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.
OBJECTIVE: To investigate the association of sitting time with mortality and major CVD in countries at different economic levels using data from the Prospective Urban Rural Epidemiology study.
DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study included participants aged 35 to 70 years recruited from January 1, 2003, and followed up until August 31, 2021, in 21 high-income, middle-income, and low-income countries with a median follow-up of 11.1 years.
EXPOSURES: Daily sitting time measured using the International Physical Activity Questionnaire.
MAIN OUTCOMES AND MEASURES: The composite of all-cause mortality and major CVD (defined as cardiovascular death, myocardial infarction, stroke, or heart failure).
RESULTS: Of 105 677 participants, 61 925 (58.6%) were women, and the mean (SD) age was 50.4 (9.6) years. During a median follow-up of 11.1 (IQR, 8.6-12.2) years, 6233 deaths and 5696 major cardiovascular events (2349 myocardial infarctions, 2966 strokes, 671 heart failure, and 1792 cardiovascular deaths) were documented. Compared with the reference group (<4 hours per day of sitting), higher sitting time (≥8 hours per day) was associated with an increased risk of the composite outcome (hazard ratio [HR], 1.19; 95% CI, 1.11-1.28; Pfor trend < .001), all-cause mortality (HR, 1.20; 95% CI, 1.10-1.31; Pfor trend < .001), and major CVD (HR, 1.21; 95% CI, 1.10-1.34; Pfor trend < .001). When stratified by country income levels, the association of sitting time with the composite outcome was stronger in low-income and lower-middle-income countries (≥8 hours per day: HR, 1.29; 95% CI, 1.16-1.44) compared with high-income and upper-middle-income countries (HR, 1.08; 95% CI, 0.98-1.19; P for interaction = .02). Compared with those who reported sitting time less than 4 hours per day and high physical activity level, participants who sat for 8 or more hours per day experienced a 17% to 50% higher associated risk of the composite outcome across physical activity levels; and the risk was attenuated along with increased physical activity levels.
CONCLUSIONS AND RELEVANCE: High amounts of sitting time were associated with increased risk of all-cause mortality and CVD in economically diverse settings, especially in low-income and lower-middle-income countries. Reducing sedentary time along with increasing physical activity might be an important strategy for easing the global burden of premature deaths and CVD.
METHODS: A retrospective audit of heart transplant recipients (n = 87) treated with tacrolimus was performed. Relevant data were collected from the time of transplant to discharge. The concordance of tacrolimus dosing and monitoring according to hospital guidelines was assessed. The observed and software-predicted tacrolimus concentrations (n = 931) were compared for the first 3 weeks of oral immediate-release tacrolimus (Prograf) therapy, and the predictive performance (bias and imprecision) of the software was evaluated.
RESULTS: The majority (96%) of initial oral tacrolimus doses were guideline concordant. Most initial intravenous doses (93%) were lower than the guideline recommendations. Overall, 36% of initial tacrolimus doses were administered to transplant recipients with an estimated glomerular filtration rate of <60 mL/min/1.73 m despite recommendations to delay the commencement of therapy. Of the tacrolimus concentrations collected during oral therapy (n = 1498), 25% were trough concentrations obtained at steady-state. The software displayed acceptable predictions of tacrolimus concentration from day 12 (bias: -6%; 95%confidence interval, -11.8 to 2.5; imprecision: 16%; 95% confidence interval, 8.7-24.3) of therapy.
CONCLUSIONS: Tacrolimus dosing and monitoring were discordant with the guidelines. The Bayesian forecasting software was suitable for guiding tacrolimus dosing after 11 days of therapy in heart transplant recipients. Understanding the factors contributing to the variability in tacrolimus pharmacokinetics immediately after transplant may help improve software predictions.