Summary: Introduction: D‐dimer assay, generally evaluated according to cutoff points calibrated for VTE exclusion, is used to estimate the individual risk of recurrence after a first idiopathic event of venous thromboembolism (VTE).Methods: Commercial D‐dimer assays, evaluated according to predetermined cutoff levels for each assay, specific for age (lower in subjects <70 years) and gender (lower in males), were used in the recent DULCIS study. The present analysis compared the results obtained in the DULCIS with those that might have been had using the following different cutoff criteria: traditional cutoff for VTE exclusion, higher levels in subjects aged ≥60 years, or age multiplied by 10.Results: In young subjects, the DULCIS low cutoff levels resulted in half the recurrent events that would have occurred using the other criteria. In elderly patients, the DULCIS results were similar to those calculated for the two age‐adjusted criteria. The adoption of traditional VTE exclusion criteria would have led to positive results in the large majority of elderly subjects, without a significant reduction in the rate of recurrent event.Conclusion: The results confirm the usefulness of the cutoff levels used in DULCIS.

The optimal duration of oral anticoagulation in patients with idiopathic venous thromboembolism is uncertain. Testing of d-dimer levels may play a role in the assessment of the need for prolonged anticoagulation. We performed d-dimer testing 1 month after the discontinuation of anticoagulation in patients with a first unprovoked proximal deep-vein thrombosis or pulmonary embolism who had received a vitamin K antagonist for at least 3 months. Patients with a normal d-dimer level did not resume anticoagulation, whereas those with an abnormal d-dimer level were randomly assigned either to resume or to discontinue treatment. The study outcome was the composite of recurrent venous thromboembolism and major bleeding during an average follow-up of 1.4 years. The d-dimer assay was abnormal in 223 of 608 patients (36.7%). A total of 18 events occurred among the 120 patients who stopped anticoagulation (15.0%), as compared with 3 events among the 103 patients who resumed anticoagulation (2.9%), for an adjusted hazard ratio of 4.26 (95% confidence interval [CI], 1.23 to 14.6; P=0.02). Thromboembolism recurred in 24 of 385 patients with a normal d-dimer level (6.2%). Among patients who stopped anticoagulation, the adjusted hazard ratio for recurrent thromboembolism among those with an abnormal d-dimer level, as compared with those with a normal d-dimer level, was 2.27 (95% CI, 1.15 to 4.46; P=0.02). Patients with an abnormal d-dimer level 1 month after the discontinuation of anticoagulation have a significant incidence of recurrent venous thromboembolism, which is reduced by the resumption of anticoagulation. The optimal course of anticoagulation in patients with a normal d-dimer level has not been clearly established. (ClinicalTrials.gov number, NCT00264277.)

Summary: In some patients with previous venous thromboembolism (VTE) D-dimer levels (D-Dimer) tend to increase after oral anticoagulant therapy (OAT) is stopped. The aim of our study was to evaluate the predictive value of D-Dimer for the risk of VTE recurrence after OAT withdrawal. After a first episode of deep vein thrombosis (DVT) of the lower limbs and/or pulmonary embolism (PE), 396 patients (median age 67 years, 198 males) were followed from the day of OAT discontinuation for 21 months. D-dimer was measured on the day of OAT withdrawal (T1), 3-4 weeks (T2) and 3 months (+/− 10 days, T3) thereafter. The main outcome events of the study were: objectively documented recurrent DVT and/or PE. D-dimer was found to be increased in 15.5%, 40.3% and 46.2% of the patients at T1, T2 and T3, respectively. In 199 (50.2%) patients, D-dimer levels were elevated in at least one measurement. During a follow-up of 628.4 years, 40 recurrences were recorded (10.1% of patients; 6.4% patient-years of follow-up). D-dimer was increased in at least one measurement in 28 of these cases, but remained normal in 11 subjects (three of whom had recurrent events triggered by circumstantial factors, three with malignancyassociated factors) (in one subject D-dimer was not measured). The negative predictive value (NPV) of D-dimer was 95.6% (95% CI 91.6-98.1) at T3 and was even higher (96.7%; 95% CI 92.9-98.8) after exclusion of the six recurrences due to circumstantial factors. Only five idiopathic recurrences occurred in the 186 patients with consistently normal D-dimer. In conclusion, D-dimer has a high NPV for VTE recurrence when performed after OAT discontinuation.

Background— We have shown that normal D-dimer levels obtained after the discontinuation of oral anticoagulant treatment (OAT) has a high negative predictive value for recurrent venous thromboembolism (VTE). The aim of the present study was to assess the predictive value of D-dimer for recurrent VTE in subjects with a previous unprovoked event who are either carriers of inherited thrombophilia or not. Methods and Results— We prospectively evaluated 599 patients (301 males) with a previous VTE episode. They were repeatedly examined for D-dimer levels after OAT withdrawal and were screened for inherited thrombophilic alterations. Alterations were detected in 130 patients (21.7%), factor V Leiden (70 patients; 2 of whom were homozygotes) and prothrombin mutation (38 patients) were the most prevalent ones. Recurrent events were recorded in 58 subjects (9.7%) during a follow-up of 870.7 patient-years. Altered D-dimer levels at 1 month after OAT withdrawal were associated with a higher rate of subsequent recurrence in all subjects investigated, especially in those with an unprovoked qualifying VTE event (hazard ratio, 2.43; 95% confidence interval, 1.18 to 4.61) and in those with thrombophilia (hazard ratio, 8.34; 95% confidence interval, 2.72 to 17.43). The higher relative risk for recurrence of altered D-dimer was confirmed by multivariate analysis after adjustment for other risk factors. The negative predictive value of D-dimer was 92.9% and 95.8% in subjects with an unprovoked qualifying event or with thrombophilia, respectively. Conclusions— D-dimer levels measured 1 month after OAT withdrawal have a high negative predictive value for recurrence in subjects with unprovoked VTE who are either carriers or not carriers of congenital thrombophilia.

Summary: Anticoagulation with vitamin K antagonists (VKAs) has been shown to be effective in the prevention and treatment of thrombotic complications in various clinical settings, including atrial fibrillation (AF), venous thromboembolism (VTE), acute coronary syndromes and after invasive cardiac procedures. Bleeding is the most important complication of VKAs and a major concern for both physicians and patients. The occurrence of bleeding during treatment is not only important for the treated subjects, but also for a correct and complete use of this therapy in all the subjects who have a clear clinical indication for anticoagulation. This review analyses the treatment- and person- associated risk factors for bleeding during VKAs and their combination in clinical prediction rules that have been proposed in the attempt to identify those patients at higher risk for bleeding. The clinical prediction rules may help physicians stratify patients into categories of risk and thus to evaluate their individual risk/benefit ratio of starting or prolonging an anticoagulant treatment.

Summary: The optimal long-term treatment of acute venous thromboembolism (VTE) in patients with malignancy remains undefined. In particular, based on current evidence, it is uncertain whether secondary prophylaxis using standard intensity oral anticoagulant therapy is associated with higher risks of bleeding and recurrent thrombosis in patients with cancer than in those without cancer. This study compared the outcome of anticoagulation courses in 95 patients with malignancy with those of 733 patients without malignancy. All patients were participants in a large, nation-wide population study and were prospectively followed from the initiation of their oral anticoagulant therapy.Based on 744 patient-years of treatment and follow-up, the rates of major (5.4% vs 0.9%), minor (16.2% vs 3.6%) and total (21.6% vs 4.5%) bleeding were statistically significantly higher in cancer patients compared with patients without cancer. Bleeding was also a more frequent cause of early anticoagulation withdrawal in patients with malignancy (4.2% vs. 0.7%; p <0.01; RR 6.2 (95%CI 1.95-19.4). There was a trend towards a higher rate of thrombotic complications in cancer patients (6.8% vs. 2.5%; p = 0.058; RR 2.5 [CI 0.96-6.5]) but this did not achieve statistical significance. In the group of patients with cancer, the bleeding rate was high across the different INR categories and was independent of the temporally associated International Normalized Ratio (INR). In contrast, the bleeding rate was increased only with INR values greater than 4.5 in the group of patients without cancer. The rate of thrombotic events was significantly higher in both cohorts when the INR was less than 2.0.In conclusion, patients with malignancy treated with oral anticoagulants have a higher rate of bleeding and possibly an increased risk of recurrent thrombosis compared with patients without malignancy. Safer and more effective anticoagulant therapy is needed for this challenging group of patients.