Hormonal contraceptive use after a first venous thrombotic event and the risk of recurrence in premenopausal women.

BACKGROUND: Extensive evidence is available on hormonal contraceptive (HC) use and the risk of a first venous thromboembolism (VTE) event. Despite recommendations to discontinue combined HC (CHC) use, some women continue or start its use after a first VTE. OBJECTIVES: We aimed to evaluate the VTE recurrence risk associated with HC use in premenopausal women. METHODS: Premenopausal women with a first VTE included in the Multiple Environmental and Genetic Assessment of Venous Thrombosis study between 1999 and 2004 were followed for a recurrence until 2010. Data on HC use were available through linkage to the Dutch Foundation for Pharmaceutical Statistics. The risk of recurrence was assessed 1) during anticoagulant therapy and 2) after cessation of anticoagulant therapy. Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs adjusted for age and body mass index at baseline and thromboprophylaxis use during follow-up. RESULTS: Six hundred fifty women were uniquely linked and followed for a total of 3538 person-years (median, 6.1 years), during which 57 VTE recurrences occurred. Five occurred (8.8%) during anticoagulation treatment, with no clear risk difference for CHC use vs nonuse (HR, 0.8; 95% CI, 0.1-8.2). After anticoagulation cessation, CHC use was associated with a 2.4-fold higher risk of recurrence (HR, 2.4; 95% CI, 1.2-5.0) compared with nonuse. Recurrence risk for levonorgestrel-releasing intrauterine device use was similar to that for nonuse (HR, 0.9; 95% CI, 0.3-3.1). CONCLUSION: CHC use after a first VTE is safe during anticoagulant use but substantially increases the risk of a recurrent VTE event in absence of anticoagulant use. This study adds to the evidence regarding the use of a levonorgestrel-releasing intrauterine device as a safe alternative.

Procoagulant factors and future risk of arterial cardiovascular disease in patients with prior venous thrombosis: A cohort study.

Patients with venous thrombosis (VT) are at increased risk of future arterial cardiovascular disease (CVD) (i.e., myocardial infarction, ischemic stroke or peripheral artery disease). We investigated whether shared risk factors for VT and CVD are associated with the levels of procoagulant factors (fibrinogen, factor VIII, and von Willebrand factor), and whether the relationship between these risk factors and subsequent CVD was mediated through these procoagulant factors in patients with VT. In a follow-up study consisting of 4956 patients with VT, 2176 patients (44%) provided blood samples and were linked to the Dutch Hospital registry of Statistics Netherlands to identify hospital admissions or procedures for subsequent CVD. In total, 52 CVD events occurred over a follow-up of 11,124 years, with an incidence rate of 4.7 per 1000 patient years (95% confidence intervals 3.5-6.1). Increasing age, male sex, smoking history, major illnesses, dyslipidemia, and impaired fasting glucose levels were associated with increased CVD risk. Procoagulant factor levels were also associated with CVD risk. When adjusted for these procoagulant factors, the association between the risk factors and CVD attenuated partially. This study provides evidence that procoagulant factors can partially explain the association between increased risks of subsequent CVD in patients with previous VT.

Correction: Prediction of recurrent venous thrombosis in all patients with a first venous thrombotic event: The Leiden Thrombosis Recurrence Risk Prediction model (L-TRRiP).

[This corrects the article DOI: 10.1371/journal.pmed.1002883.].

Prediction of recurrent venous thrombosis in all patients with a first venous thrombotic event: The Leiden Thrombosis Recurrence Risk Prediction model (L-TRRiP).

BACKGROUND: Recurrent venous thromboembolism (VTE) is common. Current guidelines suggest that patients with unprovoked VTE should continue anticoagulants unless they have a high bleeding risk, whereas all others can stop. Prediction models may refine this dichotomous distinction, but existing models apply only to patients with unprovoked first thrombosis. We aimed to develop a prediction model for all patients with first VTE, either provoked or unprovoked. METHODS AND FINDINGS: Data were used from two population-based cohorts of patients with first VTE from the Netherlands (Multiple Environment and Genetic Assessment of Risk Factors for Venous Thrombosis [MEGA] follow-up study, performed from 1994 to 2009; model derivation; n = 3,750) and from Norway (Tromsø study, performed from 1999 to 2016; model validation; n = 663). Four versions of a VTE prediction model were developed: model A (clinical, laboratory, and genetic variables), model B (clinical variables and fewer laboratory markers), model C (clinical and genetic factors), and model D (clinical variables only). The outcome measure was recurrent VTE. To determine the discriminatory power, Harrell's C-statistic was calculated. A prognostic score was assessed for each patient. Kaplan-Meier plots for the observed recurrence risks were created in quintiles of the prognostic scores. For each patient, the 2-year predicted recurrence risk was calculated. Models C and D were validated in the Tromsø study. During 19,201 person-years of follow-up (median duration 5.7 years) in the MEGA study, 507 recurrences occurred. Model A had the highest predictive capability, with a C-statistic of 0.73 (95% CI 0.71-0.76). The discriminative performance was somewhat lower in the other models, with C-statistics of 0.72 for model B, 0.70 for model C, and 0.69 for model D. Internal validation showed a minimal degree of optimism bias. Models C and D were externally validated, with C-statistics of 0.64 (95% CI 0.62-0.66) and 0.65 (95% CI 0.63-0.66), respectively. According to model C, in 2,592 patients with provoked first events, 367 (15%) patients had a predicted 2-year risk of >10%, whereas in 1,082 patients whose first event was unprovoked, 484 (45%) had a predicted 2-year risk of <10%. A limitation of both cohorts is that laboratory measurements were missing in a substantial proportion of patients, which therefore were imputed. CONCLUSIONS: The prediction model we propose applies to patients with provoked or unprovoked first VTE-except for patients with (a history of) cancer-allows refined risk stratification, and is easily usable. For optimal individualized treatment, a management study in which bleeding risks are also taken into account is necessary.

Predicting the risk of recurrent venous thrombosis: What the future might bring.

An important clinical problem in the management of venous thrombosis is to determine whether a patient can safely cease anticoagulant therapy. In this Forum article, we summarize the predictive performance of several prediction models for recurrent thrombosis, as well as for bleeding while using anticoagulants. Patients with provoked first thrombosis (considered "low risk") are now denied long-term treatment, although a strong gradient in risk can be found in this group. We furthermore discuss the problem of an unclear definition of "(un)provoked" and show that this affects the yield of currently available prediction scores plus the limitations of a "one-size-fits-all" strategy. Better prediction tools are urgently needed. We propose a strategy for future studies for which the following should be considered: (a) reporting of absolute risks next to C-statistics, (b) model applicable to all patients, (c) no discontinuation of anticoagulation for measurement of predictors.

Risk prediction of recurrent venous thrombosis; where are we now and what can we add?

BACKGROUND: Several models are available to predict recurrent venous thrombosis (VT) in patients with unprovoked first events. OBJECTIVES: To validate these prediction models externally. METHODS: Within the MEGA follow-up study (n = 3750), we externally validated the Vienna and DASH score. These models were validated (a) by using the original study's criteria for patients with unprovoked VT and (b) by using our own criteria for unprovoked VT. In addition, absolute recurrence risks based on individual VT risk factors were calculated. RESULTS: The recurrence rate was 5.2 (95% CI, 4.6-5.9) per 100 patient-years in those who had a first unprovoked VT according to our definition. For the Vienna model it was 3.4 per 100 patient-years and for DASH 3.8 per 100 patient-years. The C-statistic was 0.62 for Vienna and 0.65 for DASH. The C-statistic declined to 0.58 for both Vienna and DASH when we used our own definition of "unprovoked VT." Within the provoked group a strong gradient in risk was found dependent on the presence of traditional risk factors or biomarkers in a patient. CONCLUSIONS: The ability to distinguish patients' recurrence risks is lower than proposed in the original prediction model studies and dependent on the definition that is used for an unprovoked first event. Furthermore, our results suggest that a more-refined risk estimation is possible, also in patients with a provoked first event, who are currently all classified as low risk.

Antibiotic use as a marker of acute infection and risk of first and recurrent venous thrombosis.

A role for transient infections in the aetiology of venous thrombosis (VT) has been suggested. This study aimed to determine whether individuals who receive antibiotic treatment (as a proxy for infections) have an increased risk of first and recurrent VT and whether infections should be seen as a provoking risk factor for VT. We used the self-controlled case series method to study the risk of first VT during antibiotic prescriptions. The risk of recurrent VT during antibiotic use was estimated by of time-dependent Cox-regression. A total of 2547 patients with a first VT were included and followed for a median of 5·9 years for recurrence (1999-2010), in whom 114 first events occurred during antibiotic use. We found a five-fold increased risk of first VT during antibiotic treatment: [incidence-rate-ratio 5·0; 95% confidence interval (CI), 4·0-6·1]. Antibiotic use was associated with a 2·0-fold (95% CI, 1·1-4·0) increased risk of recurrent VT. Patients with an unprovoked first VT who used antibiotics shortly before this event, had a similar risk of recurrence as patients with a provoked first VT (adjusted hazard ratio 1·1; 95% CI, 0·7-1·7). Individuals who receive antibiotics have an increased risk of first and recurrent VT and infections should be considered a provoking risk factor for VT.

Epidemiology of cancer-associated venous thrombosis.

Cancer-associated venous thrombosis is a common condition, although the reported incidence varies widely between studies depending on patient population, start and duration of follow-up, and the method of detecting and reporting thrombotic events. Furthermore, as cancer is a heterogeneous disease, the risk of venous thrombosis depends on cancer types and stages, treatment measures, and patient-related factors. In general, cancer patients with venous thrombosis do not fare well and have an increased mortality compared with cancer patients without. This may be explained by the more aggressive type of malignancies associated with this condition. It is hypothesized that thromboprophylaxis in cancer patients might improve prognosis and quality of life by preventing thrombotic events. However, anticoagulant treatment leads to increased bleeding, particularly in this patient group, so in case of proven benefit of thromboprophylaxis, only patients with a high risk of venous thrombosis should be considered. This review describes the literature on incidence of and risk factors for cancer-associated venous thrombosis, with the aim to provide a basis for identification of high-risk patients and for further development and refinement of prediction models. Furthermore, knowledge on risk factors for cancer-related venous thrombosis may enhance the understanding of the pathophysiology of thrombosis in these patients.