The review assessed the effect of hormone replacement therapy (HRT) on the risk of arterial and venous vascular events. The authors concluded that HRT was associated with increased rates and severity of cardiovascular disease, and increased venous thromboembolism. Their conclusions are likely to be reliable.

To assess the effect of hormone replacement therapy (HRT) on the risk of arterial and venous vascular events.

MEDLINE, EMBASE, and the Cochrane Library were searched to January 2008 for studies published in English. Search terms were reported. Reference lists from identified articles and previous reviews were also scanned for further studies.

Non-confounded randomised controlled trials (RCTs) of HRT versus no HRT (open or placebo-controlled) in women were eligible for inclusion. Trials had to report event rates for one or more of cerebrovascular disease (stroke, transient ischaemic attack), coronary heart disease (myocardial infarction, unstable angina, cardiac death) and venous thromboembolism (pulmonary embolism, deep vein thrombosis).

Most trials studied progesterone and/or oestrogen (but some studied raloxifene) using a range of doses, and most were of vascular prevention, but nearly a third of trials were in patients with prior coronary heart disease. Mean ages of included participants ranged between 47 and 75 years (median 62.7 years). Women with a range of diagnoses were included, but healthy populations were the commonest to be studied.

The authors did not state how the papers were selected for the review, or how many reviewers performed the selection.

Study quality was assessed using: method of randomisation, blinding, reporting of withdrawals, generation of random numbers, and allocation concealment; the maximum score was 5 points.

The authors did not state how the validity assessment was performed.

Data were extracted and odd ratios (OR) with 95% confidence intervals (CI) were calculated. When possible, outcomes were recorded into categories (ordinal data), to allow effects on outcome severity to be assessed. Intention-to-treat data were used when available.

Two reviewers independently extracted data, with disagreements resolved by a third reviewer.

Meta-analyses of pooled odds ratios were performed using a random-effects model. An indirect comparison analysis was also performed. The authors also conducted nine (pre-specified) types of sensitivity analysis, and used ordinal logistic regression for the ordinal data. Heterogeneity was assessed using the I² statistic. Funnel plots (and Egger's test) were used to assess publication bias.

Thirty-five trials (n=61,812 women) were included in the review, with sample sizes ranging from 50 to 16,608 participants. Follow-up periods ranged between 16 weeks and 6.8 years. Study quality scores ranged from 2 to 5 out of 5 points, with the median score being 4 points. Evidence for publication bias was found for venous thromboembolism, but not for cardiovascular disease.

Hormone replacement therapy (HRT) was associated with an increase in occurrence of stroke (OR 1.32, 95% CI 1.14 to 1.53) and venous thromboembolism (OR 2.05, 95% CI 1.44 to 2.92), but not coronary heart disease events. There was little evidence of statistical heterogeneity. Ordinal analyses indicated that stroke severity was increased with HRT (OR 1.31, 95% CI 1.12 to 1.54). Age did not significantly affect risk. HRT using progesterone and oestrogen doubled the risk of venous thromboembolism. There were no differences between groups in any of the other sensitivity analyses. Further results were reported.

HRT was associated with an increased risk of stroke, stroke severity, and venous thromboembolism, but not of coronary heart disease events. Combined HRT using progesterone and oestrogen increased the risk of venous thromboembolism compared with oestrogen monotherapy.

The review addressed a clear question and was supported by appropriate inclusion criteria. Attempts to identify relevant trials were undertaken by searching databases and checking references, but the restriction to trials published in English meant that some relevant studies may have been missed. The authors did find some evidence of publication bias. Suitable methods were employed to reduce the risks of reviewer error and bias for the process of data extraction, but the authors did not report whether such methods were used to select trials for inclusion or to assess trial quality. Sufficient trial details were provided, and trial quality was assessed and used in interpreting the results of the review. Many of the large trials (which carried most weight in the analyses) achieved maximum scores in the quality assessment. Appropriate meta-analysis methods were used to pool data and heterogeneity was assessed. The authors' conclusions reflected the evidence presented and are likely to be reliable.

Practice: The authors stated that HRT cannot be recommended for long-term vascular prophylaxis in most subjects.

Research: The authors stated that future trials should uniformly report the effect of HRT on stroke, myocardial infarction, and venous thromboembolism or on the outcome after these events.

British Heart Foundation; Medical Research Council; University of Nottingham.

Bath PMW, Gray LJ. Association between hormone replacement therapy and subsequent stroke: a meta-analysis. BMJ 2005;330:342.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.