopus, Web of Sciences, and Cochrane Library databases were searched for randomized placebo-controlled trials (RCTs) assessing the effect of any nutraceutical regimen in improving erectile function when compared to each other, placebo, and/or PDE5i in men with ED. Data were included in a random-effects NMA, where efficacy of treatments was ranked by surface under the cumulative ranking curve (SUCRA). Two NMAs were also conducted separately for organic and non-organic ED. Reciprocal comparisons between all treatments were analyzed by league tables. OUTCOMES: The main outcome was the standardized mean difference in the score of the International Index of Erectile Function (IIEF)-5 or IIEF-6. RESULTS: Fifteen RCTs provided information on 1000 men with ED. In the overall NMA, compared to placebo, the combination propionyl L-carnitine (PLC) + acetyl L-carnitine (ALC) + Sildenafil was associated with the highest SUCRA (97%) in improving erectile function score, followed by L-Arginine + Tadalafil (84%), Sildenafil (79%), Tadalafil (72%), and L-Arginine (52%). No other treatment regimen showed efficacy with statistical significance. In patients with organic ED, the efficacy of Sildenafil and Tadalafil was significantly improved by PLC + ALC and L-Arginine, respectively. On the contrary, in non-organic ED, nutraceuticals did not improve the therapeutic performance of daily Tadalafil. CLINICAL IMPLICATIONS: This NMA contributes valuable insights into the potential of nutraceutical interventions for ED. STRENGTHS AND LIMITATIONS: We employed strict inclusion criteria related to study design and diagnostic tool, ensuring the assumption of transitivity and the consistency of the analysis. CONCLUSION: Against a background of general ineffectiveness of most nutraceutical interventions, L-Arginine and the mix PLC + ALC appeared to be of some usefulness in improving erectile function, especially in combination with PDE5i in organic ED.

Safety and efficacy of phosphodiesterase-5 (PDE-5) inhibitors in fetal growth restriction: a systematic literature review and meta-analysis.

Introduction: Fetal growth restriction (FGR) is associated with a higher risk of perinatal morbidity and mortality, as well as long-term health issues in newborns. Currently, there is no effective medicine for FGR. Phosphodiesterase-5 (PDE-5) inhibitors have been shown in pre-clinical studies to improve FGR. This study aimed to evaluate the latest evidence about the clinical outcomes and safety of PDE-5 inhibitors for the management of FGR. Methods: Eight databases (PubMed, Embase, Medline, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Database and WangFang Database) were searched for English and Chinese articles published from the database inception to December 2023. Randomized controlled trials (RCTs) reporting the use of PDE-5 inhibitors in FGR were included. The quality of the RCTs was assessed using the Cochrane Risk of Bias Tool. Odds ratio and mean difference (MD) (95% confidence intervals) were pooled for meta-analysis. Results: From 253 retrieved publications, 16 studies involving 1,492 pregnant women met the inclusion criteria. Only sildenafil (15 RCTs) and tadalafil (1 RCT) were studied for FGR. Compared with the control group (placebo, no treatment, or other medication therapies), sildenafil increased birth weight, pregnancy prolongation and umbilical artery pulsatility indices. However, it also increased the risk of pulmonary hypertension in newborns, as well as headache and flushing/rash in mothers. There were no significant differences in gestation age, perinatal mortality or major neonatal morbidity, stillbirth, neonate death, infants admitted to neonatal intensive care unit, intraventricular hemorrhage and necrotizing enterocolitis in infants, as well as pregnancy hypertension and gastrointestinal side effects in mothers between the treatment and the control groups. Discussion: Sildenafil was the most investigated PDE-5 inhibitors for FGR. Current evidence suggests that sildenafil can improve birth weight and duration of pregnancy but at the same time increase the risk of neonatal pulmonary hypertension. It remains uncertain whether the benefits of sildenafil in FGR outweigh the risks and further high-quality RCTs are warranted. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=325909.

Medical Advancements in Benign Prostatic Hyperplasia Treatments.

PURPOSE OF REVIEW: This review aims to identify and summarize the current literature on the most recent therapeutic agents and combination strategies for the medical management of lower urinary tract symptoms resulting from benign prostatic hyperplasia. RECENT FINDINGS: The latest advancements in BPH therapy have been in combination strategies. Alpha blockers continue to be the mainstay of treatment, but research is exploring the synergistic benefits of combining them with 5-alpha reductase inhibitors (5-ARIs), phosphodiesterase-5 (PDE5) inhibitors, and beta-3 agonists. The alpha-blocker + 5-ARI combination remains ideal for enlarged, significantly reducing clinical progression risk compared to monotherapy. Alpha-blocker + PDE5 inhibitor combinations appear safe and potentially beneficial for men with concomitant erectile dysfunction; sildenafil might hold an edge over tadalafil based on limited data. Beta-3 agonists show synergistic effects with alpha blockers for residual storage symptoms, offering similar efficacy to anticholinergics but with a better side effect profile.

Combined pre- and post-capillary pulmonary hypertension in left heart disease.

Patients with heart failure (HF) often have pulmonary hypertension (PH), which is mainly post-capillary; however, some of them also develop a pre-capillary component. The exact mechanisms leading to combined pre- and post-capillary PH are not yet clear, but the phenomenon seems to start from a passive transmission of increased pressure from the left heart to the lungs, and then continues with the remodeling of both the alveolar and vascular components through different pathways. More importantly, it is not yet clear which patients are predisposed to develop the disease. These patients have some characteristics similar to those with idiopathic pulmonary arterial hypertension (e.g., young age and frequent incidence in female gender), but they share cardiovascular risk factors with patients with HF (e.g., obesity and diabetes), with both reduced and preserved ejection fraction. Thanks to echocardiography parameters and newly introduced scores, more tools are available to distinguish between idiopathic pulmonary arterial hypertension and combined PH and to guide patients' management. It may be hypothesized to treat patients in whom the pre-capillary component is predominant with specific therapies such as those for idiopathic pulmonary arterial hypertension; however, no adequately powered trials of PH-specific treatment are available in combined PH. Early evidence of clinical benefit has been proven in some trials on phosphodiesterase type 5 inhibitors, while data on prostacyclin analogues, endothelin-1 receptor antagonists, and soluble guanylate cyclase stimulators are still controversial.

Predictors of the response to phosphodiesterase-5 inhibitors in pulmonary arterial hypertension: an analysis of the Spanish registry.

BACKGROUND: Achieving and maintaining a low-risk profile is associated with favorable outcome in pulmonary arterial hypertension (PAH). The effects of treatment on risk profile are variable among patients. OBJECTIVE: To Identify variables that might predict the response to treatment with phosphodiesterase-5 inhibitors (PDE-5i) in PAH. METHODS: We carried out a cohort analysis of the Spanish PAH registry in 830 patients diagnosed with PAH that started PDE5i treatment and had > 1 year follow-up. 644 patients started PDE-5i either in mono- or add-on therapy and 186 started combined treatment with PDE-5i and endothelin receptor antagonist (ERA). Responders were considered when at 1 year they: (1) were alive; (2) did not present clinical worsening; and (3) improved European Society of Cardiology/European Respiratory Society (ESC/ERS) risk score or remained in low-risk. Univariate and multivariate logistic regression models were used to analyze variables associated with a favorable response. RESULTS: Two hundred and ten patients (33%) starting PDE-5i alone were classified as responders, irrespective of whether it was mono- or add-on therapy. In addition to known predictors of PAH outcome (low-risk at baseline, younger age), male sex and diagnosis of portopulmonary hypertension (PoPH) or HIV-PAH were independent predictors of favorable response to PDE-5i. Diffusing capacity for carbon monoxide (DLco) ≤ 40% of predicted was associated with an unfavorable response. When PDE-5i were used in upfront combination, 58% of patients were responders. In this group, diagnosis of idiopathic PAH (IPAH) was an independent predictor of favorable response, whereas connective tissue disease-PAH was associated with an unfavorable response. CONCLUSION: Male sex and diagnosis of PoPH or HIV-PAH are predictors of favorable effect of PDE-5i on risk profile when used as mono- or add-on therapy. Patients with IPAH respond more favorably to PDE-5i when used in upfront combination. These results identify patient profiles that may respond favorably to PDE-5i in monotherapy and those who might benefit from alternative treatment strategies.

Reduction of Adverse Events With Phosphodiesterase 5 Inhibitors Post LVAD Implantation: Is It Time for a Randomized Trial?

The improved survival of patients with advanced heart failure after left ventricular assist device (LVAD) implantation together with the scarcity of donor hearts has significantly increased the population of LVAD-supported patients. However, despite the improvement in LVAD technology and the advent of third-generation continuous flow LVADs, complications such as those related to hemocompatibility and stroke rates remain ongoing clinical challenges. Thus, improvement in LVAD technology should be coupled with innovative medical management to further reduce adverse events. We have previously shown a strong association between post LVAD implant phosphodiesterase-5 inhibitors (PDE-5i) use and fewer thrombotic events, as well as improved survival in 2 observational studies. We caution, nevertheless, the use of PDE-5i based on these observations and encourage clinicians to support enrollment in a randomized control trial. A randomized control trial will determine the efficacy and safety of PDE-5i use after implantation in patients with a centrifugal flow LVAD.

Therapeutic augmentation of NO-sGC-cGMP signalling: lessons learned from pulmonary arterial hypertension and heart failure.

The nitric oxide (NO)-guanylate cyclase (GC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular, pulmonary and renal function. Phosphodiesterase-5 inhibitors (PDE-5i) inhibit cGMP degradation, whereas both soluble guanylate cyclase (sGC) stimulators and sGC activators directly increase sGC. PDE-5i (e.g. sildenafil, tadalafil) and sGC stimulators (e.g. riociguat, vericiguat) have been extensively used in pulmonary artery hypertension (PAH) and heart failure (HF). PDE-5i have also been used in end-stage HF before and after left ventricular (LV) assist device (LVAD) implantation. Augmentation of NO-GC-cGMP signalling with PDE-5i causes selective pulmonary vasodilation, which is highly effective in PAH but may have controversial, potentially adverse effects in HF, including pre-LVAD implant due to device unmasking of PDE-5i-induced RV dysfunction. In contrast, retrospective analyses have demonstrated that PDE-5i have beneficial effects when initiated post LVAD implant due to the improved haemodynamics of the supported LV and the pleiotropic actions of these compounds. sGC stimulators, in turn, are effective both in PAH and in HF due to their balanced pulmonary and systemic vasodilation, and as such they are preferable to PDE-5i if the use of a pulmonary vasodilator is needed in HF patients, including those listed for LVAD implantation. Regarding the effectiveness of PDE-5i and sGC stimulators when initiated post LVAD implant, these two groups of compounds should be tested in a randomized control trial.

Is tadalafil associated with decreased risk of major adverse cardiac events or venous thromboembolism in men with lower urinary tract symptoms?

PURPOSE: To evaluate the association of tadalafil, a phosphodiesterase-5 inhibitor (PDE5I), with major adverse cardiac events (MACE) or venous thromboembolism (VTE) in men with lower urinary tract symptoms (LUTS). METHODS: Data was obtained from the TriNetX Research Network, ICD-10 codes were used to identify men with LUTS, MACE, and VTE. In addition, demographic characteristics and use of tadalafil or alpha-blocker was evaluated. Then, unbalanced and balanced association analyses was performed to assess the relation between tadalafil and/or alpha-blocker use with MACE/VTE. RESULTS: After participant selection, analysis included 821,592 men that did not use an alpha blocker or tadalafil, 5,004 men that used tadalafil but no alpha blocker, 327,482 men that used an alpha blocker but no tadalafil, and 6,603 men that used both an alpha blocker and tadalafil. On balanced analysis, tadalafil was independently associated with a decreased risk of MACE/VTE within a 3-year time period (OR = 0.59, 95%CI 0.49-0.70, p < 0.0001). Among men with a history of alpha blocker use, tadalafil use was also independently associated with a decreased risk of MACE or VTE, both before and after controlling for potentially confounding variables (OR = 0.57, 95%CI: 0.50-0.66; p < 0.0001). CONCLUSIONS: In our study, tadalafil was associated with a decreased risk of MACE/VTE in men with LUTS with and without a history of alpha blocker use. It is time to perform further long-term prospective randomized studies to further analyze the cardiovascular effects of PDE5Is as combination treatment with alpha blockers in the management of LUTS.

Phosphodiesterase-5 inhibitors in pregnancy: Systematic review and meta-analysis of maternal and perinatal safety and clinical outcomes.

BACKGROUND: The efficacy and safety profile of phosphodiesterase-5 inhibitors (PDE-5i) in pregnancy are unclear from the few relatively small diverse studies that have used them. OBJECTIVE: To assess the safety profile and clinical outcomes of PDE-5i use in pregnancy. SEARCH STRATEGY: We searched Embase, PubMed, CENTRAL, Prospero and Google Scholar to identify randomised controlled trials (RCTs) reporting the use of any PDE-5i in pregnancy up to September 2021. SELECTION CRITERIA: RCTs reporting obstetric or perinatal outcomes or maternal adverse outcomes in women taking PDE5i in pregnancy. DATA COLLECTION AND ANALYSIS: Risk ratios (RR), 95% confidence intervals (95% CI) and 95% prediction intervals were calculated and pooled for analysis. RESULTS: We identified 1324 citations, of which 10 studies including 1090 participants met the inclusion criteria. Only tadalafil and sildenafil were reported as used in pregnancy. Two studies using tadalafil and eight sildenafil. Nine of ten studies were assessed at having of low risk of bias. PDE-5i use was associated with an increased risk of headaches (RR 1.41, 95% CI 0.97-2.05), flushing (RR 2.59, 95% CI 0.69-9.90) and nasal bleeding (RR 10.53, 95% CI 1.36-81.3); an increase in vaginal birth when used for non-fetal growth restriction (FGR) indications (RR 1.24, 95% CI 1.00-1.55) and a reduction in risk of operative birth for intrapartum fetal compromise (RR 0.58, 95% CI 0.38-0.88). There was no evidence of any increase in risk of perinatal death (RR 0.89, 95% CI 0.56-1.43). However, use for the treatment of FGR increased the risk of persistent pulmonary hypertension of the newborn (PPHN) (RR 2.52, 95% CI 1.00-6.32). CONCLUSIONS: This meta-analysis suggests PDE-5i use in pregnancy is associated with mild maternal side effects and lower risk of operative birth for intrapartum fetal distress. Prolonged use for the treatment of FGR may increase the risk of PPHN. TWEETABLE ABSTRACT: PDE-5i use in pregnancy is associated with mild maternal side effects, lower operative birth for intrapartum fetal distress and a possible increase in persistent pulmonary hypertension of the newborn when used for the treatment of fetal growth restriction.

Current trends in erectile rehabilitation after radical prostatectomy: Results from a worldwide survey.

We aimed to analyse the current trend of erectile rehabilitation (ER) following radical prostatectomy (RP) using a dedicated survey. An online survey was developed between July and September 2020, aiming to evaluate the ER protocols after RP in daily practice among urologists, andrologists, sexual medicine specialists and residents. We investigated demographics data, type of RP performed, and type, schedule, timing and duration of ER protocols. In total, 518 responders from 52 countries completed the survey. Surgical techniques reported were: 38.9% open, 22.9% laparoscopic and 38.2% robot-assisted RP. 33% of the responders begin ER at the catheter removal, 22% 1 month after surgery and 15% before surgery. Phosphodiesterase inhibitors were the most used medication as first-line treatment (99.4%). Tadalafil 20 mg was the most prescribed, and used daily in 48.2% of the cases, and 2-3 times/week in 46%. Intra-cavernosal injection of prostaglandin E1 was the second most common prescribed monotherapy (67.9%) followed by the association of phosphodiesterase inhibitors and vacuum-erection device (29.6%). The duration of ER was <6 months in 16.2%, between 6 and 11 months in 39%, between 12 and 18 months in 31.9%, between 19-24 months in 9.2% and >24 months in 3.7%. This study showed that the approach to ER after RP was inhomogeneous. International guidelines are urgently needed to standardise ER protocols.

Efficacy and safety of avanafil as compared with sildenafil in the treatment of erectile dysfunction: A randomized, double blind, multicenter clinical trial.

OBJECTIVE: To compare the efficacy and safety of avanafil as compared with sildenafil in the management of patients with erectile dysfunction. METHODS: It was a prospective, randomized, double-blind, two-arm, active-controlled, parallel, multicenter, non-inferiority clinical study carried out in patients with erectile dysfunction for at least 3 months and International Index of Erectile Function - Erectile Function domain score of <26 at enrolment. RESULTS: A total of 220 patients were randomized to receive either avanafil tablets 100 mg or sildenafil tablets 50 mg in 1:1 ratio. After 4 weeks of treatment, 40.0% of patients in the avanafil group and 45.6% of patients in the sildenafil group required dose escalation to a high dose (avanafil 200 mg/sildenafil 100 mg). The difference in the mean change of International Index of Erectile Function - Erectile Function score from baseline in the two groups increased from week 4 (1.1, 95% confidence interval -0.2 to 2.5) to week 8 (1.4, 95% confidence interval 0.1-2.7) and week 12 (2.1, 95% confidence interval 0.8-3.5), showing non-inferiority at week 4, and superiority at week 8 and week 12. Avanafil showed a faster onset of action as shown by a significantly better response to modified Sexual Encounter Profile 1 in the avanafil group (84.8%) as compared with that in the sildenafil group (28.2%; P < 0.001). Both avanafil and sildenafil were well tolerated by all the patients in the study; the most common adverse event reported during the study was headache in both the groups. CONCLUSION: Avanafil is superior to sildenafil in improving the International Index of Erectile Function - Erectile Function domain score at the end of 12 weeks of treatment with the added advantage of faster onset of action.

Erectile dysfunction: causes, assessment and management options.

Erectile dysfunction is one of the most common male sexual dysfunctions. The diagnosis can usually be made by a detailed history and examination. Men with erectile dysfunction benefit from multimodal management strategies. These include lifestyle modification, medical treatment and psychosexual counselling and therapy. An oral phosphodiesterase-5 inhibitor is often prescribed for erectile dysfunction. Providing simple and clear instructions is critical to realise the full benefits of these drugs. Those with severe vascular disease or a history of pelvic surgery may not respond to phosphodiesterase-5 inhibitors. Anxiety or unrealistic expectations can also result in a poor response.

The incidence rate of pulmonary arterial hypertension and scleroderma renal crisis in systemic sclerosis patients with digital ulcers on endothelin antagonist receptors (ERAs) and phosphodiesterase-5 inhibitors (PDE5i).

INTRODUCTION: Endothelin antagonist receptors (ERAs) and phosphodiesterase-5 inhibitors (PDE5i) are beneficial in pulmonary arterial hypertension (PAH) and digital ulcers (DU) and prevent from DU recurrences. Our study aimed to determine the difference in the incidence rate of PAH and scleroderma renal crisis (SRC) in patients with SSc and DU (SSc-DU) under ERAs/PDE5i or without treatment. METHODS: We conducted a retrospective cohort study including SSc-DU patients from the Spanish Scleroderma Registry (RESCLE). The primary outcome was the incidence rate of PAH and SRC in patients under ERAs/PDE5i or not. RESULTS: Some 544 patients out of 1817 (29.9%) in the RESCLE database had DU, 221 (40.6%) under ERAs/PDE5i and 323 (59.4%) not. The incidence rate (95% CI) difference between patients under treatment or not under did not reach statistical significance in PAH [-0.1 (-4.8, 4.69), P = 0.988] or in SRC [0.7 (-2.2, 3.7), P = 0.620]. However, the time from the first DU to the diagnosis of SRC was delayed in treated patients [mean (s.d.) 7.6 (5.8) years vs 2.9 (5.3); P = 0.021]. The dcSSc subset was more prevalent in the treatment group (36 vs 26%; P = 0.018), along with anti-topoisomerase I antibodies (34 vs 18%; P < 0.001) and tendon friction rubs (12 vs 6%; P = 0.038), whereas the lcSSc subset was more prevalent in the no-treatment group (57 vs 66%; P = 0.031) along with ACA (37 vs 46%; P = 0.031). CONCLUSION: There was no difference in the incidence rate of PAH and SRC between groups. However, treatment with ERAs and/or PDE5i appeared to delay the occurrence of SRC.

Phosphodiesterase-5 Inhibitors and Outcomes During Left Ventricular Assist Device Support: A Systematic Review and Meta-Analysis.

BACKGROUND: Phosphodiesterase-5 inhibitors (PDE5i) have been used to treat pulmonary hypertension and right ventricular failure in patients with left ventricular assist devices (LVAD). The effects of PDE5i on post-LVAD outcomes including hemocompatibility-related adverse events are not well-established. This systematic review and meta-analysis aims to evaluate the effects of PDE5i on post-LVAD outcomes. METHODS AND RESULTS: A comprehensive literature search was conducted using Pubmed and Embase databases from inception through November 25, 2020, to compare post-LVAD outcomes in patients with or without PDE5i use. Pooled odds ratio (OR) with 95% confidence intervals (CI) and I2 statistic were calculated. Thirteen observational studies were included in this analysis. The use of PDE5i was not significantly associated with lower postoperative right ventricular failure (OR 0.38, 95% CI 0.02-5.96, P = .41). There was no significant association between PDE5i and gastrointestinal bleeding (OR 1.23, 95% CI 0.76-1.98, P = .2), overall stroke (OR 0.60, 95% CI 0.21-1.68, P = .17), ischemic stroke (OR 0.61, 95% CI 0.09-4.07, P = .38), or pump thrombosis (OR 0.71, 95% CI 0.14-3.54, P = .46). CONCLUSIONS: Our meta-analysis showed no significant association between PDE5i and post-LVAD right ventricular failure. Despite the antiplatelet effects of PDE5i, there was no significant association between PDE5i and gastrointestinal bleeding, overall stroke, ischemic stroke, or pump thrombosis. Randomized controlled studies are warranted to evaluate the net benefits or harms of PDE5i in the LVAD population.

WITHDRAWN: Phosphodiesterase-5 inhibitors in Pregnancy: Systematic review and meta-analysis of maternal and perinatal safety and clinical outcomes.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause.

A Randomized, Controlled, 3-Arm Trial of Pharmacological Penile Rehabilitation in the Preservation of Erectile Function After Radical Prostatectomy.

BACKGROUND: Although the concept of penile rehabilitation after radical prostatectomy (RP) has been advocated for decades, there is little definitive evidence regarding its utility or the best strategy to optimize patient outcomes. AIM: The goal of this study is to analyze the ability of 3 different pharmacological strategies to preserve the ability of men to achieve spontaneous (non-medication assisted) erections after bilateral nerve-sparing RP. METHODS: This IRB- and FDA-approved study studied penile rehabilitation in a 3-arm fashion with a target enrollment of 200 patients. (i) Control arm: nightly placebo with sildenafil 100 mg on demand for sexual relations (up to 6 pills/month); (ii) nightly sildenafil arm: nightly sildenafil 50 mg and sildenafil 100 mg on demand for sexual relations (up to 6 pills/month); (iii) combination therapy arm: nightly sildenafil 50 mg (5 nights/week) plus intracavernosal injections twice/week. Inclusion criteria included bilateral nerve-sparing surgery, normal serum total testosterone, and good preoperative baseline erectile function as measured by the erectile function domain score of the IIEF (EFD) (≥24). Patients were followed with a medication use diary and the IIEF questionnaire at 6 weeks, 3 m, 6 m, 12 m, 18 m and 24 m. OUTCOMES: A difference was seen in the IIEF-EFD scores between the 3 groups at 24 months after RP. Secondary end points include the time to return of spontaneous functional erections, the time for patients to respond to oral erectogenic therapy, and the proportion of patients who have normalization of their IIEF-EFD scores. RESULTS: The study was interrupted because of failure to recruit the target study population in a reasonable timeframe. A total of 76 subjects with median age of 57 (IQR: 51, 63) years and mean IIEF-EFD of 29 (IQR: 27, 30) were initially randomized, but at 24 months, the sample sizes by group were (i) n = 4; (ii) n = 18; and (iii) n = 10, with median IIEF-EFD 24 (IQR: 18, 28), 24 (IQR: 18, 28), and 21 (IQR: 9, 26), respectively. There was no statistical difference among the groups in the final analysis. CLINICAL IMPLICATIONS: Definitive evidence for the ability of different pharmacological rehabilitation strategies to improve long-term EF outcomes might never be available. STRENGTHS & LIMITATIONS: This was a well-designed randomized and 3-arm designed trial intended to provide decisive evidence regarding the utility of penile rehabilitation. Failure to recruit the target population is the main limitation. CONCLUSION: The limited number of patients in the present trial precludes definitive interpretation. However, results indicate how challenging it is to conduct true rehabilitation studies. Miranda EP, Benfante N, Kunzel B, et al. A Randomized, Controlled, 3-Arm Trial of Pharmacological Penile Rehabilitation in the Preservation of Erectile Function After Radical Prostatectomy. J Sex Med 2021;18:423-429.

Efficacy and safety of oral phosphodiesterase 5 inhibitors for erectile dysfunction: a network meta-analysis and multicriteria decision analysis.

PURPOSE: To quantitatively assess the benefit-risk ratio on the efficacy and safety of all phosphodiesterase type 5 inhibitors (PDE5i) in men with erectile dysfunction. METHODS: A systematic review with network meta-analysis, surface under the cumulative ranking analysis and stochastic multicriteria acceptability analyses were performed. Searches were conducted in Pubmed, Scopus, Web of Science without limits for time-frame or language. Randomized controlled trials evaluating the efficacy or safety of any PDE5i compared to a placebo or to other PDE5i in males with erectile disfunction were included. RESULTS: Overall, 184 articles representing 179 randomized controlled trials (50,620 patients) were included. All PDE5i were significantly more efficient than placebo. Sildenafil 25 mg was statistically superior to all interventions in enhancing IIEF (with a 98% probability of being the most effective treatment), followed by sildenafil 50 mg (80% of probability). Taladafil 10 mg and 20 mg also presented good profiles (73% and 76%, respectively). Avanafil and lodenafil were less effective interventions. Mirodenafil 150 mg was the treatment that caused more adverse events, especially flushing and headaches. Sildenafil 100 mg was more related to visual disorders, while vardenafil and udenafil were more prone to cause nasal congestion. CONCLUSION: Sildenafil at low doses and tadalafil should be the first therapeutic options. Avanafil, lodenafil and mirodenafil use are hardly justified given the lack of expressive efficacy or high rates of adverse events.

Characteristics and Longitudinal Patterns of Erectile Dysfunction Drug Use Among Men Who Have Sex with Men in the U.S.

We investigated the longitudinal relationship between erectile dysfunction (ED) drug use with behavioral factors, including substance use and sexual activities in men who have sex with men from the Multicenter AIDS Cohort Study during 1998-2016 (n = 1636). We used a bivariate random-intercept model to evaluate ED drug use along with other behavioral factors to assess relationships between the two outcomes over time on a population level and also at the individual level. Average ED drug use among men who have sex with men (MSM) with HIV was positively correlated with average use of marijuana (r = .19), poppers (r = .27), and stimulants (r = .25). In this group, testosterone use (r = .32), multiple partners (r = .41), insertive anal intercourse with condom (r = .40), and insertive anal intercourse without condom (r = .43) all showed moderate correlations over time with average ED use (p < .001). Associations among MSM without HIV were similar, with average marijuana use (r = .19) and stimulant use (r = .22) being positively correlated with average ED drug use, and were also correlated with having multiple partners (r = .36), insertive anal intercourse with condom (r = .22), and insertive anal intercourse without condom (r = .18) over time. Positive within-individual associations between ED drug use and multiple partners and insertive anal intercourse with and without condom were observed regardless of HIV serostatus. This study showed that MSM who reported use of ED drugs were also, on average, more likely to use recreational drugs and engage in sexual activities, such as having multiple partners and insertive anal intercourse. Within individuals, average ED drug use was also positively correlated with sexual behaviors.

Chronic inhibition of phosphodiesterase 5 with tadalafil affords cardioprotection in a mouse model of metabolic syndrome: role of nitric oxide.

Patients with metabolic syndrome (MetS) often exhibit generalized endothelial and cardiac dysfunction with decreased nitric oxide (NO) production and/or bioavailability. Since phosphodiesterase 5 (PDE5) inhibitors restore NO signaling, we hypothesized that chronic treatment with long-acting PDE5 inhibitor tadalafil may enhance plasma NO levels and reduce cardiac dysfunction following ischemia/reperfusion (I/R) injury in C57BL/6NCrl-Leprdb-lb/Crl mice with MetS phenotypes. Adult male MetS mice were randomized to receive vehicle solvent or tadalafil (1 mg/kg,i.p.) daily for 28 days and C57BL/6NCrl mice served as healthy wild-type controls. After 28 days, cardiac function was assessed by echocardiography and hearts from a subset of mice were isolated and subjected to 30 min of global ischemia followed by 60 min of reperfusion (I/R) in ex vivo Langendorff mode. Body weight, blood lipids, and glucose levels were elevated in MetS mice as compared with wild-type controls. The dyslipidemia in MetS was ameliorated following tadalafil treatment. Although left ventricular (LV) systolic function was minimally altered in the MetS mice, there was a significant diastolic dysfunction as indicated by reduction in the ratio of peak velocity of early to late filling of the mitral inflow, which was significantly improved by tadalafil treatment. Post-ischemic cardiac function, heart rate, and coronary flow decreased significantly in MetS mice compared to wild-type controls, but preserved by tadalafil treatment. Myocardial infarct size was significantly smaller following I/R, which was associated with higher plasma levels of nitrate and nitrite in the tadalafil-treated MetS mice. In conclusion, tadalafil induces significant cardioprotective effects as shown by improvement of LV diastolic function, lipid profile, and reduced infarct size following I/R. Tadalafil treatment enhanced NO production, which may have contributed to the cardioprotective effects.