Do women with venous thromboembolism bleed more than men during anticoagulation? Data from the real-life, prospective START-Register

Abstract

Background: Venous thromboembolism (VTE) is a frequent and serious disease that requires immediate and long-term anticoagulant treatment, which is inevitably associated with a risk of bleeding complications. Some studies, though not all, reported a higher risk of bleeding in female patients treated with either old anticoagulants [vitamin k antagonists (VKAs)] or recent anticoagulants [direct oral anticoagulants (DOACs)]. Furthermore, analyses of clinical trials reported an abnormal vaginal bleeding in women of reproductive age treated with DOACs. This study aimed at comparing the risk of bleeding in an inception cohort of VTE women and men included in a prospective observational registry. Methods: Baseline characteristics and bleeding events occurring during anticoagulation in patients of both sexes, included in the START-Register after a first VTE, were analyzed. Results: In all, 1298 women were compared with 1290 men. Women were older and more often had renal diseases; their index events were often provoked (often by hormonal contraception and pregnancy), and more frequently presented as isolated pulmonary embolism (PE). The rate of bleeding was similar in women (2.9% patient-years) and men (2.1% patient-years), though it was higher when uterine bleeds were included (3.5% patient-years, p = 0.0141). More bleeds occurred in VKA- than DOAC-treated patients (6.4% versus 2.6%, respectively; p = 0.0013). At multivariate analysis, age ⩾ 75 years was associated with higher prevalence of bleeds. Conclusion: The occurrence of bleeding was not different between women and men during anticoagulation after VTE. Only after inclusion of vaginal/uterine bleeds, the rate of bleeding was higher in women. The incidence of bleeding was higher in women treated with VKAs. Plain Language Summary The risk of bleeding in women anticoagulated for deep vein thrombosis or pulmonary embolism is not higher than that in men, except for vaginal bleeding Background: The occurrence of a venous thromboembolic event (VTE, including deep vein thrombosis and pulmonary embolism) necessarily requires a period of at least 3–6 months of treatment with anticoagulant drugs [either vitamin k antagonists (VKA) or, more recently, direct oral anticoagulants (DOACs)]. Anticoagulation therapy, however, is associated with a risk of bleeding that is influenced by several factors. Sex is one of these factors as some authors have hypothesized that women are at higher risk than men. Furthermore, some studies have recently found more vaginal bleeding in VTE women treated with a DOAC compared with those who received VKAs. Methods: The present study aimed to compare the frequency of bleeds occurring in women and in men who were treated with DOACs or VKAs for a first VTE event and followed in real-life conditions. Since the beginning of their anticoagulant treatment, the patients were included in a prospective, multicenter, observational registry (the START-Register), and bleeding events were recorded. Results: A total of 1298 women were compared with 1290 men. Women were older and more often were affected by renal diseases; their VTE events were often associated with risk factors (especially hormonal contraception and pregnancy) and presented as isolated pulmonary embolism. The rate of all bleeding events (including major, non-major but clinically relevant, and minor bleeds) was higher in women (3.5% patient-years) than in men (2.1% patient-years, p = 0.0141); however, the difference was no longer statistically significant after exclusion of uterine bleeds (2.9% patient years). More bleeding occurred in women receiving VKA as anticoagulant drug compared with those treated with a DOAC (6.4% versus 2.6%, respectively; p = 0.0013). At multivariate analysis, age ⩾ 75 years was associated with higher prevalence of bleeds. Conclusion: In conclusion, we found that in real-life conditions, the rate of bleeding events occurring during anticoagulation after a VTE episode is not higher in women than in men. Only after inclusion of vaginal bleeds, the rate of bleeding was higher in women. More bleeds (including vaginal bleeding) occurred in women treated with VKA than DOACs.

Identification and comparison of sex‐specific serious adverse drug reactions in spontaneous reports and systematically collected reports (ADRED)

“…The combinations of nervous system disorders respectively paralysis and paresis , central nervous system haemorrhages and cerebrovascular accidents as well as speech and language abnormalities in combination with dabigatran were more frequently reported for males compared to females in both datasets. So far, literature is inconsistent with some studies reporting a higher prevalence of bleedings with DOACs in males while others observed higher risks of bleeding events for females or did not observe any sex differences regarding bleeding events at all 42–44 . Sex‐specific differences in the expression of enzymes affecting the metabolism and pharmacodynamics of dabigatran could contribute to these findings.…”

“…So far, literature is inconsistent with some studies reporting a higher prevalence of bleedings with DOACs in males while others observed higher risks of bleeding events for females or did not observe any sex differences regarding bleeding events at all. [42][43][44] Sex-specific differences in the expression of enzymes affecting the metabolism and pharmacodynamics of dabigatran could contribute to these findings. Thus, further research on the underlying polymorphisms could investigate sex-specific genetic risk constellations requiring a dose adjustment of dabigatran.…”

Venous Thromboembolism in Women of Childbearing Age: Insights from the START Registry

“…The design of the START registry has been previously described. 7 Briefly, the START (Clinicaltrial.gov NCT02219984 ) is an observational, prospective, multicentre, dynamic cohort study of adults (≥18 years) starting anticoagulation therapy, whatever the indication for treatment and drug/dosage. Data are captured using an electronic case report form (eCRF) designed by Softime 90 Snc (Bologna Italy) and submitted electronically via a secure Web site to the registry-coordinating center at the “Arianna Anticoagulazione” Foundation (Bologna, Italy), which is the owner of the registry and is responsible for checking the completeness and accuracy of data collected from medical records.…”

“…As for information on index events, their nature was classified as (a) unprovoked, when not temporally associated with any potential triggering conditions or RFs; (b) associated with weak RF, such as minor, arthroscopic or laparoscopic general surgery, pregnancy or puerperium, contraceptive or replacement hormonal therapy, long trip, minor trauma, stay in hospital, reduced mobility (not complete immobilization); (c) provoked by transient major RF, as elsewhere detailed. 7 The site of events was classified as (a) DVT [either proximal or isolated distal], when thrombosis of deep veins was not associated with diagnosis of PE; or (b) cases with PE, when a PE event was associated with DVT, or was isolated. Splanchnic vein thrombosis (SVT) and cerebral vein thrombosis (CVT) were defined as unusual site vein thromboses.…”

“…Details on data collection in structured case report form (CRF) via web have been previously described. 7 Briefly, baseline characteristics were the following: (a) demographic, body weight, routine laboratory data, past medical history; (b) characteristics of index VTE event and presence of risk factors (RFs); (c) anticoagulant agents used, dosages, concomitant medications (especially antiplatelet drugs).…”