Nine RCTs (n=38,779, range: 140 to 16,608 participants), 7 case-control studies and one prospective cohort study were included. The number of patients included in the observational studies was not reported.
Seven RCTs scored 5 on the validity assessment and two scored 4. Four case-controls scored 6 for validity and three scored 5, and the prospective cohort study scored 7. The duration of follow-up in the RCTs ranged from 0.99 to 7 years.
Oral versus transdermal oestrogen (17 studies).
With the exception of one RCT and one observational study, the remaining studies reported an association between oral oestrogen and increased risk of VTE (OR 2.4, 95% CI: 1.9, 3.0). One study reported an association between increased risk and equine oestrogen, but no data were presented. No associations were reported between increased risk and transdermal oestrogen or esterified oestrogen. Five case-control studies reported a significant association between increased risk of VTE and duration of treatment, with the greatest risk reported for treatment duration up to 1 year (OR 4.0, 95% CI: 2.9, 5.7) compared with treatment for more than 1 year (OR 2.1, 95% CI: 1.3, 3.8, p<0.05). Previous use of hormone therapy (4 observational studies) and use of oral oestrogen alone or in combination with progesterone were not associated with increased risk.
Outcome diagnosis (17 studies).
No significant results were reported for type of VTE and oral oestrogen use. The sensitivity analysis for 7 studies reporting the first episode of idiopathic events showed a substantial increase in risk using oral oestrogen (OR 3.1, 95% CI: 2.3, 4.1), but the results were not significantly altered for studies using transdermal oestrogen.
Results for women at high risk of VTE with the presence of factor V Leiden mutation or prothrombin G20210A mutation were reported in the review, but the studies reported were not identified as eligible for inclusion.
There was significant heterogeneity among observational studies and randomised studies using oral oestrogen (p=0.03), and for studies examining hormone therapy for more than 1 year. The authors also reported other sources of heterogeneity, but no data were presented.