The use of estrogen-containing contraceptives is associated with a two- to six-fold increased risk of venous thromboembolism (VTE) . However, it remains controversial whether a VTE associated with estrogen-containing contraceptives can be classified as "unprovoked" or "provoked" .
Although American Society of Hematology guidelines define the use of estrogen-containing contraceptives as a minor transient risk factor , VTE associated with estrogen-containing contraceptives is considered unprovoked by others . This classification is clinically relevant as it has implications for the duration of treatment.
Patients with VTE caused by a major transient risk factor, such as surgery under general anesthesia for >30 min, can be treated with short- term anticoagulant therapy for 3 to 6 months, as the estimated risk of recurrence is considered low. Indefinite treatment is suggested in those with unprovoked VTE , that is, without risk factors, if the risk of bleeding is low.
However, the duration of treatment in patients with a minor transient risk factor is debatable. While the ASH guidelines suggest short-term treatment of VTE associated with a minor transient risk factor, such as estrogen-containing contraceptives, the European Society of Cardiology (ESC) guideline states that treatment should be considered indefinite in women with VTE related to estrogen therapy based on an estimated long-term risk of recurrence of 3 to 8% per year.
However, if pulmonary embolism (PE) occurs in the first 3 months after starting estrogen-containing contraceptives, discontinuation of anticoagulation after 3 months could be considered if hormonal contraceptives are also discontinued.
Several studies evaluated the risk of recurrence after a first VTE related to estrogen-containing contraceptives, but they often had a small sample size, included heterogeneous groups of women, or reported conflicting results. These limitations add to the uncertainty about the risk of recurrence after VTE related to estrogen-containing contraceptives, and whether these women can safely discontinue anticoagulant therapy after the initial 3-month treatment phase.
Summary data with accurate estimates are needed to improve counseling and optimize treatment strategies. Therefore, the aim of this systematic review was to estimate the incidence rate of recurrent VTE after discontinuation of anticoagulant treatment in women with a first episode of VTE related to estrogen-containing contraceptives.
Background
The risk of recurrence after venous thromboembolism (VTE) related to estrogen-containing contraceptives is a key factor in guiding anticoagulant treatment decisions.
Aim
To estimate the incidence rate of recurrent VTE after discontinuation of anticoagulant therapy in women with a first episode of VTE related to estrogen-containing contraceptives.
Methods
We searched Embase, MEDLINE, and CENTRAL from January 1, 2008 to May 27, 2021 for prospective and retrospective studies reporting on recurrence after a first VTE related to estrogen-containing contraceptives.
Risk of bias was assessed using the QUIPS tool. Recurrence rates per 100 patient-years were pooled using Knapp-Hartung random-effects meta-analysis.
Incidence rates were reported separately by duration of study follow-up (≤1 year, 1–5 years, and >5 years) and for various subgroups.
Results
A total of 4,120 studies were identified , of which 14 were included. The pooled recurrence rate was 1.57 (95% CI: 1.10–2.23; I 2 = 82%) per 100 patient-years. .
Recurrence rates per 100 patient-years were 2.73 (95% CI: 0.00–3643; I 2 = 80%) for studies with ≤1 year of follow-up, 1.35 (95% CI: 0.68 –2.68; I 2 = 44%) for studies with 1–5 years of follow-up, and 1.42 (95%-CI: 0.84–2.42; I 2 = 78%) for studies with >5 years of follow-up.
Conclusion
Among women with VTE associated with estrogen-containing contraceptives, the risk of recurrence after stopping anticoagulation is low , favoring short-term anticoagulation .
Large prospective studies are needed on VTE recurrence rates and risk factors after stopping short-term anticoagulants.
Essential aspects
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Discussion
In this systematic review, the recurrence rate after stopping anticoagulant treatment for VTE in younger women using estrogen-containing contraceptives was low, with a pooled rate of 1.57 per 100 patient-years. These findings suggest that only short-term anticoagulation for 3 to 6 months after an estrogen-related VTE may be appropriate.
Our systematic review indicates that the risk of recurrent VTE among women with VTE related to estrogen-containing contraceptives is equivocal, likely due to differences in study design, duration of follow-up, and populations studied. This is reflected in the wide confidence intervals and substantial heterogeneity between studies in the meta-analysis.
The risk of VTE recurrence in women on estrogen-containing contraceptives appears to be low, supporting short-term anticoagulation for 3 to 6 months after VTE related to estrogen-containing contraceptives. However, data and contributing risk factors for this specific patient population are limited and no strong recommendations can be made regarding anticoagulant duration.
Large prospective studies are needed on VTE recurrence rates and risk factors for recurrence in patients with VTE associated with estrogen-containing contraceptives that discontinue anticoagulation after 3 to 6 months.
Comments
A low risk of recurrence was observed after discontinuation of anticoagulation.
The classification of estrogen-associated venous thromboembolism (VTE) is controversial: some consider estrogen to be a provocative risk factor, while others consider these events to be unprovoked. This classification is important, as the duration of anticoagulation is strongly influenced by context: patients with provoked events are treated with anticoagulation of finite duration, while those with unprovoked events may be candidates for longer-term anticoagulation.
This systematic review reports a relatively low risk of VTE recurrence after anticoagulant discontinuation among women with estrogen-associated VTE. The rate reported here is below the typical threshold of 3%, above which long-term anticoagulation may be justified. The authors acknowledge the limitations and point out the heterogeneity between the studies.
Furthermore, no randomized controlled trials were identified and the analysis could not identify whether recurrence rates differed by estrogen formulation, which could affect the generalisability of the findings. However, this systematic review supports the American Society of Hematology recommendation regarding short-term anticoagulation for women with oral contraceptive-associated VTE.
