The Vienna Prediction Model for identifying patients at low risk of recurrent venous thromboembolism: a prospective cohort study.

BACKGROUND AND AIMS: Patients with unprovoked venous thromboembolism (VTE) have a high recurrence risk, and guidelines suggest extended-phase anticoagulation. Many patients never experience recurrence but are exposed to bleeding. The aim of this study was to assess the performance of the Vienna Prediction Model (VPM) and to evaluate if the VPM accurately identifies these patients. METHODS: In patients with unprovoked VTE, the VPM was performed 3 weeks after anticoagulation withdrawal. Those with a predicted 1-year recurrence risk of ≤5.5% were prospectively followed. Study endpoint was recurrent VTE over 2 years. RESULTS: A total of 818 patients received anticoagulation for a median of 3.9 months. 520 patients (65%) had a predicted annual recurrence risk of ≤5.5%. During a median time of 23.9 months, 52 patients had non-fatal recurrence. The recurrence risk was 5.2% [95% confidence interval (CI) 3.2-7.2] at 1 year and 11.2% (95% CI 8.3-14) at 2 years. Model calibration was adequate after 1 year. The VPM underestimated the recurrence risk of patients with a 2-year recurrence rate of >5%. In a post-hoc analysis, the VPM's baseline hazard was recalibrated. Bootstrap validation confirmed an ideal ratio of observed and expected recurrence events. The recurrence risk was highest in men with proximal deep-vein thrombosis or pulmonary embolism and lower in women regardless of the site of incident VTE. CONCLUSIONS: In this prospective evaluation of the performance of the VPM, the 1-year rate of recurrence in patients with unprovoked VTE was 5.2%. Recalibration improved identification of patients at low recurrence risk and stratification into distinct low-risk categories.

Recurrence after stopping anticoagulants in women with combined oral contraceptive-associated venous thromboembolism: A systematic review and meta-analysis.

The risk of recurrence after discontinuation of anticoagulation for a combined oral contraceptive (COC)-associated venous thromboembolism (VTE) is unclear. Therefore, we conducted a systematic review and meta-analysis to estimate the incidence of recurrent VTE among women with COC-associated VTE, unprovoked VTE and to compare the incidence of recurrent VTE between the two groups. The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase Classic +Embase and Medline ALL to July 2020 and citations from included studies were searched. Randomized controlled trials, prospective cohort studies and meta-analyses of these study types were selected. The analysis was conducted by random-effects model. Nineteen studies were identified including 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% confidence interval (CI) 0.92-1.62, I2  = 6%] in women with COC-associated VTE, 3.89/100 PY (95% CI 2.93-5.17, I2  = 74%) in women with unprovoked VTE and the unadjusted incidence rate ratio was 0.34 (95% CI 0.26-0.46, I2  = 3%). The recurrence risk in women after COC-associated VTE is low and lower than after an unprovoked VTE.

Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Systematic Review and Meta-analysis.

BACKGROUND: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

Circumstances of provoked recurrent venous thromboembolism: the Austrian study on recurrent venous thromboembolism.

Patients with unprovoked deep-vein thrombosis (DVT) of the leg or pulmonary embolism (PE) have a high recurrence risk. How often these recurrences are provoked by a temporary risk condition is unknown. In a cohort of patients with unprovoked venous thromboembolism (VTE), we evaluated the clinical circumstances of recurrence. We studied patients with DVT of the leg and/or PE. End point was recurrence of objectively verified symptomatic VTE. Provoked recurrence was defined according to guidance criteria. 1188 patients were followed for a median of 8.9 years after withdrawal of oral anticoagulants. 312 patients had recurrent VTE, which was provoked in 42 (13%). Recurrence was related to a major risk factor in 19, to a minor risk factor in 22, and to a persistent risk factor in one patient(s). 14 recurrences occurred after major surgery and 5 during hospitalization. Ten recurrences occurred after minor surgery, eight after trauma and three during female hormone intake. Four recurrences occurred during heparin prophylaxis. The incidence of provoked VTE recurrence appears to be low. VTE can recur when prevention is stopped or even during thromboprophylaxis. Surgery and trauma are frequent risk factors.

Absorption of Direct Oral Anticoagulants in Cancer Patients after Gastrectomy.

Direct oral anticoagulants (DOACs) are safe and effective in cancer patients treated for venous thromboembolism (VTE) or atrial fibrillation (AF). Gastrectomy is the treatment of choice in patients with localized upper gastrointestinal cancer. DOACs are absorbed in the upper gastrointestinal tract, but to what extent is unclear. In a retrospective analysis, hospital data were searched for adult patients who underwent gastrectomy for gastroesophageal or pancreatic cancer, and DOAC therapy for VTE or AF after gastrectomy. DOAC blood levels were determined by chromogenic assays before and after administration, and thromboembolic and bleeding complications were recorded. Eleven patients (median age 76 years) received a factor Xa inhibitor (FXaI; apixaban (3), edoxaban (3), rivaroxaban (4)) or the factor IIa inhibitor dabigatran (1) for VTE (7) or AF (4) after gastrectomy. Eight patients on FXaI had anti-Xa (aXa) trough levels within the expected range (ER). In all of them, aXa levels increased upon DOAC administration. Two patients on 30 mg edoxaban had low aXa trough levels. Administration of 20 mg of rivaroxaban resulted in trough levels in the ER in one of them. None of the FXaI patients had thromboembolism, while two experienced bleeding (arterial puncture site, gastrointestinal). One dabigatran AF patient with trough and peak concentrations below the ER had strokes during 110 mg and 150 mg dabigatran administration. While on apixaban, aXa levels were in the ER, and no clinical complications occurred. DOACs, particularly FXaI, were adequately absorbed in cancer patients after gastrectomy. Our observation of recurrent thromboembolic events in a patient treated with dabigatran warrants cautious use in this specific patient population.

D-dimer levels over time after anticoagulation and the association with recurrent venous thromboembolism.

INTRODUCTION: D-dimer measured shortly after discontinuation of anticoagulation by an immunoturbidimetric assay predicts the risk of recurrent venous thromboembolism (VTE). We assessed the performance of this assay over time and its association with recurrent VTE. MATERIALS AND METHODS: We followed 556 patients with a first VTE for a median of 9.6 years. The study end point was recurrent VTE. D-dimer was measured 3 weeks, and 3, 9, and 15 months after discontinuation of anticoagulation in plasma using an immunoturbidimetric assay (INNOVANCE D-Dimer). To estimate the effect of longitudinal D-dimer on the recurrence risk, we used a dynamic prediction Cox model with landmark times (3 weeks, and 3, 9, 15 months) as a stratification factor. RESULTS: 135 patients had recurrent VTE. D-dimer levels varied between patients but without a consistent pattern. Levels increased slightly over time [0.7% increase (95% CI: 0.5-0.9; p < 0.001)/month]. D-dimer levels were positively correlated with body mass index (BMI) [2% (95% CI: 1.1-2.9; p < 0.001) increase/1 unit BMI increase], and were 14.8% (95% CI: 5.1-25.3; p = 0.002) higher in women than in men. The recurrence risk with doubling D-dimer levels was higher after 3 weeks, 3, 9 and 15 months [hazard ratios 1.4 (1.06-1.84), 1.37 (1.06-1.77), 1.31 (1.04-1.65) and 1.26 (1.01-1.57), respectively]. CONCLUSIONS: In patients with a first VTE, immunoturbidimetric D-dimer levels are associated with the risk of recurrence at multiple times points from 3 weeks up to 15 months after discontinuation of oral anticoagulation.

Long-term risk of recurrent venous thromboembolism among patients receiving extended oral anticoagulant therapy for first unprovoked venous thromboembolism: A systematic review and meta-analysis.

BACKGROUND: The long-term risk for recurrent venous thromboembolism (VTE) during extended anticoagulation for a first unprovoked VTE is uncertain. OBJECTIVES: To determine the incidence of recurrent VTE during extended anticoagulation of up to 5 years in patients with a first unprovoked VTE. METHODS: MEDLINE, EMBASE, and the Cochrane CENTRAL were searched to identify randomized trials and prospective cohort studies reporting recurrent VTE among patients with a first unprovoked VTE who were to receive anticoagulation for a minimum of six additional months after completing ≥3 months of initial treatment. Unpublished data on number of recurrent VTE and person-years, obtained from authors of included studies, were used to calculate study-level incidence rate, and random-effects meta-analysis was used to pool results. RESULTS: Twenty-six studies and 15 603 patients were included in the analysis. During 11 631 person-years of follow-up, the incidence of recurrent VTE and fatal pulmonary embolism per 100 person-years was 1.41 (95% CI, 1.03-1.84) and 0.09 (0.04-0.16), with 5-year cumulative incidences of 7.1% (3.0%-13.2%) and 1.2% (0.4%-4.6%), respectively. The incidence of recurrent VTE was 1.08 (95% CI, 0.77-1.44) with direct oral anticoagulants and 1.55 (1.01-2.20) with vitamin K antagonists. The case-fatality rate of recurrent VTE was 4.9% (95% CI, 2.2%-8.7%). CONCLUSIONS: In patients with a first unprovoked VTE, the long-term risk of recurrent VTE during extended anticoagulation is low but not negligible. Thus, clinicians and patients should be aware of this risk and take appropriate and timely action in case of suspicion of recurrent VTE. Estimates from this study can be used to advise patients on what to expect while receiving extended anticoagulation, and estimate the net clinical benefit of extended treatment to guide long-term management of unprovoked VTE.

Factor XI and recurrent venous thrombosis: an observational cohort study.

Essentials Factor XI is a potential target for anticoagulation. The association between factor XI and venous thrombosis recurrence was tested in a cohort study. Low factor XI was associated with reduced risk of recurrent venous thrombosis. A sex-and age-adjusted linear association between D-Dimer and factor XI was found. SUMMARY: Background and objectives Low factor XI activity (FXIa) reduces the risk of venous thromboembolism (VTE), and FXI is regarded as a potential target for anticoagulation. Patients/methods We studied the relationship between FXIa and VTE in 851 patients with unprovoked VTE in whom anticoagulation had been stopped. Results Recurrent VTE was recorded in 265 patients. The sex-adjusted and age-adjusted hazard ratio (HR) of recurrence was 0.94 (95% confidence interval [CI] 0.89-0.99) for each decrease of 10 IU dL-1 in FXIa. The HRs of recurrence were 0.73 (95% CI 0.54-0.99) for patients with FXIa below the 34th percentile, and 1.05 (95% CI 0.79-1.39) for patients with FXIa between the 34th and 67th percentiles, as compared with patients with higher FXIa. The probability of recurrence was lower among patients with FXIa below the 34th percentile than in patients with higher FXIa (P = 0.029). At 10 years, the probabilities of recurrence were 31%, 43% and 41% among patients with FXIa below the 34th percentile, with FXIa between the 34th and 67th percentiles, or with higher FXIa, respectively. We found a significant sex-adjusted and age-adjusted linear association between D-dimer levels, measured 3 weeks after anticoagulation, and FXIa. When patients' age and sex are taken into account, a patient with 10 IU dL-1 lower FXIa is expected to have a 2.79% (95% CI 0.95-4.59%) lower D-dimer value (P = 0.003). Conclusions Our findings of a lower thrombosis risk and less pronounced hemostatic system activation among patients with low FXIa is in line with the concept that FXI is a promising target for anticoagulation.

Risk of venous thromboembolism during rehabilitation of patients with spinal cord injury.

BACKGROUND: Patients with spinal cord injury (SCI) are at risk of thrombosis and bleeding. Data on the risks during rehabilitation are inconsistent, and thromboprophylactic strategies are heterogeneous. We aimed to evaluate the thrombotic risk and bleeding events of SCI patients during rehabilitation. METHODS: We retrospectively collected hospital record data of 263 consecutive SCI patients admitted at a rehabilitation clinic. 78 patients with acute venous thromboembolism (VTE) at the primary center, without acute trauma or lower extremity paresis, less than one month rehabilitation, or reasons for long-term therapeutic anticoagulation, were excluded. All patients received pharmacologic thromboprophylaxis throughout rehabilitation. Primary endpoint was objectively diagnosed VTE; secondary endpoint was bleeding. RESULTS: Of 185 patients, 162 (88%) were men; mean age was 47.8 years. 94 patients were tetraplegic, 91 paraplegic. During a mean (±SD) time of 5.1±2.1 months, VTE was diagnosed in 8 patients. After excluding five patients with VTE detected within 2 days after admission, the probability of developing VTE after 6 months of rehabilitation was 2% (95% CI 0-4.4%). Only high D-Dimer upon admission was associated with risk of VTE (adjusted HR 2.3, 95% CI 1.4-4.1). Of 24 bleedings, 14 (64%) occurred at the heparin injection site. Two patients had major bleeding and five had clinically relevant non major bleeding. CONCLUSION: SCI patients are at risk of VTE and bleeding during rehabilitation. Strategies need to be developed to identify these patients in order to initiate adequate anticoagulation. Direct oral anticoagulants, which have a favourable risk-benefit profile and are convenient, should be explored.

Prediction of recurrent venous thromboembolism by clot lysis time: a prospective cohort study.

Venous thromboembolism (VTE) is a chronic disease, which tends to recur. Whether an abnormal fibrinolytic system is associated with an increased risk of VTE is unclear. We assessed the relationship between fibrinolytic capacity (reflected by clot lysis time [CLT]) and risk of recurrent VTE. We followed 704 patients (378 women; mean age 48 yrs) with a first unprovoked VTE for an average of 46 months after anticoagulation withdrawal. Patients with natural coagulation inhibitor deficiency, lupus anticoagulant, cancer, homozygosity for factor V Leiden or prothrombin mutation, or requirement for indefinite anticoagulation were excluded. Study endpoint was symptomatic recurrent VTE. For measurement of CLT, a tissue factor-induced clot was lysed by adding tissue-type plasminogen activator. Time between clot formation and lysis was determined by measuring the turbidity. 135 (19%) patients had recurrent VTE. For each increase in CLT of 10 minutes, the crude relative risk (RR) of recurrence was 1.13 (95% CI 1.02-1.25; p = 0.02) and was 1.08 (95% CI 0.98-1.20; p = 0.13) after adjustment for age and sex. For women only, the adjusted RR was 1.14 (95% CI, 0.91-1.42, p = 0.22) for each increase in CLT of 10 minutes. CLT values in the 4(th) quartile of the female patient population, as compared to values in the 1(st) quartile, conferred a risk of recurrence of 3.28 (95% CI, 1.07-10.05; p = 0.04). No association between CLT and recurrence risk was found in men. Hypofibrinolysis as assessed by CLT confers a moderate increase in the risk of recurrent VTE. A weak association between CLT and risk of recurrence was found in women only.

Hematocrit and the risk of recurrent venous thrombosis: a prospective cohort study.

BACKGROUND: Venous thromboembolism (VTE) is a multicausal disease which recurs. Hematocrit is associated with a thrombotic risk. We aimed to investigate if hematocrit is associated with the recurrence risk. METHODS: Patients with a first VTE were followed after anticoagulation. Patients with VTE provoked by a transient risk factor, natural inhibitor deficiency, lupus anticoagulant, homozygous or double heterozygous defects, cancer, or long-term antithrombotic treatment were excluded. The study endpoint was recurrent VTE. RESULTS: 150 (23%) of 653 patients had recurrence. Only high hematocrit was significantly associated with recurrence risk [hazard ratio (HR) for 1% hematocrit increase with the third tertile 1.08; 95% CI 1.01-1.15]. No or only a weak association for hematocrits within the first and second tertile was seen (HR 1.03; 95% CI 0.97-1.09, and 1.07; 95% CI 1.00-1.13). Hematocrit was associated with recurrence risk only among women. After five years, the probability of recurrence was 9.9% (95% CI 3.7%-15.7%), 15.6% (95% CI 9.7%-21.2%) and 25.5% (95% CI 15.1%-34.6%) in women, and was 29.2% (95% CI 21.1%-36.5%), 30.1% (95% CI 24.1%-35.7%) and 30.8% (95% CI 22.0%-38.7%) in men for hematocrits in the first, second and third tertile, respectively. Men had a higher recurrence risk (1.9; 95% CI 1.1-2.7; p = 0.03), which dropped by 23.5% after adjustment for hematocrit. Hematocrit was not a significant mediator of the sex-difference in recurrence risk (p = 0.223). CONCLUSIONS: High hematocrit is associated with the recurrence only in women. The different recurrence risk between men and women is possibly partly explained by hematocrit.

Age at first venous thromboembolism and risk of recurrence: a prospective cohort study.

Risk of first venous thromboembolism (VTE) increases with age. We investigated whether age is related to the risk of recurrent VTE. We followed 694 patients for a mean of 40 months after first unprovoked proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and withdrawal of anticoagulants. We excluded patients with natural inhibitor deficiency, lupus anticoagulant, or cancer; patients who required indefinite anticoagulation; pregnant women; and women who had VTE related to female hormone use. The endpoint was symptomatic recurrent VTE.VTE recurred in 152 patients (22%). The adjusted hazard ratio (HR) of recurrence for a 10-year increase in age was 0.94 (95% confidence interval [CI], 0.82-1.08; p = 0.4). Compared with patients aged younger than 47 years (1st tercile of patient population) no significant increase in the risk of recurrent VTE was found among patients 47-61 years old (2nd tercile) or patients older than 61 years (3rd tercile) ([HR, 1.25; 95% CI, 0.78-2.01] and [HR, 0.93l; 95% CI, 0.56-1.53], respectively). Compared to patients older than 80 years, the HR of recurrence among patients younger than 50 years was 1.11 (95% CI, 0.11-10.3; p = 0.9). After 5 years, probability of recurrence was 32% (95% CI, 24%-40%) among patients aged less than 47 years; 21% (95% CI, 15%-28%) among patients 47-61 years old; and 33% (95% CI, 24%-42%) among patients older than 61 years (p = 0.5).Our results show that in patients with first unprovoked proximal DVT and/or PE, risk of recurrence is not related to age at first VTE. Regardless of age, these patients have a high risk of recurrence.