A systematic review 1 including 8 case-control studies, 6 follow-up studies and one randomised trial was abstracted in DARE. The unweighted summary relative risk for a new venous thrombosis or thromboembolism (VTE) was 2.9 (95% CI 0.5 to 17)(G test for homogeneity p<0.001). For case-control studies the RR was 4.2 (95% CI 1.3 to 14), and for follow-up studies it was 2.1 (95% CI 0.3 to 16). For the one RCT it was 1.1 (95% CI 0.4 to 2.9). The funnel plot did not reveal evidence of publication bias.
In a prospective cohort study 2 in France the risk of a recurrent VTE in women after a first oestrogen contraception associated VTE episode was assessed. Women under 50 years were consecutively enrolled between 1992 and 2011. Of the 241 women who were followed-up after stopping anticoagulation, there were 180 COC-users and 61 non-users. Median duration of follow-up off-anticoagulants was 66 months (interquartile range: 33-103). There were 14 recurrences in COC-users and 5 cases in non-users. No significant association was found between exposure to COC and the incidence of recurrent VTE after adjustment for age or after restricting the analysis to major unprovoked VTE: incidence rate of recurrence 17.9/1,000/year (95% CI: 9.6-33.2) in women with COC as compared with 17.6/1,000/year (95% CI: 6.6-47) with an incidence ratio of 0.7 (95% CI: 0.2-2.4, p=0.59).
A meta-analysis 3 assessed the thrombosis risk in thrombophilic COC-users. 12 case-control and 3 cohort studies were included. A distinction was made between 'mild' (factor V Leiden and prothrombin-G20210A mutation) and 'severe' thrombophilia (antithrombin deficiency, protein C deficiency, protein S deficiency, double heterozygosity or homozygosity of factor V Leiden and prothrombin-G20210A mutation). In COC-users, mild thrombophilia increased the risk of VTE almost 6-fold (rate ratio [RR], 5.89; 95%CI 4.21 to 8.23) and severe 7-fold (RR, 7.15; 95% CI, 2.93 to 17.45). The cohort studies showed that absolute VTE risk was far higher in COC-users with severe thrombophilia than in those with mild thrombophilia (4.3 to 4.6 vs. 0.49 to 2.0 per 100 pill-years, respectively), and these differences in absolute risks were also noted in non-affected women (0.48 to 0.7 vs. 0.19 to 0.0), but with the caveat that absolute risks were estimated in relatives of thrombophilic patients with VTE (i.e. with a positive family history). The investigators concluded that the additive VTE risk of mild thrombophilia is modest.
A systematic review and meta-analysis 5 included 19 studies with a total of 1537 women [5828 person-years (PY)] with COC-associated VTE and 1974 women (7798 PY) with unprovoked VTE]. Studies were at low risk of bias. The incidence rate of VTE recurrence was 1.22/100 PY (95% CI 0.92 to 1.62, I²=6%) in women with COC-associated VTE, 3.89/100 PY (95% CI 2.93 to 5.17, I²=74%) in women with unprovoked VTE and the unadjusted incidence rate ratio was 0.34 (95% CI 0.26 to 0.46, I²=3%). The recurrence risk in women after COC-associated VTE is low and lower than after an unprovoked VTE.
Another systematic review and meta-analysis 4 including 14 cohort studies assessed the incidence of recurrent VTE after discontinuation of anticoagulant treatment in women with a first episode of VTE related to estrogen-containing contraceptives. The pooled recurrence rate was 1.57 (95% CI 1.10 to 2.23; I²=82%) per 100 patient-years. Recurrence rates per 100 patient-years were 2.73 (95% CI 0.00 to 3643; I²=80%) for studies with ≤1 year follow-up, 1.35 (95% CI 0.68 to 2.68; I²=44%) for studies with 1-5 years follow-up, and 1.42 (95% CI 0.84 to 2.42; I²=78%) for studies with >5 years follow-up. Thus the writers suggested short-term anticoagulation.
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