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.

Effects of Bladder Cancer on UK Healthcare Costs and Patient Health-Related Quality of Life: Evidence From the BOXIT Trial.

BACKGROUND: Limited evidence exists regarding the cost and health-related quality of life (HRQoL) effects of non-muscle-invasive bladder cancer (NMIBC) recurrence and progression to muscle-invasive bladder cancer (MIBC). We examined these effects using evidence from a recent randomized control trial. MATERIAL AND METHODS: The costs and HRQoL associated with bladder cancer were assessed using data from the BOXIT trial (bladder COX-2 inhibition trial; n = 472). The cost and HRQoL effects from clinical events were estimated using generalized estimating equations. The costs were derived from the recorded resource usage and UK unit costs. HRQoL was assessed using the EQ-5D-3L and reported UK preference tariffs. The events were categorized using the TMN classification. RESULTS: Cases of grade 3 recurrence and progression were associated with statistically significant HRQoL decrements (-0.08; 95% confidence interval [CI], -0.13 to -0.03; and -0.10; 95% CI, -0.17 to -0.03, respectively). The 3-year average cost per NMIBC patient was estimated at £8735 (95% CI, 8325-9145). Cases of grade 1, 2, and 3 recurrence were associated with annual cost effects of £1218 (95% CI, 403-2033), £1677 (95% CI, 920-2433), and £3957 (95% CI, 2332-5583), respectively. Progression to MIBC was associated with an average increase in costs of £5407 (95% CI, 2663-8152). CONCLUSION: Evidence from the BOXIT trial suggests that patients with NMIBC will both experience decrements in HRQoL and incur significant costs, especially in the event of a grade 3 recurrence or a progression to MIBC.

Evaluating the cost of surveillance for non-muscle-invasive bladder cancer: an analysis based on risk categories.

INTRODUCTION: Non-muscle-invasive bladder cancer (NMIBC) is a biologically heterogeneous disease and is one of the most expensive malignancies to treat on a per patient basis. In part, this high cost is attributed to the need for long-term surveillance. We sought to perform an economic analysis of surveillance strategies to elucidate cumulative costs for the management of NMIBC. METHODS: A Markov model was constructed to determine the average 5-year costs for the surveillance of patients with NMIBC. Patients were stratified into low, intermediate, and high-risk groups based on the EORTC risk calculator to determine recurrence and progression rates according to each category. The index patient was a compliant 65-year-old male. A total of four health states were utilized in the Markov model: no evidence of disease, recurrence, progression and cystectomy, and death. RESULTS: Cumulative costs of care over a 5-year period were $52,125 for low-risk, $146,250 for intermediate-risk, and $366,143 for high-risk NMIBC. The primary driver of cost was progression to muscle-invasive disease requiring definitive therapy, contributing to 81% and 92% of overall cost for intermediate- and high-risk disease. Although low-risk tumors have a high likelihood of 5-year recurrence, the overall cost contribution of recurrence was 8%, whereas disease progression accounted for 71%. CONCLUSION: Although protracted surveillance cystoscopy contributes to the expenditures associated with NMIBC, progression increases the overall cost of care across all three patient risk groups and most notably for intermediate- and high-risk disease patients.