The recent clinical trials on use of the novel direct oral anticoagulants in patients with venous thromboembolism: a review

Venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism, requires an immediate anticoagulation, that has been carried out so far by administering a parenteral anticoagulant drug (heparin or derivatives) overlapped with an oral vitamin K antagonist (VKA), more often warfarin. Several new direct oral anticoagulants (DOACs), with a mechanism of action completely different than VKA, have been developed in recent years. Recent clinical trials have investigated their use in VTE patients showing results at least equal for efficacy and safety, and sometime even better, as the standard anticoagulant treatment. There are differences in the design of the trials. In two cases the involved DOAC was administered immediately after VTE diagnosis as a single drug treatment (rivaroxaban and apixaban), whereas in the other trials (involving dabigatran and edoxaban) the DOAC was administered after an initial course of approximately 7 days with heparin or derivatives. Some clinical trials have also investigated the use of DOACs for extended anticoagulant treatment after the acute phase. Aim of this article is to review the results of the currently available clinical trials that have compared the use of DOACs versus the standard of care in patients with VTE

The American College of Chest Physician score to assess the risk of bleeding during anticoagulation in patients with venous thromboembolism: reply

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Optimal duration of anticoagulant therapy in patients with venous thromboembolism

Venous thromboembolism, a frequent and severe disease, has clinically important early and late complications and a strong tendency to recur. Anticoagulant therapy is the mainstay of treatment, performed by immediate administration of: i) parenteral anticoagulants followed by vitamin K antagonists, either dabigatran or edoxaban, two direct oral anticoagulants (DOACs); or ii) direct rivaroxaban or apixaban, two DOACs that can be used as single-drug approach. Treatment should last no less than 3 months in all patients though how long it should last thereafter is a more complex issue. The risk of recurrence results from several event- or patient-associated factors. Some patients have low risk and may be treated for 3 to 6 months only. Others (the majority) have a high risk of recurrence (approximately 50% in 10 years). Unfortunately, the protective effect of anticoagulation against recurrence is present only during treatment and is lost when therapy is stopped. For this reason, international guidelines recommend that there is no pre-definite period of anticoagulation (e.g. 1 or 2 years, and so on) in patients at high risk and suggest instead indefinite (extended) anticoagulation, provided there is no high risk of bleeding. When the decision is difficult, adjunctive criteria may be adopted, such as male sex and abnormal D-dimer assessed after anticoagulation is stopped, to identify patients at high risk who need indefinite therapy. The use of DOACs, especially at lower doses with a lower risk of bleeding, may make indefinite anticoagulation for patients easier

Clinical Phenotypes of Atrial Fibrillation and Mortality Risk—A Cluster Analysis from the Nationwide Italian START Registry

: Patients with atrial fibrillation (AF) still experience a high mortality rate despite optimal antithrombotic treatment. We aimed to identify clinical phenotypes of patients to stratify mortality risk in AF. Cluster analysis was performed on 5171 AF patients from the nationwide START registry. The risk of all-cause mortality in each cluster was analyzed. We identified four clusters. Cluster 1 was composed of the youngest patients, with low comorbidities; Cluster 2 of patients with low cardiovascular risk factors and high prevalence of cancer; Cluster 3 of men with diabetes and coronary disease and peripheral artery disease; Cluster 4 included the oldest patients, mainly women, with previous cerebrovascular events. During 9857 person-years of observation, 386 deaths (3.92%/year) occurred. Mortality rates increased across clusters: 0.42%/year (cluster 1, reference group), 2.12%/year (cluster 2, adjusted hazard ratio (aHR) 3.306, 95% confidence interval (CI) 1.204-9.077, p = 0.020), 4.41%/year (cluster 3, aHR 6.702, 95%CI 2.433-18.461, p < 0.001), and 8.71%/year (cluster 4, aHR 8.927, 95%CI 3.238-24.605, p < 0.001). We identified four clusters of AF patients with progressive mortality risk. The use of clinical phenotypes may help identify patients at a higher risk of mortality

Patients with isolated pulmonary embolism in comparison to those with deep venous thrombosis. Differences in characteristics and clinical evolution

Abstract Background Patients with acute pulmonary embolism (PE) often have leg deep vein thrombosis (DVT); sometimes, however, a DVT is not detected (isolated PE, I-PE). We aimed at assessing the proportion of patients with I-PE, and their characteristics and clinical evolution compared to those with DVT with/without PE (DVT/PE). Methods Among 3573 patients included in the START2-Register for a venous thromboembolic event, 2880 (80.6%) had DVT/PE, the remaining I-PE (19.4%). Results Patients with I-PE were older [(≥75 years, OR 1.4 (95%CI 1.13–1.69)], and more frequently females [OR 1.4 (1.19–1.67)]. Young females (aged ≤ 50 years) with an index event occurring during hormonal contraception (HC), were more prevalent in I-PE [OR 1.96 (1.26–3.03)]. At multivariate analysis, age > 75 years, female sex, heart failure, cancer and use of HC were risk factors significantly associated with I-PE, whereas thrombophilic alterations were associated with DVT/PE. During a follow-up of 4504 years (during anticoagulation), the rate of bleeding events was 1.1% patient/years and 1.0% patient/years in I-PE and DVT/PE, respectively. Venous thromboembolic events were equally prevalent in DVT/PE or I-PE (1.94% vs 0.86%, ns), whereas arterial complications were more prevalent in the latter group (1.01% vs 0.28%, p = 0.008). Conclusion I-PE and DVT/PE have important differences. Older age, female sex, heart failure and cancer, were risk factors for I-PE; thrombophilic alterations were associated with DVT/PE. HC use was more frequent in the I-PE group. The prevalence of arterial complications was higher in patients with I-PE. Further studies, specifically designed on this issue, are warranted

Diagnosis and treatment of pulmonary embolism: a multidisciplinary approach

The diagnosis of pulmonary embolism (PE) is frequently considered in patients presenting to the emergency department or when hospitalized. Although early treatment is highly effective, PE is underdiagnosed and, therefore, the disease remains a major health problem. Since symptoms and signs are non specific and the consequences of anticoagulant treatment are considerable, objective tests to either establish or refute the diagnosis have become a standard of care. Diagnostic strategy should be based on clinical evaluation of the probability of PE. The accuracy of diagnostic tests for PE are high when the results are concordant with the clinical assessment. Additional testing is necessary when the test results are inconsistent with clinical probability. The present review article represents the consensus-based recommendations of the Interdisciplinary Association for Research in Lung Disease (AIMAR) multidisciplinary Task Force for diagnosis and treatment of PE. The aim of this review is to provide clinicians a practical diagnostic and therapeutic management approach using evidence from the literature

Safety and efficacy of treatment with vitamin K antagonists in patients managed in a network of anticoagulation services or as routine general care

This is a retrospective, record-linkage study aimed at comparing the effectiveness and safety of two management models of vitamin K antagonists: a Network model (NAS), in which anticoagulation clinics and general practitioners (GP) share the same management software and database, and an individual General Practitioners model. Main outcomes were thromboembolic events (TE), major bleeding (MB) and all-cause mortality. Crude incidence rate and sub-distribution hazard ratio were calculated. Fine and Grey models were used to calculate SHR in multi-variable analysis. 9,418 patients in the NAS and 5,508 in the Routine General Care (RGC) cohort were included. Patients in the NAS cohort had a lower incidence of TE and mortality in respect to the RGC (sHR 0.76%, 95% CI 0.64-0.90 and 0.82%, 95% CI 0.75-0.89, respectively). More patients in the NAS than in the RGC cohort attained a Time in Therapeutic Range >60% (62.2% vs 35.7%, p<0.001). No statistically significant difference was found in MB incidence. This study shows that the NAS model for vitamin K antagonist oral anticoagulants management significantly improves the TTR and reduces the incidence of TE and mortality, without affecting the MB rate

Major bleedings in mechanical prosthetic heart valves patients on Vitamin K antagonist treatment. Data from the PLECTRUM Study

Patients with mechanical prosthetic heart valves (MHV) need vitamin K antagonist (VKA) treatment, due to the high thrombotic risk. The need to evaluate the bleeding risk of these patients is of great clinical relevance. This is an observational retrospective multicenter study among Centers affiliated to the Italian Federation of Anticoagulation Clinics on MHV patients, with the aim to evaluate the risk of major bleeding (MB) and associated risk factors. 2357 patients with MHV were included in the study, patients were followed for 24.081 pt-years; 246 patients had MB (rate 1.0 ×100 pt-yrs), 54 were intracranial hemorrhage (rate 0.22 ×100 pt-yrs). Patients with MB were significantly older, more affected by peripheral obstructive arterial disease (POAD) and atrial fibrillation (AF), and presented a history of previous MB, with respect to patients who did not bleed. Patients with MB showed a trend for lower time in therapeutic range (TTR), and a significant number of patients had a TTR in the lower quartile. Patients with MB had a higher mortality rate with respect to patients who did not bleed (p=0.001). The history of previous bleeding, the presence of POAD or of AF, and a TTR in the lowest quartile, were significantly associated with MB. MHV patients treated with VKAs followed by Anticoagulation Clinics, showed a low bleeding risk. Risk factors associated with major bleeding are older age, the presence of POAD or AF, the history of previous bleeding, and poor quality of anticoagulation. Patients who experienced MB during anticoagulation are at high risk of death