Phosphodiesterase-5 Inhibitor Therapy Research Articles

Phosphodiesterase 5 Inhibitor Treatment Is Associated With Improved Survival in Pulmonary Hypertension Associated With COPD in the Pulmonary Vascular Research Institute GoDeep Meta-Registry

BackgroundPatients with COPD frequently develop pulmonary hypertension (PH-COPD). Severe PH-COPD, identified by a pulmonary vascular resistance (PVR) >5 Wood Units (WU), is closely linked to impaired transplant-free survival. The impact of PH-targeting pharmacotherapy in this context remains unclear. Research QuestionIs PH-targeted therapy associated with improved transplant-free survival in PH-COPD? Study Design and MethodsThis study included PVRI GoDeep meta-registry patients with PH-COPD and available right heart catheterization at diagnosis. We investigated PH-targeted therapy prevalence and its association with transplant-free survival using diverse statistical methods, including Cox regression and subgroup analyses based on PH severity, comorbidities, and pulmonary function tests. Immortal time bias was addressed through a landmark approach. ResultsAs of December 2023, the GoDeep meta-registry included 26981 patients (28% PH-Group 1, 13% PH-Group 2, 12% PH-Group 3, 10% PH-Group 4, 2% PH-Group 5, 26% undefined and 9% control). Out of these, 836 patients were diagnosed as PH-COPD and included in this analysis, with median age 66 [59,73]years, FEV1 51 [34,69]%predicted, mPAP 35 [28,44]mmHg, PVR 5 [4,8]WU, cardiac index 2.5 [2.0,2.9]L/min.m2, and mostly WHO functional class III were included. 5-year transplant-free survival was 42%, significantly worse than group 1 PH. A multivariable Cox proportional hazards model identified PVR, but not FEV1 as a major predictor of outcome. 418 patients (50%) received phosphodiesterase-5 inhibitor (PDE5i) therapy, which was associated with significantly reduced mortality: hazard ratio 0.65 [0.57,0.75] for the entire PH-COPD cohort and 0.83 [0.74,0.94] when performing landmark analysis. This PDE5i effect was robustly reproduced when performing subgroup analyses for patients with moderate/severe PH, various comorbidities, and supplemental oxygen requirement, and when assessing the impact of unobserved confounders. InterpretationPH-COPD patients exhibit poor transplant-free survival, with PVR being a predictor of mortality. In this meta-registry, PDE5i therapy was associated with a significant reduction in mortality across all tested models.

(302) THE PREVALENCE OF PHOSPHODIESTERASE-5 INHIBITOR USAGE IN MEN WITH RETROGRADE EJACULATION

Abstract Introduction Retrograde ejaculation (RE) represents a disruption and reversal in the normal antegrade seminal pathway, frequently resulting in sexual dissatisfaction and potential subfertility among men. Established etiologies of RE include alpha-adrenergic blockers used for benign prostatic hyperplasia (BPH) and certain psychotropic medications; however, the exact mechanism of action is not yet understood. Phosphodiesterase-5 inhibitors (PDE5Is), which like alpha-adrenergic blockers similarly result in vasodilation, are commonly administered for lower urinary tract symptoms, including erectile dysfunction and BPH. Despite their widespread use, there is limited literature exploring the association between PDE5I administration and the onset of retrograde ejaculation. Objective The purpose of this study is to elucidate if a relationship exists between PDE5I usage and retrograde ejaculation. Methods An IRB-approved retrospective review at a tertiary referral center identified men with a diagnosis of retrograde ejaculation via ICD-9 or ICD-10 codes and through retrograde semen analysis. Exclusion criteria included men without retrograde ejaculation based on semen analysis or electronic health record review. Baseline demographics included comorbidities, medications, and PDE5I usage. Data were analyzed using descriptive statistics and chi-square tests. Results Search criteria resulted in 98 male patients with a diagnosis of retrograde ejaculation (93 via ICD-9 or 10 code, 5 confirmed via semen analysis with post-ejaculatory urinalysis) with a mean age of 51.68 ± 15.99 years. 19 of these patients (19.4%) had recorded use of PDE5I at the time of RE diagnosis. 26 of the resulting patients (26.5%) were previously exposed to PDE5Is at the time of RE diagnosis. Men who were previously prescribed PDE5Is were more likely on average to be older at time of diagnosis (58.19 ± 13.31 years, p = 0.016). There were no statistically significant differences in BMI, race, ethnicity, smoking status, or presence of diabetes between men with previous PDE5I usage versus those without (p > 0.062). Of the men exposed to PDE5Is at any point, 34.6% were on sildenafil, 30.8% were on tadalafil, and 34.6% were on a combination of the two. There was no significant difference between concomitant alpha blocker use or use of psychotropic medications in men who had a history of PDE5Is usage compared to those who had not (p > 0.086). Conclusions In our findings, 19.4% patients had noted concurrent PDE5I use at the time of diagnosis of retrograde ejaculation. The use of PDE5I therapy is not uncommon in men with retrograde ejaculation. Further prospective studies to navigate this association are warranted. Disclosure No.

Effect of different physical activities on erectile dysfunction in adult men not receiving phosphodiesterase-5 inhibitors therapy: A systematic review and meta-analysis.

Erectile dysfunction (ED) is prevalent not only among older males but also in younger. The physical activity has been considered a potential protective factor against ED. However, there is a lack of comprehensive research on the impact of exercise interventions specifically on ED patients. This study aimed to assess the effectiveness of the physical activity in addressing ED symptoms among adult males, without the use of the phosphodiesterase-5 inhibitors (PDE5i) therapy. Additionally, subgroup analysis was performed to evaluate the effects of different exercise modes. Employing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a systematic literature search. A registered protocol is available at PROSPERO (CRD42023441717). Our search spanned PubMed, Web of Science, Embase, and Cochrane Library, with data collection ending on 11 April 2024. The Cochrane Risk of Bias tool was applied by two independent authors to assess randomized controlled trial (RCT) quality. The primary endpoint was determined as the International Index of Erectile Function (IIEF) scores. A total of seven RCTs were included. Utilizing a random-effects model, the estimated standardized mean difference (SMD) was 0.69 (95% confidence interval [CI] 0.37 to 1.02, p<0.0001) for the overall impact of the physical activity. Subgroup analysis revealed SMDs of 0.81 (95% CI 0.56 to 1.06; p<0.00001) for aerobic training alone. However, no significant improvement was observed with pelvic floor muscle training (PFMT) (SMD 0.03; 95% CI -0.68 to 0.75; p=0.93) and a combination of aerobic and resistance training (SMD 0.84; 95% CI -0.41 to 2.09; p=0.19) CONCLUSION: The findings of this study highlight a significant improvement in the erectile function following exercise interventions for adult men with ED, who are not receiving the PDE5i therapy, especially in conducting aerobic training alone. However, PFMT and a combination of aerobic and resistance training did not show significant improvements in erectile function from this study.

Recovery of optimal vitamin D improves responsiveness to phosphodiesterase-5 inhibitors therapy in pulmonary arterial hypertension

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): R.A. has received funding from the European Union’s Horizon 2020 research and innovation programme under Marie-Curie grant agreement Nº 847635. Introduction Vitamin D (vitD) deficiency is highly prevalent in patients with pulmonary arterial hypertension (PAH). Moreover, PAH-patients with lower levels of vitD have worse prognosis. We demonstrated that in animals with PAH and severe deficit of vitD, restoring vitD levels to an optimal range partially improves some pathophysiological features of PAH. Also, recent evidence suggests that vitD deficiency may cause insufficient response to phosphodiesterase-5 inhibitors (PDE5i), such as sildenafil, in some patients with PAH. Thus, in this study, we hypothesize that the recovery of optimal vitD levels in experimental PAH might help to improve responsiveness to PDE5i therapy. Methods Male Wistar rats were fed a vitD-free diet for five weeks and then received a single dose of Su5416 (20 mg/Kg) and were exposed to vitD-free diet and chronic hypoxia (10% O2) for three weeks to induce PAH. Following this, vitD deficient rats with PAH were housed in room air and divided into two groups: (a) daily tadalafil therapy (oral;10mg/kg) + continued vitD-free diet (n=9) or (b) daily tadalafil therapy (oral;10mg/kg) + single oral dose of 50,000 IU/Kg of vitD plus standard diet (n=9) for four weeks. Animals were then used for exercise capacity evaluation, invasive haemodynamic, pulmonary vascular analysis, and sample collection. Evolution of cardiac (dys)function was assessed by echocardiography. Results Recovering optimal vitD levels improved pulmonary endothelial function, measured by an increase in the endothelium-dependent vasodilator response to acetylcholine. It also increased the vasodilator response to sildenafil. Moreover, pulmonary small artery (&amp;lt;55 µm) remodeling was decreased in vitD-restored group, as measured by a decline in mean lumen/total ratio and mean medial thickness. In a morphometric analysis, vitD treatment attenuated increases in both right ventricle (RV) and right atrial hypertrophy, as well as the fulton index. VitD supplementation also improved the exercise capacity with increases seen in distance run, evaluated by endurance tests in a treadmill set. RV catheterization showed that vitD did not decreased the RV dysfunction, evaluated by end-systolic and end-diastolic pressure. Similar to the RV, no alterations were observed in pulmonary artery pressures. However, echocardiographic analysis revealed an improved pulmonary flow in the vitD-restored group, where pulmonary artery acceleration time normalized to ejection time ratio and pulmonary artery velocity-time integral were increased. It also improved tricuspid annular plane systolic excursion (TAPSE). Conclusion Altogether, these data suggest that in animals with PAH treated with tadalafil, restoring vitD levels to an optimal range improves some pathophysiological features of PAH. Therefore, in addition to recovery of optimal vitD status being indicated to restore calcium homeostasis in those PAH patients with severe deficiency, it might help to improve responsiveness to PDE5i.

Abstract 18596: Sildenafil Modulates Metabolic Remodeling by Increasing Fatty Acid β-Oxidation in Single Ventricle Congenital Heart Disease

Introduction: Sildenafil, a phosphodiesterase-5 inhibitor (PDE5i), is used to treat heart and circulatory failure (HF) in single ventricle congenital heart disease (SV). We previously demonstrated that human SVHF myocardium is characterized by increased PDE5 activity and impaired mitochondrial energetics, which are improved with PDE5i. Using an in vitro model in combination with SV myocardial tissue, we test the hypothesis that mitochondrial fatty acid β-oxidation (FAO) is improved with PDE5i therapy via activation of sirtuin-3 (Sirt3) and resulting protein deacetylation. Methods: Primary cardiomyocytes (neonatal rat ventricular myocytes, NRVMs) were treated with 2% serum from SVHF patients or non-failing (NF) controls +/-PDE5i (72 hours). To mechanistically interrogate whether PDE5i acts via Sirt3, we utilized siRNAs against Sirt3 +/-PDE5i. FAO was directly assessed via the Seahorse Bioanalyzer (Agilent). Mitochondrial protein levels and acetylation profiles were quantified via Western blot. Sirt3 activity was measured in isolated mitochondria from SVHF myocardium using a fluorescent-based enzymatic assay. Statistical analysis was performed using a Welch ANOVA with post-hoc Dunnett’s multiple comparisons test (FAO) or a paired T test (Sirt3 activity). Results: NRVMs treated with SVHF serum have impaired mitochondrial FAO and while PDE5i therapy results in improved FAO, siRNA knockdown of Sirt3 abolishes the PDE5i protective effect (A). Mitochondria isolated from SVHF myocardium are hyperacetylated, and ex vivo PDE5i treatment enhances Sirt3 deacetylase activity (B-C), and deacetylates mitochondrial proteins. Conclusions: SVHF serum treatment of cardiomyocytes is a novel in vitro platform for mechanistic investigations of SV-related pathophysiology. These data suggest PDE5i directly augments mitochondrial FAO via Sirt3-mediated protein deacetylation and provides important insight into the myocardial specific mechanisms of PDE5i.

Carotid artery intima media thickness can predict the response to phosphodiesterase 5 inhibitors in patients with moderate erectile dysfunction.

Increased carotid artery intima-media thickness (CIMT) has been shown to be associated with erectile dysfunction (ED), but studies evaluating the efficacy of CIMT in predicting drug response are lacking in the literature. We aimed to evaluate the efficacy of CIMT in predicting the response to phosphodiesterase-5 inhibitors (PDE5-I). A total of 274 subjects were divided into two groups: ED patients (n = 150) and controls (n = 124). The patients in the ED group were further divided into the subgroups of severe, moderate, mild-moderate, and mild ED. Blood tests, carotid ultrasonography, and the International Index of Erectile Function-5 (IIEF-5) diagnostic tool were applied to all subjects. Tadalafil was administered to each patient. The patients were re-evaluated using the IIEF-5 questionnaire after 2 months of treatment. According to their response to medication, the patients were evaluated as responders or nonresponders. Increased CIMT was significantly associated with the failure of PDE5-I therapy, especially in patients with moderate/mild-moderate ED. Fasting blood glucose, body mass index, and CIMT were significantly higher in the ED group compared to the control group (P =.021, P = .006, and P < .001, respectively). The IIEF-5 score was significantly lower in the ED group (P < .001). CIMT was significantly correlated with the IIEF-5 score. When the total patient group was evaluated, the CIMT value of the responders was significantly lower than that of the nonresponders (P = .001). CIMT was significantly higher among the nonresponders with moderate/mild-moderate ED compared to the responders (P = .004 and .008, respectively), while there was no significant difference in CIMT between the responders and nonresponders with severe or mild ED. A receiver operating characteristic (ROC) analysis of CIMT was performed for discrimination between nonresponders and responders with moderate/mild-moderate ED. The area under the ROC curve was 0.801 (0.682-0.921) (P = .001), and the cutoff value was determined to be 0.825mm, at which CIMT predicted the response to treatment with 65% sensitivity and 89% specificity. Using a validated CIMT cutoff value can help the physician inform the patient about the possibility of drug failure and avoid attempting second-line therapy too soon. There are three main limitations to our study. First, the number of participants was low. Second, ultrasound is a relatively subjective method, and third, all measurements were made by the same radiologist. CIMT can be used as a predictor of response to PDE5-I therapies in patients with moderate/mild-moderate ED.

(206) Erectile Dysfunction and Hypogonadism in Men with Spina Bifida

Abstract Introduction Spina Bifida is a congenital neurological defect associated with genitourinary anomalies, requiring comprehensive urological care from pediatrics to adulthood. For men with spina bifida, a significant focus is on urinary tract surveillance to maintain continence, preserve kidney and bladder health, and optimize fertility and sexual function. While men with SB have an increasing interest in exploring their sexuality and sexual health, these concerns may be under-discussed and undertreated depending on their burden of illness. ED is associated with diminished body image and low self-confidence resulting in poor sexual health. Additionally, it creates barriers to maintaining intimate relationships. Current data tackling the prevalence of erectile dysfunction demonstrates variations in value, yet low quantifications of treatment for SB patients. Prior studies have shown a positive response to phosphodiesterase-5 (PDE5) inhibitor therapy (80%). Concurrently, the impact of hypogonadism on the SB is unknown. Hypogonadism is associated with increased insulin resistance in young males, hyperlipidemia, and other adverse vascular effects. These risk factors play a role in the vascular etiology of erectile dysfunction and can be a burden on sexual health. With a scarcity of men’s sexual health data focused on the adult SB male population, there is a need to illustrate the prevalence of ED and HG in men with SB while investigating treatment utilization. We hypothesize that men with SB will experience a higher rate of diagnosis of ED and HG compared to the general adult male population, and lower treatment utilization rates. Objective To calculate the estimated prevalence of erectile dysfunction and hypogonadism in adult men with spina bifida Methods This retrospective claims study used the MarketScan® databases from 2008 to 2017 to derive prevalence estimates for erectile dysfunction and hypogonadism in men with spina bifida, to compare these estimates to those in men without spina bifida, and to describe treatment patterns in this cohort. All men in aged 18 years and older with a diagnosis of SB were included for analysis. Patients with congenital hormonal disorders were excluded. To analyze treatment utilization, the National Drug Codes for pharmacotherapies for ED or HG and Current Procedural Terminology (CPT) codes for penile prosthesis were used. Results The estimated prevalence of erectile dysfunction and hypogonadism in men with spina bifida was 7.83% and 7.71%, respectively. Men with spina bifida in the sample exhibited high rates of smoking and metabolic comorbidities, but were diagnosed less frequently with erectile dysfunction when controlling for age and metabolic comorbidities than men without spina bifida. Most men with spina bifida and ED (66.6%) or hypogonadism (77.4%) do not receive treatment. However, a diagnosis of spina bifida did not appear to affect the likelihood of treatment for either condition on multivariate analysis. Conclusions Based on the results, claims data suggest that HG and ED are diagnosed less frequently than expected. While there are some limitations to the population being examined in this database, improving health care delivery of sexual health concerns during the surveillance of men with spina bifida will enhance their quality of life and optimize their sexual and metabolic function. Disclosure No

Phosphodiesterase-5 inhibitors for left ventricular assist device implantation complicated by right ventricular failure.

Phosphodiesterase-5 inhibitors (PDE5I) are frequently implemented after left ventricular assist device (LVAD) implantation to improve haemodynamics in patients with early postoperative right ventricular (RV) failure. It is unknown if long-term PED5I therapy beyond the early post-operative period provides any clinical benefit in stable outpatients, who have recovered from post-operative RV failure under univentricular device support. This study aimed to investigate the impact of PDE5I discontinuation on RV function and cardiopulmonary exercise capacity in patients on durable LVAD support. We enrolled 31 clinically stable LVAD recipients on long-term oral PDE5I therapy. The mean age was 53years, and 90% were male. Patients discontinued PDE5I and underwent cardiopulmonary exercise testing, echocardiography, LVAD interrogation, and biomarker analysis at baseline and 4weeks after PDE5I withdrawal. At 4weeks, no significant changes were observed in echocardiographic indices of RV morphology and function but an increase in peak tricuspid regurgitation velocity (2.1 vs. 2.4m/s, P=0.01). Peak oxygen consumption (11.4 vs. 11.8mL/min/kg, P=0.52), minute ventilation/carbon dioxide production slope (33 vs. 35, P=0.56), N-terminal pro-brain natriuretic peptide (1455 vs. 1399pg/mL, P=0.55), flow and power readings of the device, and quality of life (Kansas City Cardiomyopathy Questionnaire score 78.3% vs. 77.5%, P=0.62) exhibited no significant changes. We observed an increase in 6-min walking distance (346 vs. 364m, P=0.03). Two patients were hospitalized for non-cardiac reasons (subtherapeutic INR, driveline infection). No patient was hospitalized for cardiac decompensation. In LVAD patients with a history of early post-operative RV failure, discontinuation of long-term PDE5I therapy was not associated with deterioration of RV function, exercise capacity, and quality of life. PDE5I should be critically evaluated until more evidence regarding the net clinical benefit of this pharmacologic intervention becomes available.

PORTOPULMONARY HYPERTENSION PRACTICE PATTERNS AFTER LIVER TRANSPLANTATION

PORTOPULMONARY HYPERTENSION PRACTICE PATTERNS AFTER LIVER TRANSPLANTATION

C57. Left Main Coronary Artery Compression by A Dilatated Pulmonary Artery in Patients with Pulmonary Arterial Hypertension: What Should We Do?

Abstract Background Pulmonary artery hypertension (PAH) is often associated with angina and extrinsic compression of left main coronary artery (LMCA) by a dilatated pulmonary artery is recognized as the cause. The optimal management for pulmonary arterial hypertension with extrinsic LMCA compression has not been clearly established. Case Summary We report on 31-year-old female with secundum atrial septal defect and 44 -year-old female with incomplete atrioventricular septal defect complain of progressive typical angina that aggravated with exertion. The electrocardiogram showed right heart strain and chest radiograph showed cardiomegaly involving the right cavities with enlargement of the pulmonary arch. Right heart catheterization showed pulmonary arterial hypertension with the mean pulmonary artery pressure of 61 mmHg and 65 mmHg respectively. Cardiac CT demonstrated compression of proximal LMCA by dilatated pulmonary artery. Although with optimal phosphodiesterase-5 (PDE5) inhibitor and prostacyclin analog therapy, patients still complain of angina. Discussion LMCA compression may be associated with additional complications of severe myocardial ischemia, including myocardial infarction, left ventricle dysfunction, arrhythmia, and eventually, sudden death. It may occur in patients with PAH with severely dilated PA and can be identified with either computed tomographic coronary angiography or selective coronary angiography. Furthermore, there are no guidelines recommending optimal management of this disease entity. Optimalization of pharmacologic treatment of PAH may reduce compression-related symptoms. A stent implantation is a promising alternative option for the treatment of LMCA compression and provides an optimal risk-to-benefit ratio, both for symptom relief and for long-term outcomes.

C57. Left Main Coronary Artery Compression by A Dilatated Pulmonary Artery in Patients with Pulmonary Arterial Hypertension: What Should We Do?

Abstract Background Pulmonary artery hypertension (PAH) is often associated with angina and extrinsic compression of left main coronary artery (LMCA) by a dilatated pulmonary artery is recognized as the cause. The optimal management for pulmonary arterial hypertension with extrinsic LMCA compression has not been clearly established. Case Summary We report on 31-year-old female with secundum atrial septal defect and 44 -year-old female with incomplete atrioventricular septal defect complain of progressive typical angina that aggravated with exertion. The electrocardiogram showed right heart strain and chest radiograph showed cardiomegaly involving the right cavities with enlargement of the pulmonary arch. Right heart catheterization showed pulmonary arterial hypertension with the mean pulmonary artery pressure of 61 mmHg and 65 mmHg respectively. Cardiac CT demonstrated compression of proximal LMCA by dilatated pulmonary artery. Although with optimal phosphodiesterase-5 (PDE5) inhibitor and prostacyclin analog therapy, patients still complain of angina. Discussion LMCA compression may be associated with additional complications of severe myocardial ischemia, including myocardial infarction, left ventricle dysfunction, arrhythmia, and eventually, sudden death. It may occur in patients with PAH with severely dilated PA and can be identified with either computed tomographic coronary angiography or selective coronary angiography. Furthermore, there are no guidelines recommending optimal management of this disease entity. Optimalization of pharmacologic treatment of PAH may reduce compression-related symptoms. A stent implantation is a promising alternative option for the treatment of LMCA compression and provides an optimal risk-to-benefit ratio, both for symptom relief and for long-term outcomes.

Impact of phosphodiesterase-5 inhibitors on right ventricular function and exercise capacity after left ventricular assist-device implantation: the PIVAD study

Abstract Background Long-term therapy with oral phosphodiesterase-5 inhibitors (PDE5I) is frequently implemented after left ventricular assist-device (LVAD) implantation to improve hemodynamics and prevent late-onset right ventricular (RV) failure or to facilitate listing for heart transplantation in individuals with persistent pulmonary hypertension. The safety and efficacy of this appoach has not been prospectively studied. Recent analyses of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) demonstrated improved survival for patients under long-term PDE5I after 48 months but higher incidence of early postoperative RV failure as well as a higher risk for gastrointestinal bleeding. Purpose To evaluate the impact of discontinuation of PDE5I in patients on LVAD support. Methods In this prospective, single-arm, interventional study we enrolled LVAD recipients on oral PDE5I (sildenafil or tadalafil) after at least 1 month post-implant who were clinically stable on optimal medical therapy. The patients underwent physical examination, ECG, 6-minute walking test, cardiopulmonary exercise testing, transthoracic echocardiography, LVAD interrogation, questionnaire based evaluation of quality of life and testing of serum biomarkers at baseline and 4 weeks after discontinuation of oral PDE5I therapy. Results From 10/2019 to 02/2021 thirty patiens were included in the study and completed the follow-up. Mean age was 54 years, 90% were male. Destination therapy was the primary treatment goal in 13% of this cohort while 87% received LVAD as a bridge to transplant. Mean dosis of tadalafil was 24.6 mg, of sildenafil 42.5 mg. At follow-up no significant changes were elicited in echocardiographic markers of RV function, peak oxygen consumption, VE/VCO2 slope, eGFR, N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, quality of life and average flow and power readings of the device but mild increase in walking distance (Table 1). Two patients were hospitalized for non-cardiac reasons (subtherapeutic INR, driveline infection). No patient was hospitalized for cardiac decompensation. Conclusion Discontinuation of PDE5I was not associated with deterioration of RV function, exercise capacity and quality of life after 4 weeks. The risk/benefit profile of PDE5I in LVAD patients needs to be further investigated in context of randomized controlled trials. Funding Acknowledgement Type of funding sources: None. Table 1

31 Immediate Post-Operative Phosphodiesterase-5 Inhibitors (PDE5i) Therapy Improves Early Erectile Function Outcomes After Robot Assisted Radical Prostatectomy (RARP)

Abstract Introduction To assess whether the timing of post-RARP PDE5i therapy affects early erectile function, continence, or safety outcomes. Method Data from 158 patients treated with PDE5is post-RARP was prospectively collected over two years from a single surgeon at one tertiary centre and retrospectively evaluated. Therapy was started: immediately (day 1-2) in 29%, early (day 3-14) in 37% and late (after day 14) post-op in 34%. EPIC-26 Erectile Function (EF) scores were collected pre-op and post-op after a median 43-day follow-up interval. Results Drop in EF scores and percentage return to baseline post unilateral nerve sparing (UNS) compared to bilateral nerve sparing (BNS) RARP was respectively 9 and 11.1% versus 3.5 and 42.9% of immediate therapy, 7 and 14.8% versus 5.5 and 35.5% of early and 9.7 and 9.5% versus 7.3 and 25% of late. Pad free and social continence was achieved in 54% and 37% of those receiving immediate therapy, 60% and 33% for early and 26% and 54% for late. Conclusions Immediate post RARP PDE5i therapy may protect EF and should be considered clinically, with more benefits for BNS than UNS patients. Immediate or early, rather than late, PDE5i therapy improved early continence in BNS patients.

Long-term tolerability of phosphodiesterase-5 inhibitors in pulmonary hypertension of sickle cell disease.

Sickle cell disease-related pulmonary hypertension (SCD-PH) is a complex disorder with multifactorial contributory mechanisms. Previous trials have evaluated the efficacy of pulmonary arterial hypertension (PAH) therapies in SCD-PH with mixed results. We hypothesized that a subset of patients with right heart catheterization (RHC) confirmed disease may benefit from PAH therapy. We performed a retrospective chart review of patients with SCD-PH diagnosed by RHC who were treated with phosphodiesterase 5 inhibitor (PDE5-I) therapy for ≥4months between 2008 and 2019 at two institutions. Thirty-six patients were included in the analysis. The median age (IQR) upon PDE5-I initiation was 47.5years (35-51.5years); 58% were female and twenty-nine (81%) had HbSS disease. Of these, 53% of patients had a history of acute chest syndrome, 42% had a history of venous thromboembolism, and 38% had imaging consistent with chronic thromboembolic PH. Patients were treated for a median duration of 25months (IQR 13-60months). Use of PDE5-I was associated with a significant improvement in symptoms as assessed by NYHA Class (P=.002). In SCD patients with PH defined by RHC, PDE5-I therapy was tolerated long-term and may improve physical activity.

Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial

Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pulmonary arterial hypertension (PAH), act on the same pathway via different mechanisms. Riociguat might be an alternative option for patients with PAH who do not respond sufficiently to treatment with PDE5i, but comparisons of the potential benefits of riociguat and PDE5i in these patients are needed. The aim of this trial was to assess the effects of switching to riociguat from PDE5i therapy versus continued PDE5i therapy in patients with PAH at intermediate risk of 1-year mortality. Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy (REPLACE) was an open-label, randomised controlled trial in 81 hospital-based pulmonary hypertension centres in 22 countries. The study enrolled patients aged 18-75 years with symptomatic PAH at intermediate risk of 1-year mortality (based on the European Society for Cardiology-European Respiratory Society guideline thresholds for WHO functional class and 6-min walk distance [6MWD]) who were receiving treatment with a PDE5i with or without an endothelin receptor antagonist for at least 6 weeks before randomisation. Patients were excluded if they had been previously treated with riociguat, had used prostacyclin analogues or prostacyclin receptor agonists within 30 days before randomisation, had clinically significant restrictive or obstructive parenchymal lung disease, or had left heart disease. Patients were randomly assigned (1:1) to remain on PDE5i treatment (oral sildenafil [≥60 mg per day] or oral tadalafil [20-40 mg per day]; the PDE5i group) or to switch to oral riociguat (up to 2·5 mg three times per day; the riociguat group), using an interactive voice and web response system, stratified by cause of PAH. The primary endpoint was clinical improvement by week 24, defined as an absence of clinical worsening and prespecified improvements in at least two of three variables (6MWD, WHO functional class, and N-terminal prohormone of brain natriuretic peptide), analysed using last observation carried forward in all randomly assigned patients with observed values at baseline and week 24 who received at least one dose of study medication (the full analysis set). Secondary endpoints included clinical worsening events. The trial has been completed and is registered with ClinicalTrials.gov, NCT02891850. Between Jan 11, 2017, and July 31, 2019, 293 patients were screened, of which 226 patients were randomly assigned to the riociguat group (n=111) or to the PDE5i group (n=115). 211 patients completed the study and 14 patients discontinued (seven in each group). One patient assigned to the PDE5i group did not receive treatment, so 225 patients were included in the safety analysis, and one further patient in the PDE5i group had missing components of the composite primary endpoint at baseline, so 224 patients were included in the full analysis set. The primary endpoint was met by 45 (41%) of 111 patients in the riociguat group and 23 (20%) of 113 patients in the PDE5i group; odds ratio [OR] 2·78 (95% CI 1·53-5·06; p=0·0007). Clinical worsening events occurred in one (1%) of 111 patients in the riociguat group (hospitalisation due to worsening PAH) and 10 (9%) of 114 patients in the PDE5i group (hospitalisation due to worsening PAH [n=9]; disease progression [n=1]; OR 0·10 [0·01-0·73]; p=0·0047). The most frequently occurring adverse events were hypotension (15 [14%]), headache (14 [13%]), and dyspepsia (10 [9%]) in the riociguat group, and headache (eight [7%]), cough (seven [6%]), and upper respiratory tract infection (seven [6%]) in the PDE5i group. Serious adverse events were reported in eight (7%) of 111 patients in the riociguat group and 19 (17%) of 114 patients in the PDE5i group. During the study, four patients died in the PDE5i group, one of them during the safety follow-up period. Switching to riociguat from PDE5i treatment, both of which act via the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, could be a strategic option for treatment escalation in patients with PAH at intermediate risk of 1-year mortality. Bayer AG, Merck Sharp & Dohme.

Thrombotic Lesion of the Pulmonary Vessels in Patients with Pulmonary Embolism

After suffering pulmonary embolism (PE), doctors are confronted with various consequences of the disease, from asymptomatic residual pulmonary thrombosis to the formation of chronic thromboembolic pulmonary hypertension (CTEPH). There is also a subgroup of patients who have undergone pulmonary embolism, who experience shortness of breath during physical exertion, absent before pulmonary embolism, or shortened dyspnea preceding PE, combined with residual thrombosis of pulmonary artery (PA) and normal average pressure in PA at rest during catheterization of the right heart (CRH). This condition is defined as chronic thromboembolic pulmonary disease or post thromboembolic syndrome. Pathogenetic aspects of this condition are not fully investigated. It is important to predict the development of postembolic syndrome and to develop algorithms for the diagnosis, treatment and rehabilitation of patients with symptoms and residual pulmonary thrombosis. In case of the development of pulmonary vasculopathy in some patients who have undergone pulmonary embolism, a severe life-threatening condition forms - CTEPH, characterized by an increase in pressure in the pulmonary artery, right heart failure due to the presence of organized blood clots that have entered the pulmonary vascular bed during PE. The volume of thrombotic masses does not always correlate with clinical symptoms, which indicates the importance of microvascular remodeling. If CTEPH is suspected, a diagnostic algorithm is required, including ventilation-perfusion scintigraphy, CT angiopulmonography and catheterization of the right heart. Treating a patient with CTEPH is a difficult task fora doctor. The timely referral of the patient to the center where they are involved in treatment, including surgery and CTEPH is extremely important. Timely performed thrombendarterectomy in some cases allows to completely cure the patient. In the case of inoperable CTEPH or residual pulmonary hypertension after thrombendarterectomy, balloon angioplasty of the PA is used as well as drug treatment with specific drugs that reduce the pressure in the PA (riociguat), endothelin receptor antagonists (bosentan, macitentan), prostanoids (inhalant illoprost) phosphodiesterase-5 inhibitor and combined therapy. In this article we considered some consequences directly related to PE: asymptomatic residual pulmonary thrombosis, chronic thromboembolic pulmonary disease, chronic thromboembolic pulmonary hypertension.

Poor outcome of patients with pulmonary arterial hypertension with insufficient response to phosphodiesterase-5 inhibitors alone or in combination with other specific therapy: a registry-based study.

Phosphodiesterase-5 inhibitors are commonly used in pulmonary arterial hypertension but, as suggested by the RESPITE study, phosphodiesterase-5 inhibitor therapy (mono-/combination) does not always have a satisfactory treatment effect. This study aimed to investigate the clinical course of pulmonary arterial hypertension patients not at treatment goal after at least 90 days of treatment with phosphodiesterase-5 inhibitors, alone or in combination with other pulmonary arterial hypertension therapies. The study included 106 incident patients from the Swedish Pulmonary Arterial Hypertension Registry, treated with phosphodiesterase-5 inhibitors for ≥90 days, who were not at a pre-specified treatment goal, i.e. in World Health Organisation functional class III, with 6-min walking distance 165–440 m, and N-terminal prohormone of brain natriuretic peptide >300 ng/L. Changes in World Health Organisation functional class, 6-min walking distance, N-terminal prohormone of brain natriuretic peptide, and risk group between index and follow-up were assessed. Of patients with complete follow-up data, (n = 53) 77% were on combination therapy and risk assessment yielded 98% at intermediate risk at index. At follow-up, 11 patients transitioned from World Health Organisation functional class III to World Health Organisation functional class II, the median (Q1; Q3) change in 6-min walking distance was 6 (−30; 42) meters and in N-terminal prohormone of brain natriuretic peptide 47 (−410; 603) ng/L, while 89% remained at an intermediate risk. Of those without complete follow-up data, 11 patients died and 2 underwent lung transplantation. In conclusion, pulmonary arterial hypertension patients treated with phosphodiesterase-5 inhibitors, as single or combination therapy and not achieving the pre-specified treatment goals after ≥90 days have an unfavourable clinical course.

Current therapeutic strategies for erectile function recovery after radical prostatectomy – literature review and meta-analysis

Current therapeutic strategies for erectile function recovery after radical prostatectomy – literature review and meta-analysis

High rates of medication adherence in patients with pulmonary arterial hypertension: An integrated specialty pharmacy approach.

Phosphodiesterase-5 inhibitors (PDE-5I) have demonstrated improvement in disease symptoms and quality of life for patients with pulmonary arterial hypertension (PAH). Despite these benefits, reported adherence to PDE-5I therapy is sub-optimal. Clinical pharmacists at an integrated practice site are in a unique position to mitigate barriers related to PAH therapy including medication adherence and costs. The primary objective of this study was to assess medication adherence to PDE-5I therapy within an integrated care model at an academic institution. The secondary objective was to assess the impact of out-of-pocket (OOP) cost, frequency of dosing, adverse events (AE) and PAH-related hospitalizations on medication adherence. We performed a retrospective cohort analysis of adult patients with PAH who were prescribed PDE-5I therapy by the center’s outpatient pulmonary clinic and who received medication management through the center’s specialty pharmacy. We defined optimal medication adherence as proportion of days covered (PDC) ≥ 80%. Clinical data including AEs and PAH-related hospitalizations were extracted from the electronic medical record, and financial data from pharmacy claims. Of the 131 patients meeting inclusion criteria, 94% achieved optimal adherence of ≥ 80% PDC. In this study population, 47% of patients experienced an AE and 27% had at least one hospitalization. The median monthly OOP cost was $0.62. Patients with PDC<80% were more likely to report an AE compared to patients with PDC≥ 80% (p = 0.002). Hospitalization, OOP cost, and frequency of dosing were not associated with adherence in this cohort. Patients receiving PDE-5I therapy through an integrated model achieved high adherence rates and low OOP costs.

Preimplant Phosphodiesterase-5 Inhibitor Use Is Associated With Higher Rates of Severe Early Right Heart Failure After Left Ventricular Assist Device Implantation.

Background Early right heart failure (RHF) occurs commonly in left ventricular assist device (LVAD) recipients, and increased right ventricular (RV) afterload may contribute. Selective pulmonary vasodilators, like phosphodiesterase-5 inhibitors (PDE5i), are used off-label to reduce RV afterload before LVAD implantation, but the association between preoperative PDE5i use and early RHF after LVAD is unknown. Methods and Results We analyzed adult patients from the INTERMACS registry (Interagency Registry for Mechanically Assisted Circulatory Support) who received a continuous flow LVAD after 2012. Patients on PDE5i were propensity-matched 1:1 to controls. The primary outcome was the incidence of severe early RHF, defined as the composite of death from RHF within 30 days, need for RV assist device support within 30 days, or use of inotropes beyond 14 days. Of 11 544 continuous flow LVAD recipients, 1199 (10.4%) received preoperative PDE5i. Compared to controls, patients on PDE5i had higher pulmonary artery systolic pressure (53.4 mm Hg versus 49.5 mm Hg) and pulmonary vascular resistance (2.6 WU versus 2.3 WU; P<0.001 for both). Before propensity matching, the incidence of severe early RHF was higher among patients on PDE5i than in controls (29.4% versus 23.1%; unadjusted odds ratio (OR), 1.32; 95% CI, 1.17-1.50). This association persisted after propensity matching (PDE5i, 28.9% versus control 23.7%; OR, 1.31; 95% CI, 1.09-1.57), driven by a higher incidence of prolonged inotropic support. Similar results were observed across a wide range of subgroups stratified by markers of pulmonary vascular disease and RV dysfunction. Conclusions Patients treated with preoperative PDE5i had markers of increased RV afterload and HF severity compared to unmatched controls. Even after propensity matching, patients receiving preimplant PDE5i therapy had higher rates of post-LVAD RHF.