Health Technology Assessment (Aug 2024)
The effects and safety of testosterone replacement therapy for men with hypogonadism: the TestES evidence synthesis and economic evaluation
Abstract
Background Low levels of testosterone cause male hypogonadism, which is associated with sexual dysfunction, tiredness and reduced muscle strength and quality of life. Testosterone replacement therapy is commonly used for ameliorating symptoms of male hypogonadism, but there is uncertainty about the magnitude of its effects and its cardiovascular and cerebrovascular safety. Aims of the research The primary aim was to evaluate the safety of testosterone replacement therapy. We also assessed the clinical and cost-effectiveness of testosterone replacement therapy for men with male hypogonadism, and the existing qualitative evidence on men’s experience and acceptability of testosterone replacement therapy. Design Evidence synthesis and individual participant data meta-analysis of effectiveness and safety, qualitative evidence synthesis and model-based cost-utility analysis. Data sources Major electronic databases were searched from 1992 to February 2021 and were restricted to English-language publications. Methods We conducted a systematic review with meta-analysis of individual participant data according to current methodological standards. Evidence was considered from placebo-controlled randomised controlled trials assessing the effects of any formulation of testosterone replacement therapy in men with male hypogonadism. Primary outcomes were mortality and cardiovascular and cerebrovascular events. Data were extracted by one reviewer and cross-checked by a second reviewer. The risk of bias was assessed using the Cochrane Risk of Bias tool. We performed one-stage meta-analyses using the acquired individual participant data and two-stage meta-analyses to integrate the individual participant data with data extracted from eligible studies that did not provide individual participant data. A decision-analytic Markov model was developed to evaluate the cost per quality-adjusted life-years of the use of testosterone replacement therapy in cohorts of patients of different starting ages. Results We identified 35 trials (5601 randomised participants). Of these, 17 trials (3431 participants) provided individual participant data. There were too few deaths to assess mortality. There was no difference between the testosterone replacement therapy group (120/1601, 7.5%) and placebo group (110/1519, 7.2%) in the incidence of cardiovascular and/or cerebrovascular events (13 studies, odds ratio 1.07, 95% confidence interval 0.81 to 1.42; p = 0.62). Testosterone replacement therapy improved quality of life and sexual function in almost all patient subgroups. In the testosterone replacement therapy group, serum testosterone was higher while serum cholesterol, triglycerides, haemoglobin and haematocrit were all lower. We identified several themes from five qualitative studies showing how symptoms of low testosterone affect men’s lives and their experience of treatment. The cost-effectiveness of testosterone replacement therapy was dependent on whether uncertain effects on all-cause mortality were included in the model, and on the approach used to estimate the health state utility increment associated with testosterone replacement therapy, which might have been driven by improvements in symptoms such as sexual dysfunction and low mood. Limitations A meaningful evaluation of mortality was hampered by the limited number of defined events. Definition and reporting of cardiovascular and cerebrovascular events and methods for testosterone measurement varied across trials. Conclusions Our findings do not support a relationship between testosterone replacement therapy and cardiovascular/cerebrovascular events in the short-to-medium term. Testosterone replacement therapy improves sexual function and quality of life without adverse effects on blood pressure, serum lipids or glycaemic markers. Future work Rigorous long-term evidence assessing the safety of testosterone replacement therapy and subgroups most benefiting from treatment is needed. Study registration The study is registered as PROSPERO CRD42018111005. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/68/01) and is published in full in Health Technology Assessment; Vol. 28, No. 43. See the NIHR Funding and Awards website for further award information. Plain language summary Testosterone is a hormone which is vital for sexual activity, bone growth and muscle development in men. Men with low testosterone levels may experience problems with erections and may suffer from brittle bones (osteoporosis), weakness, feeling down (low mood) and tiredness. The manifestations of low testosterone can be treated with testosterone replacement therapy. However, there is current uncertainty about the positive effects of testosterone replacement therapy and its safety. We brought together results from all available medical studies that looked at the use of testosterone replacement therapy in men with low testosterone and contacted the doctors who led these studies to gather further information on their participants. We found 35 studies (5601 participants) conducted in different countries, 17 of which provided additional information on their participants. We did not find any evidence to show that testosterone replacement therapy increases the risk of heart problems, or any evidence to show that some men who take testosterone replacement therapy benefit more than others. Men with low testosterone reported having low mood, poor concentration and lack of energy; however, medical studies often failed to prove that these manifestations improved with testosterone replacement therapy. Most medical studies were conducted among white men in North America using questionnaires designed specifically for them; therefore, the results may not reflect the experiences of men in other countries and from more diverse ethnic backgrounds. There is too much uncertainty about the benefits of testosterone replacement therapy to accurately estimate its value for money for the NHS. We think our findings offer some reassurance to doctors and patients that testosterone replacement therapy does not increase the risk of heart problems. New studies are needed to find out whether some groups of men (such as older or younger men) are more likely to benefit from testosterone replacement therapy more than others. It is also important to develop tools which better reflect the experience of men from a diverse range of social and ethnic backgrounds. To inform men with low testosterone about our findings, we are creating a website with dedicated YouTube video clips. Scientific summary Background and objectives Low levels of the testicular androgen hormone testosterone cause male hypogonadism (MH), which is associated with sexual dysfunction, hot flushes, reduced physical energy, mood disturbance and complications such as osteoporosis. Testosterone (androgen) replacement therapy (TRT) is the standard of treatment for MH. Prescribing rates of TRT in the UK have risen between 2001 and 2010 without an observable increase in the prevalence of hypogonadism, which may reflect increasing media awareness among men about MH. Randomised controlled trials (RCTs) of TRT in men with MH have produced varying and sometimes conflicting results regarding the safety and efficacy of TRT. In particular, there is considerable uncertainty regarding the impact of TRT on cardiovascular (CV) event risk in men with MH, which has led to mandatory safety labelling in some countries. Lack of clarity about the effects of TRT have led to variations in clinical practice among clinicians, which in turn exposes men with MH to inconsistent standards of clinical care and potentially life-threatening healthcare risks. The overarching aim of this project was to conduct a comprehensive and unbiased appraisal of quantitative, qualitative and economic evidence for the use of TRT in symptomatic men with MH. This evidence synthesis had three specific objectives: (1) to perform an individual patient data meta-analysis to estimate the clinical effectiveness and safety of TRT for men with testosterone deficiency syndrome; (2) to synthesise the existing qualitative evidence reporting men’s experience and acceptability of TRT; (3) to develop a decision model to estimate the cost-effectiveness of TRT for the treatment of symptomatic men with testosterone deficiency syndrome. Review methods Methods for the quantitative synthesis and individual participant data meta-analysis We conducted a quantitative synthesis including a meta-analysis of individual participant data (IPD) according to current methodological standards, to identify evidence from placebo-controlled RCTs evaluating the effects of TRT in men with low testosterone. The methods were pre-specified in a research protocol (PROSPERO database registration number: CRD42018111005; www.crd.york.ac.uk/prospero/display_record.php?RecordID=111005). Comprehensive searches of major electronic databases were conducted, including MEDLINE, MEDLINE In-process & Other Non-indexed Citations, MEDLINE Epub Ahead of Print, EMBASE, Science Citation Index and CENTRAL. Searches were restricted to publications from 1992 to date. Searches were carried out in August 2018 and updated in February 2021. The population considered was men with low testosterone. The intervention was TRT and the comparator was placebo. Primary outcomes were all-cause mortality and CV and cerebrovascular (CBV) events. Other outcomes of interest were sexual function, physical health parameters, functional activities, psychological symptoms, other comorbidities, prostate-related outcomes, physiological markers and quality of life (QoL). Outcomes were assessed at 12 months or at the closest time point to 12 months. Two reviewers independently screened all records identified by the searches and one reviewer screened all potentially relevant full texts, with a 10% sample independently checked by a second reviewer. Data were extracted by one reviewer with a random sample of 10% cross-checked by a second reviewer and all outcome data further cross-checked by the statistician. Risk of bias of the included RCTs was assessed by two independent reviewers using the Cochrane Risk of Bias tool (version 1). Data were analysed using both a one-stage meta-analysis for each outcome using the acquired IPD and a two-stage approach to enable the integration of the IPD along with the extracted published data from eligible studies without IPD. Methods for qualitative synthesis and patient-reported outcome measures analysis A comprehensive search was conducted to identify published papers reporting qualitative data and/or the development of patient-reported outcome measures (PROMs) for men with hypogonadism who received or were considered to receive TRT, and papers reporting the views of care providers. Electronic databases (Ovid MEDLINE, Embase, PsycInfo, EBSCO CINAHL and Proquest ASSIA) were searched for publication from 1992 to February 2020. The same eligibility criteria used for the IPD meta-analysis were applied. One review author (MA-M) independently screened all titles and abstracts with a randomly selected sample of 10% cross-checked by a second review author (KG). A third author (JC) was consulted when consensus could not be reached regarding eligibility. For the qualitative evidence synthesis, we appraised eligible studies for methodological rigour and theoretical relevance using the Critical Appraisal Skills Programme (CASP) tool. We conducted a thematic synthesis using both inductive and deductive approaches to analysis and we applied grading of recommendations assessment, development and evaluation-confidence in the evidence from reviews of qualitative research (GRADE-CERQual) to the findings of the thematic synthesis. For the PROMs analysis, we analysed the individual verbatim items from each PROM using a directed content analysis approach informed by the included papers and the relevant health domain was the World Health Organization International Classification of Functioning, Disability and Health (WHO-ICF). Domain mapping was conducted by two reviewers (MA-M and KG) independently, with any conflicts resolved through discussion. Descriptive statistics were used to describe general information and measure detail with narrative synthesis of the PROM and their inter-related domains. Methods for the systematic review of economic evaluations and the development of a new economic model The economic evidence on TRT was assessed through a systematic review (SR) of economic evaluations and a new model-based economic evaluation comparing TRT with standard of care (SoC; e.g. no treatment). Systematic review of economic evaluations Full economic evaluations (i.e. studies reporting cost and consequences – regardless of the way these were estimated – for at least two strategies including TRT) were included. Relevant electronic databases [i.e. MEDLINE, Embase, NHS Economic Evaluations Database (NEED), the HTA Database, Cost-Effectiveness Analysis Registry and Research Papers in Economics] were searched from 1992 until 4 February 2021. In addition, conference proceedings of key professional organisations (endocrinology, cardiology and men’s health) from 2018 to 2020 and International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Scientific Presentations Databases were searched. One reviewer screened titles and abstracts, selected studies for inclusion and extracted data following the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Economic model A cost–utility analysis was conducted using a cohort Markov model that was developed following best practice on decision modelling. The model care pathways were informed by existing clinical guidelines, the results of the IPD meta-analysis, and by discussion with clinical and methodological experts. Similar structures including five Markov states (no complications, post-Cardiac pathology, post-Peripheral Vascular System Pathology, post-Cerebrovascular System Pathology and Death) were used for TRT and SoC. The analysis of the TestES IPD provided key input data (i.e. all-cause mortality, CV and CBV complications and utility weights for TRT and SoC). NHS and personal and social services perspectives were adopted for costs. Ten-year and lifetime time horizons were considered. Cost and effects were discounted at 3.5% annual discount rate. We attached probability distributions to input mean parameter values and the model was run probabilistically using 10,000 Monte Carlo simulations. Three cohorts were defined according to the patients’ starting age (40-year-old cohort, 60-year-old cohort, 75-year-old cohort). Mean total cost, mean quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. Probabilistic results were reported using cost-effectiveness acceptability curves (CEAC). Results Results of the quantitative synthesis and individual participant data meta-analysis Thirty-five trials with a total of 5601 randomised participants were included in the review of clinical effectiveness. Of these, 17 studies provided IPD for a total of 3431 participants. Overall risk of bias was assessed as being low for 12/17 studies providing IPD and unclear for the remaining five studies. Of the 18 studies not providing IPD, risk of bias was assessed as low for three studies, unclear for 13 studies and high for two studies. Mortality was lower in the TRT group (0.4%) than in the placebo group (0.8%) [odds ratio (OR) 0.46, 95% confidence interval (CI) 0.17 to 1.24; p = 0.13], but there were too few events for a reliable evaluation. There was no difference in the occurrence of CV and/or CBV events in the TRT group (7.5%) and the placebo group (7.2%; OR 1.07, 95% CI 0.81 to 1.42; p = 0.62). Effects of TRT on QoL were more variable, with some scales showing a difference in favour of TRT [International Index of Erectile Function-15 items (IIEF-15), ageing males’ symptoms (AMS), 3/10 subscales of the short form-36 items/short form-12 items (SF-36/SF-12)]. Serum testosterone was higher in the TRT group and serum cholesterol, triglycerides, haemoglobin and haematocrit were all lower in the TRT than the placebo group. Results of the qualitative synthesis and patient-reported outcome measures Five studies, reported in nine publications, were included in the qualitative evidence synthesis. Six broad themes (with several linked subthemes) were identified in relation to men’s, and their care providers’, experiences of low testosterone and receiving TRT as treatment. Five broad patient-facing themes were identified and ordered to reflect key timeline stages and decision points that a man with low testosterone may experience: symptoms of low testosterone and impact on daily life; diagnosis of low testosterone; access to treatment information; perceived effects of TRT; expectations, experience and preference of the type of TRT. A sixth theme on providers’ perception of diagnosis and treatment was also identified. We identified several interconnected subthemes highlighting the complexity of how low testosterone symptoms influence many aspects of men’s lives and their experiences of treatment. The PROMs search identified a total of nine eligible PROMs measuring experiences of men with low testosterone. The number of items varied across PROMs and ranged from 3 to 53 items (median = 7) with a cumulative total of 98 individual items across the nine PROMs. Our review identified 10 relevant health domains across the 98 items from the 9 PROMs. The 10 domains were defined according to the WHO-ICF classifications and were identified as: Cognition, Energy, General Well-being, Mood, Pain, Physical-General, Role, Sexual, Sleep, Social. The domain most frequently identified across PROMs was the sexual domain, with 29 (29.6% of total items) items measuring this concept across the PROMs. Results of the systematic review of economic evaluations and of the cost-effectiveness analyses Only one study met our inclusion criteria for the systematic review of economic evaluations. The study was a model-based cost–utility analysis conducted in Sweden. The model accounted for TRT benefits from reduced risk of fractures, depression, and type 2 diabetes and for a higher risk of CV and CBV events associated with diabetes. The authors concluded that the lifelong treatment with testosterone undecanoate (TU) depot injection was a cost-effective treatment option for men diagnosed with hypogonadism in Sweden. Our model results show that the cost-effectiveness of TRT is dependent on the relative risk (RR) of all-cause mortality and the methods used to derive health state utility scores [i.e. through the short form-6 dimensions (SF-6D) algorithm or a mapping exercise between Beck depression inventory (BDI) score and EuroQol-5 dimensions (EQ-5D) score] for the TRT versus SoC. When the RR of mortality favouring TRT and the BDI-based utility scores were used for the 10-year time horizon, ICERs remained below the £20,000 threshold, irrespective of the cohort starting age. ICERs also stayed below the £20,000 threshold for the 60- and 75-year-old cohorts when the RR of mortality favouring TRT and the SF-6D utility difference were applied for 10 years. However, ICERs increased above the £20,000 threshold when the difference in all-cause mortality between TRT and SoC was dropped, and the utility scores were defined using the SF-6D. Extending the model time horizon for lifetime for the later scenario further increased the ICER as the impact of complications became more pronounced, eroding the modest SF-6D-based QALY increment. Limitations Inclusion was restricted to studies published in English. Lack of long-term data on the effects and safety of TRT. A meaningful evaluation of the association between mortality and TRT was hampered by the limited number of defined events. Definition and reporting of CV and CBV events and methods for testosterone measurement varied across studies. Length of follow-up in many included trials precluded the accumulation of enough CV or CBV events. There were too few studies of oral testosterone to assess whether the incidence of CV or CBV events was affected by the mode of administration of testosterone therapy. There were only a limited number of available qualitative studies assessing the experience of men with low testosterone; these were predominantly conducted in North America among white men. There were limited data for generating preference-based health-related QoL weights to be used in the economic evaluation. Implications for health care Our collaborative IPD meta-analysis failed to show a relationship between TRT and CV or CBV events in the short-to-medium term (within 12 months). Our findings indicate that TRT improves sexual function and patients’ QoL without adverse effects on blood pressure, serum lipids or glycaemic markers. Overall, there is a paucity of qualitative evidence on the effects of low testosterone and consequences of TRT when compared with the number of existing clinical trials assessing the effectiveness of TRT. Our results indicate that the effects of low testosterone and subsequent treatment with TRT have multiple impacts and concerns for men. This study has shown the considerable variability that exists in disease-specific PROMs for men with low testosterone regarding development and domain coverage. It has also highlighted the lack of input from men in the development of these PROMs, bringing into questions their relevance and adequacy in capturing outcomes that matter to men with low testosterone. Results of our economic model suggest that the cost-effectiveness of TRT is dependent on its effects on all-cause mortality and health state utility resulting from improvements in symptoms associated with hypogonadism such as sexual dysfunction, low mood and reduced QoL. We also noticed that the choice of the instrument and approach to estimate QoL weights (BDI or SF-6D) was crucial to the cost-effectiveness of TRT. Further clarity on the CV safety of TRT in men with hypogonadism and more in-depth mapping of clinical outcomes to generic preference-based measures of health-related QoL will be crucial to inform more robust estimates of the cost-effectiveness of TRT for men with hypogonadism. Recommendations for future research Future research should assess the safety of long-term use of TRT including its impact on mortality, identify the threshold of baseline serum testosterone associated with improvement of sexual function, cognition, mood and QoL in men with hypogonadism and compare the effects of transdermal versus intramuscular TRT. Moreover, further research aiming at mapping QoL instruments commonly used in existing trials of MH to generic preference-based health-related QoL instruments would facilitate the integration of existing evidence into future economic evaluations and models. There is also the need to gather more data on the experience of men with hypogonadism from multiethnic populations and develop a holistic symptom score for TRT response. Study registration The study is registered as PROSPERO CRD42018111005. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/68/01) and is published in full in Health Technology Assessment; Vol. 28, No. 43. See the NIHR Funding and Awards website for further award information.
Keywords
