Use Of Phosphodiesterase Inhibitors Research Articles

Peyronie’s Disease: Management and New Therapeutic Acquisitions

Peyronie's disease is a condition known for a long time but which has long been stigmatized as a malformation, misunderstood and generating shame and embarrassment on the part of patients. Because of its multifactorial aspect and its association with certain metabolic diseases, the treatment for many years consisted of a simple observation, the prescription of vitamin E or other anti-inflammatory or vasodilator molecules. We present here à new acquisition thanks to the application of linear shock waves, a promising and quite interesting element in the therapeutic arsenal. This technique, especially when coupled with the use of PDE-5 inhibitors and electroporation should make it possible to treat and improve not only punctually the fibrous nodule by improving the elasticity of the tissues concerned, but also of activate the circulation of the cavernous bodies of the penis thus improving erectile function allowing to give hope to many patients who are desperately seeking a solution to their problem.

Effect of phosphodiesterase type 5 inhibitors on sperm motility and acrosome reaction: An in vitro study

PurposePhosphodiesterase type 5 (PDE5) inhibitors are effective treatments for erectile dysfunction, and several recent studies have reported positive effects of PDE5 inhibitors on semen parameters as well. However, the data are still controversial. We investigated the effect of PDE5 inhibitors on sperm function by analyzing sperm motility and acrosome reaction.Materials and MethodsThis study included young healthy men who underwent fertility evaluation; 32 cases were finally included. Men were excluded if they used a PDE5 inhibitor within 2 weeks or if they had insufficient semen volume (≤2 mL), leukocytospermia, or a genitourinary infection. Changes in sperm motility and acrosome reaction were determined after in vitro exposure to the maximal semen concentration of oral intake of sildenafil (100 mg) or tadalafil (20 mg).ResultsMean age of the participants was 35.4±4.9 years, mean sperm concentration was 68.7±32.4 ×106/mL, and mean sperm motility was 50.38%±8.41%. All three groups (control, sildenafil, tadalafil) experienced trends of decreased average sperm motility over time, but these changes were not significant. There were no significant differences between the three groups in the acrosome reaction after 120 minutes of drug exposure, either. The maximal semen concentration of oral intake of sildenafil (100 mg) or tadalafil (20 mg) did not substantially affect sperm motility or acrosome reaction.ConclusionsOur results suggest that on-demand use of a PDE5 inhibitor is safe and useful for the male partner of an infertile couple; however, further studies are warranted for daily PDE5 inhibitor use.

Thinking About Pathomechanisms and Current Treatment of Erectile Dysfunction-"The Stanley Beamish Problem." Review, Recommendations, and Proposals.

Up to 50% of all men over 50 years of age suffer from erectile dysfunction. Since the late 1990s erectile dysfunction has been treated mostly with phosphodiesterase 5 inhibitors (PDE5I). Over the past 20 years, numerous scientific findings on the development of erectile dysfunction have been collected, which have so far received little attention in the treatment of erectile dysfunction. The objectives of this study were to review the existing medical literature on erectile dysfunction regarding physiology, pathophysiology, and especially therapeutic options beyond treatment with PDE5I and to enable a more effective and especially sustainable treatment for erectile dysfunction. A literature review was performed by using PubMed from 1985 to 2020 regarding the physiology, pathophysiology, and treatment of erectile dysfunction. Since the end of the 1990s an enormous amount of knowledge has been gained about the physiology/pathophysiology of erection/erectile dysfunction. Based on these findings, numerous physical, drug, and holistic therapeutic options (beyond the application of PDE5I) have been developed for the treatment of erectile dysfunction. However, these are still relatively rarely used in the therapeutic concept of erectile dysfunction today. Based on scientific findings of the last 20 years, there are numerous therapeutic approaches, including lifestyle modification, specific pelvic floor exercises, shock wave treatment, and the application of different supplements. The long-term treatment of erectile dysfunction should now go beyond the purely symptomatic use of PDE5I. W-D Beecken, M Kersting, W Kunert, etal. Thinking About Pathomechanisms and Current Treatment of Erectile Dysfunction-"The Stanley Beamish Problem." Review, Recommendations, and Proposals. Sex Med Rev 2021;9:445-463.

Peyronie’s Disease: Management and New Therapeutic Acquisitions

Peyronie’s disease is a condition known for a long time but which has long been stigmatized as a malformation, misunderstood and generating shame and embarrassment on the part of patients. Because of its multifactorial aspect and its association with certain metabolic diseases, the treatment for many years consisted of a simple observation, the prescription of vitamin E or other anti-inflammatory or vasodilator molecules. We present here a new acquisition thanks to the application of linear shock waves, a promising and quite interesting element in the therapeutic arsenal. This technique, especially when coupled with the use of PDE-5 inhibitors and electroporation should make it possible to treat and improve not only punctually the fibrous nodule by improving the elasticity of the tissues concerned, but also of activate the circulation of the cavernous bodies of the penis thus improving erectile function allowing to give hope to many patients who are desperately seeking a solution to their problem.

Association between sexual activity-related death and non-prescription use of phosphodiesterase type 5 inhibitors.

In recent years, there has been an increase in the use of phosphodiesterase type 5 inhibitors (PDE5i) that are purchased from abroad without a doctor's diagnosis via the Internet or other means. We report six cases in which nonprescription use of PDE5i may have led to death. Among the four deceased individuals who were believed to have experienced sudden cardiac death, three (cases 1-3) had a history of cardiovascular disease, which is a contraindication, and the remaining case (case 4) involved combined use of multiple PDE5i. Sildenafil (0.063µg/mL, 0.087µg/mL) was detected in two of the four cases of sudden cardiac death. Tadalafil (0.096µg/mL) was detected in one of the remaining two cases, and tadalafil (0.197µg/mL) and vardenafil (0.011µg/mL) were detected in the other case. Sildenafil (0.032µg/mL), tadalafil (0.062µg/mL), and ethanol were detected in a traffic accident case with a history of contraindications. In a case of asphyxiation by vomit aspiration, autopsy showed 90% stenosis in the anterior descending branch of the coronary artery, and sildenafil (0.063µg/mL) was detected. To the best of our knowledge, this is the first report of postmortem blood levels of tadalafil and vardenafil likely contributing to the cause of death. Despite all the warnings about the dangers of using PDE5 inhibitors, cases of PDE5i contributing to death are still identified during autopsies. Therefore, raising public awareness of the risks of the risks associated with the imported drug use by individuals is necessary.

Abstract 15731: Sildenafil Improves Mitochondrial Function in Failing Single Ventricles

Introduction: Heart failure (HF) remains a leading cause of death and indication for transplant in single ventricle congenital heart disease (SV). However, little is known regarding the molecular mechanisms leading to HF in SV. The purpose of this study was to characterize mitochondrial function in the myocardium of failing (SVHF) and non-failing (SVNF) SV patients compared to biventricular NF controls (BVNF). Furthermore, we investigated the effect of ex vivo treatment with the phosphodiesterase-5 inhibitor (PDE5i) sildenafil on mitochondrial function. Methods: Freshly explanted ventricular tissue was saponin permeabilized and mitochondrial oxygen consumption was measured sequentially throughout the electron transport system using SUbstrate-Inhibitor-Titration (“SUIT”) protocols and an Oroboros O2k high resolution respirometer. Permeabilized ventricular tissue was treated for 40 min with sildenafil [1μM] prior to measurement of oxygen consumption. A Western blot for PDE5 was performed in isolated mitochondrial proteins from SVHF subjects ± PDE5i. Results: Compared to BVNF (n=15) and SVNF (n=6), SVHF (n=8) hearts have decreased function of Complex I and Complex I and II (A, B), and decreased maximal respiration (C), all of which improve with acute ex vivo treatment with sildenafil in SVHF (SVHF+PDE5i, n=6). Importantly, mitochondrial function is impaired in BVNF+PDE5i (n=5) and SVNF+PDE5i hearts (n=5) (A-C, one-way Anova p<0.05). PDE5 protein is expressed in SVHF mitochondria, but expression is not affected by ex vivo PDE5i treatment (D). Conclusions: Our results indicate that mitochondrial function is impaired in SVHF, PDE5 protein is expressed in SVHF mitochondria, and PDE5i improves mitochondrial function in SVHF, but may be detrimental to mitochondrial function in SVNF and BVNF. Together these data suggest that mitochondrial PDE5 is a potential therapeutic target, but that indiscriminate use of PDE5i in SV patients may not be advisable.

Oral Testofen, L-Citrulline, Resveratrol, and Caffeine Supplement Drink Improves Sexual Function in Men with Phosphodiesterase 5 Inhibitors: Randomized, Double-Blind, Placebo-Controlled Crossover Pilot Study.

PurposeSexuality is very important for men's health. Currently, phosphodiesterase type 5 inhibitors (PDE5i) remain the first-line therapy for erectile dysfunction, and no other oral drugs or drinks are approved and used clinically to treat male libido or orgasm dysfunction. In reference to a pharmaceutical dosage document, growing health consciousness is said to have boosted yearly sales of supplement drinks to more than 170 billion yen (1.58 billion US dollars) in Japan. We have created a supplement drink comprised of testofen, L-citrulline, resveratrol, and caffeine. We hypothesized that our supplement drink would be effective for men with sexual dysfunction, and especially libido dysfunction.Materials and MethodsIn this study, men with sexual dysfunction received a placebo drink for 14 days or our supplement drink (testofen, 600 mg/d; L-citrulline, 800 mg/d; resveratrol, 300 mg/d; and caffeine, 40 mg/d) for another 14 days separated by a 7-day washout period. Patients continued on-demand use of PDE5i. The International Index of Erectile Function (IIEF) score and adverse events were assessed.ResultsTwenty patients aged 30–7 years old were enrolled in and concluded the study with no adverse events experienced. The IIEF domains of desire frequency, erection frequency, erection firmness, erection confidence, intercourse satisfaction, ejaculation frequency, orgasm frequency, and overall satisfaction were significantly improved with our supplement drink.ConclusionsThis is the first study to show that our supplement drink may not only be effective for erection but also for libido, orgasm, and ejaculation.

Phosphodiesterase type 5 inhibitor use among pregnant and reproductive-age women in the United States.

To assess the prevalence and potential indications of PDE5 inhibitor use among pregnant and reproductive-age women in the United States. We identified women 15 to 50 years with a livebirth from January 2001 through March 2018 in Sentinel Database. We assessed the prevalence of PDE5 inhibitor use prior to and during pregnancy by trimester, identified potential on- and off-label indications using predefined diagnosis codes recorded within 90 days before the estimated last menstrual period through delivery. Separately, we used data from IQVIA's National Prescription Audit and Total Patient Tracker to estimate the dispensed prescriptions for PDE5 inhibitors and the number of patients with PDE5 inhibitor prescriptions. We identified approximately 3.3 million pregnancies during 2001 to 2018, 96 of which had PDE5 inhibitor use during pregnancy. Prevalence of PDE5 inhibitor use was 2.61, 0.62, and 0.62 per 100, 000 live-born pregnancies during the first, second, or third trimesters, respectively. Among women exposed to a PDE5 inhibitor from 90 days before conception to the end of pregnancy, 25.0%, 31.1%, and 15.5% had a diagnosis code for fetal growth restriction, preeclampsia, and pulmonary arterial hypertension. In IQVIA data, an estimated 223, 000 prescriptions from July 2015 through June 2018 and 58, 000 women received prescriptions for PDE5 inhibitors in 2017, of whom approximately 15, 000 (26%) were aged 15 to 50 years. We found a low prevalence of PDE5 inhibitor use in pregnant and reproductive-age women. Given the very low prevalence of use and the inconsistency of neonatal mortality data across STRIDER centers, the risk to public health is low at present.

Retrospective comparison of focused shockwave therapy and radial wave therapy for men with erectile dysfunction.

BackgroundLow-intensity shockwave therapy (SWT) is an emerging treatment for erectile dysfunction (ED). Devices used for SWT include focused shockwave therapy (fSWT) or radial wave therapy (rWT), which differ in how the waves are generated, their tissue penetration, and the shape of their pressure waves. Most studies of SWT for ED to date have utilized fSWT. Although widely used, the efficacy of rWT for ED is unknown. Our objective is to compare the efficacy of rWT and fSWT for ED at our institution.MethodsA retrospective chart review was performed to identify all men with ED treated by fSWT or rWT. Men with history suggesting non-vasculogenic ED were excluded. All men received 6 consecutive weekly treatments. The fSWT group received 3,000 shocks per treatment at 0.09 mJ/mm2. The rWT group received 10,000 shocks per treatment at 90 mJ and 15 Hz. Pre-treatment and 6-week post-treatment Sexual Health Inventory in Men (SHIM) scores were measured. Treatment response was categorized on a scale of 1–3 (1 if no improvement, 2 if erections sufficient for intercourse with phosphodiesterase 5 inhibitors (PDE5i), or 3 if sufficient erections without PDE5i). Primary endpoint was self-reported improvement score of 2 or greater.ResultsA total of 48 men were included: 24 treated by fSWT and 24 by rWT. There were no significant differences in age, duration of ED, pre-treatment PDE5i use, or pre-treatment SHIM scores between the groups. Following treatment with rWT, the mean SHIM score improved from 9.3 to 16.1 (P<0.001). The mean SHIM following fSWT improved from 9.3 to 15.5 (P<0.001). The mean improvement in SHIM score did not differ between rWT (6.8) and fSWT (6.2) (P=0.42). 54% of men treated by fSWT experienced a significant clinical improvement (≥ grade 2 response) compared to 75% in the rWT group (P=0.42). There were no reported side effects with either device.ConclusionsIn our patient population, both fSWT and rWT were moderately effective treatments for arteriogenic ED with no observable difference in efficacy between the two modalities.

Phosphodiesterase Type 5 Inhibitors and Risk of Skin Cancers in Men: A Meta-Analysis and Trial Sequential Analysis Involving 7,479,852 Subjects.

PurposeWe conducted a systematic review and meta-analysis to quantify the association between phosphodiesterase type 5 inhibitors (PDE5Is) use and skin cancers and we also examined whether down-expression of the PDE5A gene was related to worse prognosis for malignant melanoma (MM) patients.Materials and MethodsThe PubMed, Cochrane Library, Web of Science, EMBASE, and ClinicalTrails.gov databases were searched. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the association between PDE5Is use and risk of skin cancers. Cumulative meta-analysis and trial sequential analysis (TSA) were also conducted. Survival outcomes were analyzed online.ResultsAfter pooling all 8 eligible studies comprising 7,479,852 subjects, we found that PDE5Is use was significantly associated with slightly increased risk of developing MM (OR: 1.13, 95% CI: 1.05 to 1.21, I2=67.1%), basal cell carcinoma (OR: 1.16, 95% CI: 1.13 to 1.19, I2=49.6%), and squamous cell carcinoma (OR: 1.07, 95% CI: 1.01 to 1.13, I2=0.0%). Totally, PDE5Is increased the risk of developing skin cancers (OR: 1.13, 95% CI: 1.09 to 1.17, I2=70.8%). TSA results showed that the sample size was enough to reach a positive conclusion.ConclusionsThe use of PDE5Is may be slightly associated with increased risk of developing skin cancers. There should be a balance between drug benefits and potential safety issues. However, the pooled results should be considered tentative until confounding factors such as sun exposure and lifestyle are well-controlled in further studies.

The Phosphodiesterase Type 5 Inhibitor Sildenafil Improves DNA Stability and Redox Homeostasis in Systemic Sclerosis Fibroblasts Exposed to Reactive Oxygen Species.

Systemic sclerosis (SSc) is a multi-system connective tissue disease characterized by the increased deposition of extracellular matrix proteins such as collagen and fibronectin. Although the pathogenesis is not completely understood, a number of studies suggest that free radicals could be the major contributors to the disease. Indeed, different studies demonstrated how oxidative stress could contribute to the fibrotic process activation at the level of the skin and visceral organs. Emerging evidences highlight the beneficial effects of sildenafil, a phosphodiesterase type 5 inhibitor (PDE5i), which protects different cell lines from the cell damage induced by reactive oxygen species (ROS). These data make sildenafil a good candidate for therapeutic treatment aimed to protect biological macromolecules against oxidative damage, thus preserving cell viability. The purpose of this study was to evaluate the sensitivity of SSc dermal fibroblasts to an oxidative insult and the ability for sildenafil to prevent/reduce the DNA damage due to ROS action. Additionally, we evaluated the capacity for sildenafil to influence redox homeostasis and cytotoxicity, as well as cell proliferation and cell cycle progression. We demonstrated that SSc fibroblasts have an increased sensitivity to a pro-oxidant environment in comparison to healthy controls. The sildenafil treatment reduced ROS-induced DNA damage, counteracted the negative effects of ROS on cell viability and proliferation, and promoted the activity of specific enzymes involved in redox homeostasis maintenance. To our knowledge, in this report, we demonstrate, for the first time, that sildenafil administration prevents ROS-induced instability in human dermal fibroblasts isolated by SSc patients. These results expand the use of PDE5i as therapeutic agents in SSc by indicating a protective role in tissue damage induced by oxidative insult.

Management of erectile dysfunction following robot-assisted radical prostatectomy: a systematic review.

We aimed to summarize evidences about the efficacy of available treatments for erectile disfunction after robotic assisted radical prostatectomy (RARP). A systematic literature review searching on PubMed (Medline), Scopus, and Web of Science databases was performed in December 2019. PRISMA guidelines were followed. Population consisted of patients with erectile disfunction after RARP (P), conservative and surgical intervention were considered of interest (I). No comparator was considered mandatory (C). Outcomes of interest were the recovery of erectile function after conservative treatments and sexual function after surgical treatments (O). Eleven studies were included. Seven studies focused on the use of phosphodiesterase-5 inhibitors (PDE5i) alone (five studies) or associated with other treatments (two studies). All the studies confirmed the efficacy of PDE5i, while the most promising association is with vacuum pump erectile devices. Two studies investigated topical treatments, namely low intensity extracorporeal shock wave therapy and alprostadil. Low intensity extracorporeal shock wave therapy may be a promising option in patients in whom nerve-sparing surgery was performed. The use of alprostadil could be an effective alternative to intracorporeal injection in those who underwent non-nerve-sparing surgery. One study focused and confirmed the efficacy of penile implants. Furthermore, one study reported the efficacy of a multi-modal treatment with preoperative medication, showing the benefits of a multimodal approach. Penile rehabilitation with PDE5i is effective after nerve sparing RARP. The association of PDE5i with vacuum devices could led to a faster recovery. A multimodal approach with preoperative specific care seems to be effective to fasten erectile function recovery.

Shift Work Sleep Disorder and Night Shift Work Significantly Impair Erectile Function

ObjectivesHere we examine the association between shift work sleep disorder (SWSD) and erectile dysfunction (ED) in shift workers. MethodsMen presenting to a single andrology clinic between January 2014 and July 2017 completed validated questionnaires: International Index of Erectile Function (IIEF), Patient Health Questionnaire-9 (PHQ-9), and the nonvalidated SWSD Questionnaire. Men were also asked about shift work schedule, comorbidities, phosphodiesterase 5 (PDE5) inhibitor use, and testosterone use. Serum total testosterone values were determined for each visit. Linear regression was performed controlling for testosterone use, testosterone levels, PDE5 inhibitor use, age, and comorbidities to determine the effect of SWSD on ED as assessed using the IIEF. ResultsOf the 754 men completing questionnaires, 204 reported nonstandard shift work (begins before 7 am or after 6 pm, regularly extends out of that frame, or rotates frequently) and 48 were found to have SWSD using a screening questionnaire. Nonstandard shift work alone did not result in worse IIEF-EF scores (P = .31), but those who worked nonstandard shifts and had SWSD demonstrated IIEF-EF scores 2.8 points lower than men without SWSD (P < .01). When assessing for the type of shift work performed, men who worked night shifts had IIEF-EF scores 7.6 points lower than men who worked during the day or evening (P < .01). Testosterone use improved IIEF-EF scores for men with SWSD by 2.9 points, ameliorating the effect of SWSD on ED. However, baseline testosterone levels were not associated with worse erectile function in this cohort. ConclusionMen with SWSD have worse erectile function, with men who work night shifts having even poorer erectile function. These findings suggest that circadian rhythm disturbance may significantly impact erectile function. While testosterone therapy may partly reverse the effects of SWSD, shift work is a potential risk factor for ED and should be assessed for as part of the evaluation of men with ED.Rodriguez KM, Kohn TP, Kohn JR, et al. Shift Work Sleep Disorder and Night Shift Work Significantly Impair Erectile Function. J Sex Med 2020;17:1687–1693.

The treatment rate of erectile dysfunction (ED) in younger men with type 2 diabetes is up to four times higher than the equivalent non-diabetes population.

Erectile dysfunction (ED) is common in older age and in diabetes mellitus (DM). Phosphodiesterase type 5-inhibitors (PDE5-is) are the first-line for ED. We investigated how the type of diabetes and age of males affect the PDE5-i use in the primary care setting. From 2018 to 2019, the general practice level quantity of all PDE5-i agents was taken from the general practice (GP) Prescribing Dataset in England. The variation in outcomes across practices was examined across one year, and for the same practice against the previous year. We included 5761 larger practices supporting 25.8 million men of whom 4.2 million ≥65years old. Of these, 1.4 million had T2DM, with 0.8 million of these >65. About 137000 people had T1DM. About 28.8 million tablets of PDE5-i were prescribed within the 12months (2018-2019) period in 3.7 million prescriptions (7.7 tablets/prescription), at total costs of £15.8 million (£0.55/tablet). The NHS ED limit of one tablet/user/wk suggests that 540000 males are being prescribed a PDE5-i at a cost of £29/y each. With approximately 30000 GPs practising, this is equivalent to one GP providing 2.5 prescriptions/wk to overall 18 males. There was a 3x variation between the highest decile of practices (2.6tablets/male/y) and lowest decile (0.96tablets/male/y). The statistical model captured 14% of this variation and showed that T1DM males were the largest users, while men age <65 with T2DM were being prescribed four times as much as non-DM. Those T2DM >65 were prescribed 80% of the non-DM amount. There is a wide variation in the use of PDE5-is. With only 14% variance capture, other factors including wide variation in patient awareness, prescribing rules of local health providers, and recognition of the importance of male sexual health by GP prescribers might have a significant impact.

Pre-, intra- and postoperative predictors of functional outcome following radical prostatectomy

Maintaining continence and erectile function is crucial for quality of life after radical prostatectomy. This review provides an overview of available evidence concerning preoperative risk stratification as well as intra- and postoperative factors determining functional outcomes after radical prostatectomy.Current data indicate that patient factors including age, baseline erectile function, prostate size, body-mass index and comorbidity status are valid predictors of functional outcome after prostatectomy. While surgical methods do not seem to have any influence, intraoperative procedures like nerve-sparing techniques, the extent of pelvic floor reconstruction as well as surgeons' experience have a significant impact on postoperative potency and continence. Rehabilitation consisting of pelvic floor training and use of PDE-5 inhibitors also contributes significantly to the recovery of erectile function and urinary continence.In summary, numerous adjustments of treatment can help to improve functional results and thus the quality of life after prostatectomy. A careful preoperative selection of suitable patients by urologists and integration of knowledge of periprostatic nerve and fascial structures into the surgical procedure are decisive factors.

Phosphodiesterase-5 inhibitors use and risk for mortality and metastases among male patients with colorectal cancer

Phosphodiesterase-5 (PDE5) inhibitors are suggested to have anti-tumor effects and to inhibit surgery-induced immunosuppression. We aimed to explore whether post-diagnostic use of PDE5 inhibitors was associated with a better prognosis among male patients with colorectal cancer (CRC) and the role of open surgery in the association. Here we show that post-diagnostic use of PDE5 inhibitors is associated with a decreased risk of CRC-specific mortality (adjusted HR = 0.82, 95% CI 0.67-0.99) as well as a decreased risk of metastasis (adjusted HR = 0.85, 95% CI 0.74-0.98). Specifically, post-operative use of PDE5 inhibitors has a strong anti-cancer effect. The reduced risk of metastasis is mainly due to distant metastasis but not regional lymphatic metastasis. PDE5 inhibitors have the potential to be an adjuvant drug for patients with CRC to improve prognosis, especially those who have undergone open surgery.

Factors Associated With Potentially Inappropriate Phosphodiesterase-5 Inhibitor Use for Pulmonary Hypertension in the United States, 2006 to 2015.

Use of phosphodiesterase-5 inhibitors (PDE5i) for groups 2 and 3 pulmonary hypertension (PH) is rising nationally, despite guidelines recommending against this low-value practice. Although receiving care across healthcare systems is encouraged to increase veterans' access to specialists critical for PH management, receiving care in 2 systems may increase risk of guideline-discordant prescribing. We sought to identify factors associated with prescribing of PDE5i for group 2/3 PH, particularly, to test the hypothesis that veterans prescribed PDE5i for PH in the community (through Medicare) will have increased risk of subsequently receiving potentially inappropriate treatment in Veterans Health Administration (VA). We constructed a retrospective cohort of 34 775 Medicare-eligible veterans with group 2/3 PH by linking national patient-level data from VA and Medicare from 2006 to 2015. We calculated adjusted odds ratios (ORs) of receiving daily PDE5i treatment for PH in VA using multivariable models with facility-specific random effects. In this cohort, 1556 veterans received VA prescriptions for PDE5i treatment for group 2/3 PH. Supporting our primary hypothesis, the variable most strongly associated with PDE5i treatment in VA for group 2/3 PH was prior treatment through Medicare (OR, 6.5 [95% CI, 4.9-8.7]). Other variables strongly associated with increased likelihood of VA treatment included more severe disease as indicated by recent right heart failure (OR, 3.3 [95% CI, 2.8-3.9]) or respiratory failure (OR, 3.7 [95% CI, 3.1-4.4]) and prior right heart catheterization (OR, 3.8 [95% CI, 3.4-4.3]). Our data suggest a missed opportunity to reassess treatment appropriateness when pulmonary hypertension patients seek prescriptions from VA-a relevant finding given policies promoting shared care across VA and community settings. Interventions are needed to reinforce awareness that pulmonary vasodilators are unlikely to benefit group 2/3 pulmonary hypertension patients and may cause harm.

Lymphatic flow modulation as adjunct therapy for septic shock

The lymphatic system is an important component of human health and is critical in maintaining microcirculatory flow and immune system homeostasis. During septic shock, increased capillary permeability results in excess filtration of intravascular fluid and solutes producing interstitial edema with subsequent hydrostatic and oncotic gradient breakdown. The accumulation of interstitial fluid results in impaired solute exchange, leukocyte signaling, and aberrancy in capillary flow. Modulation of lymphatic flow during times of interstitial volume overload such as septic shock may decrease interstitial volume resulting in improved perfusion, decreased end-organ damage, and contribute to disease resolution. Multiple studies in both humans and animals have shown nitric oxide to be a potent modulator of lymphatic function. The present study suggests a hypothetical adjunct therapy for patients with septic shock through the use of phosphodiesterase inhibitors, which may improve microcirculatory flow by decreasing interstitial fluid volume via increased lymphatic fluid drainage.

No association between use of phosphodiesterase 5 inhibitors and colorectal cancer in men with erectile dysfunction.

There is an increase interest on the potential chemoprotective effect of selective phosphodiesterase 5 (PDE5) inhibitors. Several authors have shown in vivo the immune-mediated anti-tumor effect of these inhibitors on tumors arising from the digestive tract. To test the potential effect of selective PDE5 inhibitors against colorectal cancer (CRC) onset previously observed. We used data from The Health Improvement Network database and identified an established cohort of 200 000 new users of low-dose aspirin and a matched comparison cohort aged 40-84 years between 1 January 2000 and 31 December 2011. A follow-up to identify CRC cases was performed within an extensive validation exercise. Nested case-control analyses compared PDE5 inhibitors vs non-use on CRC risk were performed. Restricting to males (59.3% controls and 59.5% cases), no association was observed among current users of PDE5 inhibitors (1.05 [95% CI: 0.69-1.60]) and neither among recent (1.36 [95% CI: 0.81-2.28]) or past users (1.06 [95% CI: 0.72-1.58]). No duration response effect was found. Our results do not support an increased risk of CRC associated with the use of PDE5 inhibitors among men with erectile dysfunction.

P167 Pulmonary hypertension in patients with systemic sclerosis: an audit of screening practices, incidence and cost over 10 years

Abstract Background Patients with systemic sclerosis (SSc) are at risk of developing pulmonary arterial hypertension (PAH), a subtype of pulmonary hypertension (PH) which is not due to left-heart disease, chronic hypoxia or pulmonary arterial thrombus. The European Society of Cardiology recommends annual screening of patients with SSc due to the insidious presentation of PAH, poor outcomes, and the availability of effective treatments. Transthoracic echocardiography is the standard screening investigation, but NT pro-BNP, a biochemical marker of ventricular stretch, may be a cost-effective initial test with echocardiography reserved for patients with new or worsening symptoms or increasing NT pro-BNP. Our centre introduced NT pro-BNP as an adjunct to echocardiography in 2014. Methods We audited our SSc-PAH screening programme from 2009-2018 against the standard that every SSc patient should be screened annually with echocardiography or NT pro-BNP. Patients seen by the regional PH service prior to the first rheumatology clinic were excluded. We used our centre’s database of SSc patients and electronic patient records to determine if a patient had undergone PH screening. We calculated cost estimates from our hospital’s biochemistry and echocardiography departments. Results From 2009 to 2018, the number of SSc patients requiring annual screening rose from 81 to 215. In 2009, 65% of patients were screened - all with echocardiography. In 2018, 88% of patients were screened - 25% had an echocardiogram and 83% had a NT pro-BNP. 63% of patients were screened only through NT pro-BNP. Across the 1476 patient-years studied, only 6 new cases of PH were identified. PH was secondary to ILD in two cases, and true PAH in three cases (one patient refused diagnostic right-heart catheterisation). All three PAH diagnoses came from echocardiograms requested for worsening dyspnoea, so are not attributable to the screening programme. On 31 December 2018, 55% of these patients were taking phosphodiesterase 5 inhibitors (PDE-5i) for severe Raynaud’s phenomenon (50% on sildenafil and 5% on tadalafil). 4% of patients were prescribed bosentan and 3% of patients were prescribed dual therapy with a PDE5i and bosentan. This may explain our centre’s low incidence of PAH. The annual cost of screening per patient has dropped from £82 in 2014 to £59 in 2018, and the total annual cost has plateaued since 2014, despite rising patient numbers and improved screening rates. Conclusion Since introducing NT pro-BNP alongside echocardiography as a screening tool for PAH in SSc patients, we spend less on our screening programme per patient and achieve higher screening rates. However, in 10 years, our screening programme has not detected any asymptomatic cases of PAH, raising questions about the necessity of screening asymptomatic SSc patients. Widespread PDE-5i use may contribute to the low incidence of PAH in our cohort. Disclosures L. Spray None. J. Vila None. B. Griffiths None.