D-dimer levels during and after anticoagulation withdrawal in patients with venous thromboembolism treated with non-Vitamin K anticoagulants

Background D-dimer levels measured during and after vitamin K antagonist withdrawal may be used in clinical practice to assess the individual risk of recurrent venous thromboembolism. Currently, direct oral anticoagulants (DOACs) are frequently used in venous thromboembolism treatment; however, their pharmacokinetics and pharmacodynamics characteristics are completely different than vitamin K antagonists. The present study aimed at comparing the results of D-dimer levels during and after anticoagulation withdrawal in patients with venous thromboembolism treated with DOACs or warfarin. Material and methods D-dimer levels were measured in 527 patients (\u201ccases\u201d) during DOACs treatment (T0) and after 15 (T15), 30 (T30), 60 (T60) and 90 (T90) days after their discontinuation and in 527 patients (\u201ccontrols\u201d) enrolled in the DULCIS study (all treated with warfarin), matched for sex, age (+/-3 y), type of D-dimer assay and site of venous thromboembolism. Both cases and controls received anticoagulant treatment after a first venous thromboembolism event that was unprovoked or associated with weak risk factors. Results The rate of positive D-dimer results was significantly higher in cases than in controls at T0 (10.8% vs 5.1%, p = 0.002) and at T30 (18.8% vs 11.8%, p = 0.019), as well as at the other time-points, though not statistically significant. Conclusion D-dimer levels during and after stopping an anticoagulant treatment for a venous thromboembolism episode differ between patients treated with a DOAC than in those treated with warfarin. Specifically designed prospective studies are warranted to reassess the use of D-dimer as predictor of the risk of recurrent venous thromboembolism in patients treated with DOACs

Clinical outcomes during anticoagulant therapy in fragile patients with venous thromboembolism.

Subgroup analyses from randomized trials suggested favorable results for the direct oral anticoagulants in fragile patients with venous thromboembolism (VTE). The frequency and natural history of fragile patients with VTE have not been studied yet. To compare the clinical characteristics, treatment and outcomes during the first 3 months of anticoagulation in fragile vs non-fragile patients with VTE. Retrospective study using consecutive patients enrolled in the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry. Fragile patients were defined as those having age ≥75 years, creatinine clearance (CrCl) levels ≤50 mL/min, and/or body weight ≤50 kg. From January 2013 to October 2016, 15 079 patients were recruited. Of these, 6260 (42%) were fragile: 37% were aged ≥75 years, 20% had CrCl levels ≤50 mL/min, and 3.6% weighed ≤50 kg. During the first 3 months of anticoagulant therapy, fragile patients had a lower risk of VTE recurrences (0.78% vs 1.4%; adjusted odds ratio [OR]: 0.52; 95% confidence intervals [CI]: 0.37-0.74) and a higher risk of major bleeding (2.6% vs 1.4%; adjusted OR: 1.41; 95% CI: 1.10-1.80), gastrointestinal bleeding (0.86% vs 0.35%; adjusted OR: 1.84; 95% CI: 1.16-2.92), haematoma (0.51% vs 0.07%; adjusted OR: 5.05; 95% CI: 2.05-12.4), all-cause death (9.2% vs 3.5%; adjusted OR: 2.02; 95% CI: 1.75-2.33), or fatal PE (0.85% vs 0.35%; adjusted OR: 1.77; 95% CI: 1.10-2.85) than the non-fragile. In real life, 42% of VTE patients were fragile. During anticoagulation, they had fewer VTE recurrences and more major bleeding events than the non-fragile

Thrombocytopenia and Mortality Risk in Patients With Atrial Fibrillation: An Analysis From the START Registry

Background: Thrombocytopenia is associated with increased mortality in the general population, but few data exist in patients with atrial fibrillation (AF) taking oral anticoagulants. We investigated factor determinants of thrombocytopenia in a large cohort of patients affected by AF and its association with total mortality. Methods and Results: Multicenter prospective cohort study, including 5215 patients with AF from the START (Survey on Anticoagulated Patients Register) registry, 3877 (74.3%) and 1338 (25.7%) on vitamin K or non\u2013vitamin K antagonist oral anticoagulants, respectively. Thrombocytopenia was defined by a platelet count <150 7109/L. Determinants of thrombocytopenia were investigated, and all-cause mortality was the primary survival end point of the study. Thrombocytopenia was present in 592 patients (11.4%). At multivariable logistic regression analysis, chronic kidney disease (odds ratio [OR], 1.257; P=0.030), active cancer (OR, 2.065; P=0.001), liver cirrhosis (OR, 7.635; P<0.001), and the use of diuretics (OR, 1.234; P=0.046) were positively associated with thrombocytopenia, whereas female sex (OR, 0.387; P<0.001) and the use of calcium channel blockers (OR, 0.787; P=0.032) were negatively associated. During a median follow-up of 19.2 months (9942 patient-years), 391 deaths occurred (rate, 3.93%/year). Mortality rate increased from 3.8%/year to 9.9%/year in patients with normal platelet count and in those with moderate-severe thrombocytopenia, respectively (log-rank test, P=0.009). The association between moderate-severe thrombocytopenia and mortality persisted after adjustment for CHA2DS2 VASc score (hazard ratio, 2.431; 95% CI, 1.254\u20134.713; P=0.009), but not in the fully adjusted multivariable Cox regression analysis model. Conclusions: Thrombocytopenia is common in patients with AF. Despite an increased incidence of mortality, thrombocytopenia was not associated with mortality at multivariable analysis. Thrombocytopenia may reflect the presence of comorbidities associated with poor survival in AF

Comparison of anticoagulation quality between acenocoumarol and warfarin in patients with mechanical prosthetic heart valves: Insights from the nationwide PLECTRUM study

Vitamin K antagonists are indicated for the thromboprophylaxis in patients with mechanical prosthetic heart valves (MPHV). However, it is unclear whether some differences between acenocoumarol and warfarin in terms of anticoagulation quality do exist. We included 2111 MPHV patients included in the nationwide PLECTRUM registry. We evaluated anticoagulation quality by the time in therapeutic range (TiTR). Factors associated with acenocoumarol use and with low TiTR were investigated by multivariable logistic regression analysis. Mean age was 56.8 ± 12.3 years; 44.6% of patients were women and 395 patients were on acenocoumarol. A multivariable logistic regression analysis showed that patients on acenocoumarol had more comorbidities (i.e., ≥3, odds ratio (OR) 1.443, 95% confidence interval (CI) 1.081-1.927, p = 0.013). The mean TiTR was lower in the acenocoumarol than in the warfarin group (56.1 ± 19.2% vs. 61.6 ± 19.4%, p < 0.001). A higher prevalence of TiTR (<60%, <65%, or <70%) was found in acenocoumarol users than in warfarin ones (p < 0.001 for all comparisons). Acenocoumarol use was associated with low TiTR regardless of the cutoff used at multivariable analysis. A lower TiTR on acenocoumarol was found in all subgroups of patients analyzed according to sex, hypertension, diabetes, age, valve site, atrial fibrillation, and INR range. In conclusion, anticoagulation quality was consistently lower in MPHV patients on acenocoumarol compared to those on warfarin

Rate and duration of hospitalisation for acute pulmonary embolism in the real-world clinical practice of different countries : Analysis from the RIETE registry

publishersversionPeer reviewe

Low in‑hospital mortality rate in patients with COVID‑19 receiving thromboprophylaxis: data from the multicentre observational START‑COVID Register

Abstract COVID-19 infection causes respiratory pathology with severe interstitial pneumonia and extra-pulmonary complications; in particular, it may predispose to thromboembolic disease. The current guidelines recommend the use of thromboprophylaxis in patients with COVID-19, however, the optimal heparin dosage treatment is not well-established. We conducted a multicentre, Italian, retrospective, observational study on COVID-19 patients admitted to ordinary wards, to describe clinical characteristic of patients at admission, bleeding and thrombotic events occurring during hospital stay. The strategies used for thromboprophylaxis and its role on patient outcome were, also, described. 1091 patients hospitalized were included in the START-COVID-19 Register. During hospital stay, 769 (70.7%) patients were treated with antithrombotic drugs: low molecular weight heparin (the great majority enoxaparin), fondaparinux, or unfractioned heparin. These patients were more frequently affected by comorbidities, such as hypertension, atrial fibrillation, previous thromboembolism, neurological disease,and cancer with respect to patients who did not receive thromboprophylaxis. During hospital stay, 1.2% patients had a major bleeding event. All patients were treated with antithrombotic drugs; 5.4%, had venous thromboembolism [30.5% deep vein thrombosis (DVT), 66.1% pulmonary embolism (PE), and 3.4% patients had DVT + PE]. In our cohort the mortality rate was 18.3%. Heparin use was independently associated with survival in patients aged ≥ 59 years at multivariable analysis. We confirmed the high mortality rate of COVID-19 in hospitalized patients in ordinary wards. Treatment with antithrombotic drugs is significantly associated with a reduction of mortality rates especially in patients older than 59 years

Rivaroxaban treatment for six weeks versus three months in patients with symptomatic isolated distal deep vein thrombosis: Randomised controlled trial

Objective: To compare two different treatment durations of rivaroxaban in patients with symptomatic isolated distal deep vein thrombosis (DVT). Design: Randomised, double blind, placebo controlled clinical trial. Setting: 28 outpatient clinics specialising in venous thromboembolism. Participants: 402 adults (≥18 years) with symptomatic isolated distal DVT. Interventions: After receiving standard dose rivaroxaban for six weeks, participants were randomly assigned to receive rivaroxaban 20 mg or placebo once daily for an additional six weeks. Follow-up was for 24 months from study inclusion. Main outcomes measures: The primary efficacy outcome was recurrent venous thromboembolism during follow-up after randomisation, defined as the composite of progression of isolated distal DVT, recurrent isolated distal DVT, proximal DVT, symptomatic pulmonary embolism, or fatal pulmonary embolism. The primary safety outcome was major bleeding after randomisation until two days from the last dose of rivaroxaban or placebo. An independent committee adjudicated the outcomes. Results: 200 adults were randomised to receive additional rivaroxaban treatment and 202 to receive placebo. Isolated distal DVT was unprovoked in 81 (40%) and 86 (43%) patients, respectively. The primary efficacy outcome occurred in 23 (11%) patients in the rivaroxaban arm and 39 (19%) in the placebo arm (relative risk 0.59, 95% confidence interval 0.36 to 0.95; P=0.03, number needed to treat 13, 95% confidence interval 7 to 126). Recurrent isolated distal DVT occurred in 16 (8%) patients in the rivaroxaban arm and 31 (15%) in the placebo arm (P=0.02). Proximal DVT or pulmonary embolism occurred in seven (3%) patients in the rivaroxaban arm and eight (4%) in the placebo arm (P=0.80). No major bleeding events occurred. Conclusions: Rivaroxaban administered for six additional weeks in patients with isolated distal DVT who had an uneventful six week treatment course reduces the risk of recurrent venous thromboembolism, mainly recurrent isolated distal DVT, over a two year follow-up without increasing the risk of haemorrhage. Trial registration: EudraCT 2016-000958-36; ClinicalTrials.gov NCT02722447

Risk factors for recurrent events in subjects with superficial vein thrombosis in the randomized clinical trial SteFlux (Superficial Thromboembolism Fluxum)

Background/Aims: To evaluate risk factors for recurrent events in patients enrolled in the SteFlux (Superficial Thromboembolism Fluxum) clinical trial which compared different doses and duration of low molecular weight heparin (parnaparin) for superficial vein thrombosis (SVT). Materials and Methods: Outpatients with acute SVT of at least 4 cm in length of the internal or external saphenous veins or their collaterals were randomized in a double blind fashion to receive either parnaparin 8500 UI aXa od for ten days followed by placebo for 20 days or 8500 UI aXa od for ten days followed by 6400 UI aXa od for 20 days or 4250 UI aXa od for 30 days. Outcomes were the composite of symptomatic and asymptomatic deep vein thrombosis, pulmonary embolism and SVT recurrence or extension in the first 30+/-3 days with a 60+/-3 day follow-up. Results: 98 outcomes (14.7\%) were recorded during 93 days among 664 patients (M/F: 246/418, mean age 65). After correction for treatment, outcomes during 33 days were associated with previous venous thromboembolism (VTE) and/or SVT and/or family history of VTE (odds ratio-OR: 2.5; 95\% confidence interval -CI: 1.4-4.8; p = 0.003). After stopping LMWH treatment, only the absence of varicose veins (OR: 2.5; 95\% CI 1.3-5.0; p = 0.004) and previous VTE and/or SVT and/or family history of VTE (OR: 1.9; 95\% CI: 1.0-3.7; p = 0.048) were significantly associated with outcomes. Conclusions: SVT patients with these factors may deserve a higher intensity and/or longer anticoagulant treatment. (C) 2013 Elsevier Ltd. All rights reserved

D-dimer and reduced dose apixaban for extended treatment after unprovoked venous thromboembolism: the Apidulcis study.

D-dimer assay is used to stratify patients with unprovoked venous thromboembolism (VTE) for the risk of recurrence. However, this approach was never evaluated since direct oral anticoagulants are available. With this multicenter, prospective cohort study we aimed at assessing the value of an algorithm incorporating serial D-dimer testing and administration of reduced dose apixaban (2.5 mg twice daily) only to patients with positive test. 732 outpatients aged 18 to 74 years, anticoagulated for at least 12 months after a first unprovoked VTE were included. Patients underwent D-dimer testing with commercial assays and pre-established cutoffs. If the baseline D-dimer, during anticoagulation, was negative, anticoagulation was stopped and testing repeated after 15, 30, and 60 days. Patients with serially negative results (286; 39.1%) were left without anticoagulation. At first positive result, the remaining 446 patients (60.9%) were given apixaban for 18 months. All patients underwent follow-up planned for 18 months. The study was interrupted after a planned interim analysis for the high rate of primary outcomes (7.3%; 95% CI, 4.5 to 11.2), including symptomatic proximal DVT or PE recurrence, death for VTE, major bleeding, occurring in patients off anticoagulation, versus that in those receiving apixaban (1.1%; 95% CI, 0.4 to 2.6; adjusted HR, 8.2; 95% CI, 3.2 to 25.3). In conclusion, in patients anticoagulated for at least one year after a first unprovoked VTE, the decision whether to further extend anticoagulation should not be based on D-dimer testing. The results confirmed the high efficacy and safety of reduced dose apixaban against recurrences. ClinTrials.gov: NCT03678506