Chiara Piovella

Major bleeding as a predictor of mortality in patients with venous thromboembolism: findings from the RIETE Registry

Although there is emerging evidence that bleeding is a strong predictor of mortality in patients with acute arterial thrombosis receiving antithrombotic therapy [1–3], whether a similar association between bleeding and mortality also exists in patients with venous thromboembolism (VTE) has not been thoroughly investigated. In a recent systematic review of randomized trials addressing the value of fondaparinux for prevention of VTE in high-risk surgical or medical patients, Eikelboom et al. [4] were able to confirm this association. Comparable results were obtained in a large series of patients who had received antithrombotic drugs for the treatment of VTE in a community setting [5]. Recently, Nieto et al. [6] reported a high mortality rate in the follow-up of 407 patients, who belonged to the RIETE registry and had developed major bleeding while on conventional anticoagulation. However, in this study no attempt was made to compare the mortality rate between patients who bled and those who did not, and nor were study results adjusted for potential confounders. We describe here the association between major bleeding and mortality after the enrollment of almost 30 000 patients with acute VTE in the multicenter RIETE registry. Between March 2001 and December 2009, 29 903 consecutive patients with acute VTE, as confirmed by objective tests, were enrolled in the RIETE registry, received conventional anticoagulation, and were followed up for 3 months (80% of the study cohort) or longer periods of time after the index episode. Bleeding complications were classified as major if they were overt and required a transfusion of at least two units of blood, were retroperitoneal, spinal or intracranial, or were immediately (within 24 h) fatal [6]. The primary study aim was to compare the overall risk of death occurring during the follow-up between patients who bled and those who did not. The baseline characteristics of patients who bled and those who did not were compared with the use of the chi-square test for categorical variables and the Student t-test for continuous variables. All variables possibly associated with bleeding (P < 0.10 after univariate analysis) were included in the model, and Cox proportional hazards regression analyses were used to examine the association between patients demographic, clinical and treatment characteristics and major bleeding. Cox proportional hazards regression analyses were used to examine the association between baseline and treatment characteristics and death, with major bleeding as a timedependent covariate. All P-values were two-sided and were considered to be statistically significant at the 5% level. Statistical analyses were performed with the use of SPSS 15.0 (SPSS Inc., Chicago, IL, USA). At any time during patient observation, 888 patients (3.0%) experienced major bleeding. The most common sites of bleeding were gastrointestinal (38.3%), cerebral (16.4%), muscular (8.9%), urinary (8.7%), and retroperitoneal (6.4%). Table 1 reports the main characteristics of the recruited patients, separately for patients who bled and those who did not. As shown in Table 1, patients who bled were significantly older, and had a significantly higher incidence of cancer, severe renal insufficiency, chronic heart disease, chronic lung disease, anemia, and previous bleeding. Bleeding was fatal in 222 of the 888 patients (25.0%). Of the 666 patients who survived the hemorrhagic complication, 189 (28.4%) died during the subsequent follow-up [median delay between bleeding and death, 5 days (range, 2–577 days)]. Overall, 411 (46.3%) of the 888 patients who experienced major bleeding died, as compared with 3082 of the 29 015 (10.6%)

The value of 64-detector row computed tomography for the exclusion of pulmonary embolism

Recently, a diagnostic strategy using a clinical decision rule, D-dimer testing and spiral computed tomography (CT) was found to be effective in the evaluation of patients with clinically suspected pulmonary embolism (PE). However, the rate of venous thromboembolic complications in the three-month follow-up of patients with negative CT was still substantial and included fatal events. It was the objective to evaluate the safety of withholding anticoagulants after a normal 64-detector row CT (64-DCT) scan from a cohort of patients with suspected PE. A total of 545 consecutive patients with clinically suspected first episode of PE and either likely pre-test probability of PE (using the simplified Wells score) or unlikely pre-test probability in combination with a positive D-dimer underwent a 64-DCT. 64-DCT scanning was inconclusive in nine patients (1.6%), confirmed the presence of PE in 169 (31%), and ruled out the diagnosis in the remaining 367. During the three-month follow-up of the 367 patients one developed symptomatic distal deep-vein thrombosis (0.27%; 95%CI, 0.0 to 1.51%) and none developed PE (0 %; 95%CI, 0 to 1.0%). We conclude that 64-DCT scanning has the potential to safely exclude the presence of PE virtually in all patients presenting with clinical suspicion of this clinical disorder.

Venous thromboembolism and arterial complications.

An increasing body of evidence suggests the likelihood of a link between venous and arterial thrombosis. The two vascular complications share several risk factors, such as age, obesity, smoking, diabetes mellitus, blood hypertension, hypertriglyceridemia, and metabolic syndrome. Moreover, there are many examples of conditions accounting for both venous and arterial thrombosis, such as the antiphospholipid antibody syndrome, hyperhomocysteinemia, malignancies, infections, and the use of hormonal treatment. Finally, several recent studies have consistently shown that patients with venous thromboembolism are at a higher risk of arterial thrombotic complications than matched control individuals. We, therefore, speculate the two vascular complications are simultaneously triggered by biological stimuli responsible for activating coagulation and inflammatory pathways in both the arterial and the venous system. Future studies are needed to clarify the nature of this association, to assess its extent, and to evaluate its implications for clinical practice.

Fondaparinux in the initial and long-term treatment of venous thromboembolism

BACKGROUND Even in the absence of evidence on its long-term efficacy and safety, a number of patients with venous thromboembolism (VTE) receive long-term therapy with fondaparinux alone in everyday practice. METHODS We used the Registro Informatizado de Enfermedad Tromboembólica (RIETE) registry to compare the rate of VTE recurrences and major bleeding at 10 and 90 days in patients with and without cancer. For long-term therapy, fondaparinux was compared with vitamin K antagonists (VKA) in patients without cancer and with low-molecular-weight heparin (LMWH) in those with cancer. RESULTS Of 47,378 patients recruited, 46,513 were initially treated with heparin, 865 with fondaparinux. Then, 263 patients (78 with cancer) were treated for at least 3 months with fondaparinux. After propensity-score matching, there were no differences between patients receiving initial therapy with heparin or fondaparinux. Among patients with cancer, there were no differences between fondaparinux and LMWH. Among patients without cancer, the long-term use of fondaparinux was associated with an increased risk of major bleeding (3.24 % vs. 0.95 %, p<0.05). CONCLUSIONS An unexpected high rate of major bleeding was observed in non-cancer patients treated with long-term fondaparinux. Our small sample does not allow to derive relevant conclusions on the use of fondaparinux in cancer patients.

Heart disease in patients with pulmonary embolism

Purpose of review Several heart diseases are promoters of left-side cardiac thrombosis and could lead to arterial embolism. The same mechanism may be responsible for right-side cardiac thrombosis and therefore be a direct source of pulmonary embolism. Recent findings Yasuoka et al. showed a higher incidence of perfusion defects in lung scan in patients with spontaneous echocontrast in the right atrium than in those without it (40% and 7% respectively; P = 0.006). We recently assessed the prevalence of heart diseases in 11.236 consecutive patients older than 60 years discharged from Venetian hospitals with a diagnosis of pulmonary embolism. We observed a higher prevalence of all-cause heart diseases (odds ratio 1.26; 95% confidence interval, 1.13–1.40) in patients with a diagnosis of pulmonary embolism alone (secondary or unprovoked) compared with those discharged with a diagnosis of pulmonary embolism associated with deep vein thrombosis, generating the hypothesis that some specific heart diseases in older patients could themselves be a possible source of pulmonary emboli. Summary Further prospective studies are required to confirm these findings, which have the potential to open new horizons for the interpretation and management of venous thromboembolic disease.

The impact of disseminated intravascular coagulation on the outcome of cancer patients with venous thromboembolism

The impact of disseminated intravascular coagulation on the outcome of cancer patients with venous thromboembolism Luca Spiezia, Elena Campello, Javier Trujillo-Santos, Chiara Piovella, Benjamin Brenner, Manuel Monreal, Paolo Prandoni, The RIETE Investigators Department of Medicine, University Hospital of Padua, Padua, Italy, Department of Internal Medicine, Hospital Universitario de Santa Lucı́a, Cartagena, Spain, Department of Hematology, Rambam Healthcare Campus, Haifa, Israel and Department of Internal Medicine. Hospital Universitari Germans Trias I Pujol, Badalona, Barcelona, Spain

What are the pharmacotherapy options for treating venous thromboembolism in cancer patients

Introduction: Venous thromboembolism (VTE) is a frequent complication in patients with malignancies. The treatment of VTE disorders in cancer patients remains a difficult clinical task. Areas covered: Current evidence on the most appropriate initial and long-term treatment of cancer patients with VTE was addressed, as was the management of recurrent VTE despite anticoagulation, the management of incidentally detected isolated pulmonary embolism (PE), the potential role of the novel direct oral anticoagulants and the impact of low-molecular-weight heparin (LMWH) on cancer evolution. Expert opinion: LMWHs are the cornerstone of VTE treatment in cancer patients. The intensity and duration of treatment are dependent on several factors that need to be individually evaluated. The novel oral anticoagulants should be investigated more carefully before being routinely implemented in the treatment of cancer-associated VTE. Incidentally detected isolated sub-segmental PE is unlikely to require systematic full-dose anticoagulation. Evidence favoring an impact of LMWH on survival in cancer patients is weak.

Incidence of arterial embolism in patients on treatment with old and new anticoagulants for venous thromboembolism.

The separate nature of venous and arterial thrombotic disorders has recently been challenged. Patients with venous thromboembolism (VTE) have an increased risk of subsequent symptomatic arterial cardiovascular events, the risk being higher in those with unexplained episodes. Among the implications of this association, there is the potential for old and new antithrombotic drugs to impact on the development of both venous and arterial cardiovascular events. According to the results of recent studies, aspirin in low doses, when administered for the long-term management of patients with unprovoked VTE, reduces by approximately 35% the risk of recurrent VTE while offering a considerable protection against the development of arterial cardiovascular events. By contrast, there is no room to expect a reduction in the risk of subsequent arterial cardiovascular events in patients treated with vitamin K antagonists (VKA) in comparison to patients in whom VKAs are discontinued. According to the results from recent randomized clinical trials, the likelihood of arterial cardiovascular events in patients on the novel direct factor Xa inhibitors is unlikely to differ from that of patients receiving conventional anticoagulation. As dabigatran has been associated with a slight increase in the risk of myocardial infarction over warfarin, its use should be discouraged in patients with coronary heart disease. The long-term use of low-dose apixaban beyond the first months in patients with unprovoked VTE may decrease the long-term risk of arterial, as well as venous, thrombotic events.