Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis.

BACKGROUND: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment. METHODS: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005. FINDINGS: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ2=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory). INTERPRETATION: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme.

Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis.

Background: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD. Methods: We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. Findings: 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17-1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81-1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92-1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82-1·15]; p=0·69), smoking status (interaction 1·68 [0·41-6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89-4·82; p=0·025) were not associated with cardiovascular risk. Interpretation: We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. Funding: National Institute for Health Research Health Technology Assessment Programme.

The ability of men to assess their suitability to take a phosphodiesterase type 5 inhibitor: an assessment of the comprehension of patient information materials.

INTRODUCTION: Erectile dysfunction is a treatable condition that affects a large proportion of men. Most men do not seek medical help for their ED because of embarrassment or social stigma that may lead some men to self-treat. AIM: To evaluate men's ability to self-assess their suitability for 50 mg sildenafil use after reviewing patient information materials. MAIN OUTCOME MEASURES: Patient rating of patient information materials, self-assessment of suitability for sildenafil use, and clinician assessment of sildenafil suitability. METHODS: Men in the UK were recruited through newspaper, radio, and internet advertisements. Eligible men reviewed the 50 mg sildenafil patient information materials (packaging materials and patient information leaflet) at the in-person visit and then completed a survey to rate the materials and self-assess their suitability for sildenafil use. A clinician, blinded to the participant's ED status and self-assessed sildenafil suitability, then conducted a one-on-one interview to assess the participant's ED status and suitability for sildenafil treatment. The primary analysis was the concordance of self-assessed suitability versus clinician-assessed suitability. RESULTS: The initial study phase included 113 generally healthy men, mean age 40.2 ± 13.1 years. The second phase included 70 men with comorbid prostate or cardiac conditions, mean age 60.7 ± 7.8 years. The 183 men rated the patient information materials as easy to understand; few participants reported problems understanding the materials, and many participants learned new information. The concordance rate between clinician-assessed suitability and self-assessed suitability was 73.9% (95% confidence interval [CI] = 66.7-81.2%). When accounting for men who would not take sildenafil even though they were suitable or would seek additional information from a healthcare professional prior to using sildenafil, the concordance rate was 90.1% (95% CI = 85.8-94.4%). CONCLUSION: The results of this UK study suggest that men are capable of using written sildenafil patient education materials to accurately assess their suitability for treatment with 50 mg sildenafil.

The cost to the United Kingdom National Health Service of managing erectile dysfunction: the impact of sildenafil and prescribing restrictions.

OBJECTIVE: To estimate the annual direct cost of managing erectile dysfunction (ED) to the UK National Health Service (NHS) and to examine the impact of the introduction of sildenafil in 1998 and Schedule 11 restrictions in 1999. DESIGN: A prevalence-based cost-of-illness approach was used. The period 1997 to 2000 was covered. The numbers of ED prescriptions, prosthesis implantations and general practitioner (GP) consultations were retrieved retrospectively from UK resource utilisation databases. The number of specialist consultations and psychosexual therapy sessions were estimated from NHS clinic data. National resource unit costs were applied. MAIN OUTCOMES AND RESULTS: Between 1997 and 2000 the number of men presenting with ED increased from 79,800 to 257,984. The cost to the NHS increased from pounds sterling 29.4 million to pounds sterling 73.8 million (2000 estimates). The cost per patient fell from pounds sterling 368 to pounds sterling 286. In 1997, most NHS costs came from psychosexual therapy (30.7%), specialist consultations (20.2%) and intracavernosal injections (26.6%). By 2000, NHS costs came primarily from specialist consultations (32.0%), sildenafil prescriptions (26.2%), psychosexual therapy (13.6%) and GP consultations (12.0%). The annual cost was most sensitive to the number of drug prescriptions and specialist consultations. CONCLUSIONS: The increased NHS cost of managing ED was due mainly to a three-fold increase in the number of men presenting to GPs, substantial numbers of whom were then referred for specialist consultations under Schedule 11 restrictions. This naturally resulted in the increased use of all resources including sildenafil. The cost effectiveness of transferring prescribing responsibility in cases of severe distress from specialists to GPs in primary care remains to be determined.