What is the effect of testosterone therapy on cardiovascular related events in randomized controlled trials?
We will search PubMED, and the WHO trial registry for trials of testosterone therapy reporting cardiovascular related events (including death) specifically or as adverse events. To identify further articles we will hand search references and related citations in PubMed. We will search from the beginning of time until the end of November 2011. If there is a significant delay between completion and publication, we will update the search to the current date. We will also search all published reviews on this topic to identify any additional studies.
We will search PubMed for studies in english using (“testosterone" or "androgen") and trial and (random*) in title, abstract or any field with the selection limited to adult men. We will also search the WHO trial registry for any trial using testosterone as the intervention. We will also search the references of any included study.
Types of study to be included
Placebo controlled randomized controlled trial, which provides information explicitly on all cardiovascular related events by study arm, as cardiovascular related events or as adverse events.
Condition or domain being studied
Randomized controlled trial of testosterone compared with a placebo. Duration of at least 12 weeks, because this study concerns the effects of regular rather than of acute testosterone use.
We will exclude trials that use androgens other than testosterone as the treatment.
Randomized controlled trial of testosterone compared with a placebo.
Given, that many of these trials are in older men with chronic diseases, we will include trials where there is a comparison of testosterone with placebo against the background of other drug use as long as the groups only differ in their use of testosterone.
No restriction on setting
Cardiovascular-related events, because we do not anticipate a great deal of data so we are focusing on one key outcome.
Study duration of at least 12 weeks
Relative risk as effect measure
Data extraction, (selection and coding)
Two people will search independently and compare their selections at the end of the search process. Any differences will be resolved by consensus or if necessary by reference to a third investigator.
After the first automated query in the databases, we will use a two step process for screening. Firstly, we will screen the titles and abstracts. Secondly, we will screen the remaining publications on the basis of the corresponding full text for reports of adverse events, causes of death or cardiovascular related events by trial arm.
A statistician will abstract data from the selected studies, using a standard template. A second investigator will check all the extracted data.
We will extract the following information for each trial:
• Publication details (author, year of publication, title, journal)
• Study population, including health status (major chronic diseases), pre-trial testosterone status (‘low’ or ‘normal’), age and setting
• Primary study outcome
• Duration of follow-up
• Number of participants in each arm at start and end (testosterone and placebo groups)
• Dose of testosterone and method of administration
• Number of occurrences of cardiovascular related events and cardiovascular related deaths by trial arm.
• Funding source
• Affiliations and competing interests of investigators
• Trial implementation and reporting including information on:
o treatment allocation
o comparison of groups at baseline
o trial eligibility criteria
o ‘blinding’ of outcome assessors, care providers, adverse event assessors and participants
o Adverse or cardiovascular related event reporting
o Type of analysis, intention to treat, per-protocol or other
• Source of cardiovascular related or adverse events, as summarized in a table, surmised from the text or obtained from the study authors.
Risk of bias (quality) assessment
We will use an established tool to evaluate the quality of each trial. Two investigators will independently rate each study and settle any differences by consensus or reference to a third investigator. Because we are not studying the main outcomes of these trials but largely unexpected events in this systematic review we will focus our assessment on the quality of reporting of these events.
We will use Begg and Egger's methods to assess publication bias. We will also use the trim and fill method to assess the impact of publication bias on the pooled effect.
Strategy for data synthesis
We will use the Mantel-Haenszel estimator with random or fixed effects depending on the heterogeneity between trials.
Analysis of subgroups or subsets
Contact details for further information
The Silberman building
2180 Third Avenue
Organisational affiliation of the review
Dr C Schooling, CUNY, School of Public Health at Hunter College Dr L Xu, The University of Hong Kong Dr Guy Freeman, The University of Hong Kong Dr Benjamin Cowling, The University of Hong Kong
Details of any existing review of the same topic by the same authors
Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials, BMC Medicine, in press, 2013
Stage of review at time of this submission
Piloting of the study selection process
Formal screening of search results against eligibility criteria
Risk of bias (quality) assessment
PROSPERO This information has been provided by the named contact for this review. CRD has accepted this information in good faith and registered the review in PROSPERO. CRD bears no responsibility or liability for the content of this registration record, any associated files or external websites.