Marco P. Donadini

Risk of deep vein thrombosis following a single negative whole-leg compression ultrasound: a systematic review and meta-analysis

CONTEXT In patients with suspected lower extremity deep vein thrombosis (DVT), compression ultrasound (CUS) is typically the initial test to confirm or exclude DVT. Patients with an initial negative CUS result often require repeat CUS after 5 to 7 days. Whole-leg CUS may exclude proximal and distal DVT in a single evaluation. OBJECTIVE To determine the risk of venous thromboembolism after withholding anticoagulation in patients with suspected lower extremity DVT following a single negative whole-leg CUS result. DATA SOURCES MEDLINE, EMBASE, CINAHL, LILACS, Cochrane, and Health Technology Assessments databases were searched for articles published from January 1970 through November 2009. Supplemental searches were performed of Internet resources, reference lists, and by contacting content experts. STUDY SELECTION Included studies were randomized controlled trials and prospective cohort studies of patients with suspected DVT and a negative whole-leg CUS result who did not receive anticoagulant therapy, and were followed up at least 90 days for venous thromboembolism events. DATA EXTRACTION Two authors independently reviewed and extracted data regarding a single positive or negative whole-leg CUS result, occurrence of venous thromboembolism during follow-up, and study quality. RESULTS Seven studies were included totaling 4731 patients with negative whole-leg CUS examinations who did not receive anticoagulation. Of these, up to 647 patients (13.7%) had active cancer and up to 725 patients (15.3%) recently underwent a major surgery. Most participants were identified from an ambulatory setting. Venous thromboembolism or suspected venous thromboembolism-related death occurred in 34 patients (0.7%), including 11 patients with distal DVT (32.4%); 7 patients with proximal DVT (20.6%); 7 patients with nonfatal pulmonary emboli (20.6%); and 9 patients (26.5%) who died, possibly related to venous thromboembolism. Using a random-effects model with inverse variance weighting, the combined venous thromboembolism event rate at 3 months was 0.57% (95% confidence interval, 0.25%-0.89%). CONCLUSION Withholding anticoagulation following a single negative whole-leg CUS result was associated with a low risk of venous thromboembolism during 3-month follow-up.

Incidence of chronic pulmonary hypertension in patients with previous pulmonary embolism

INTRODUCTION The true incidence of chronic thromboembolic pulmonary hypertension (CTPH) remains a matter of debate. Symptomatic CTPH is probably more common than previously reported, whereas the occurrence of asymptomatic CTPH has not been defined since very limited evidence on the incidence of asymptomatic CTPH diagnosed with echocardiography Doppler are currently available. We therefore carried out a prospective cohort study to assess the incidence of CTPH diagnosed with echocardiography Doppler in consecutive patients with a first episode of PE. METHODS Consecutive patients with a first episode of PE were evaluated with Doppler transthoracic echocardiography within 6 to 12 months after the index event. Pulmonary hypertension was defined as a systolic pulmonary artery pressure > or =40 mmHg at rest in the presence of residual perfusion defects at perfusion scintigraphy. Presence of symptoms related to pulmonary hypertension was evaluated with a standardized questionnaire. RESULTS Ninety-one patients (mean age 61.9+/-15.7 years; range 22-89; 39 men) were enrolled. Eight patients (8.8%; 95% CI 4.5,16.4) had CTPH: of these, 4 (4.4%; 95% CI 2.0, 9.3) were symptomatic. CONCLUSIONS Asymptomatic CTPH is not an uncommon finding after PE. Larger prospective trials with a longer follow up should assess the prognostic significance of asymptomatic CPTH.

Oral rivaroxaban after symptomatic venous thromboembolism: the continued treatment study (EINSTEIN-extension study).

Over recent years, research on anticoagulant drugs has been guided by the requirement for convenient administration and a wide therapeutic window to allow fixed dosing without the need for coagulation monitoring. Rivaroxaban is the first of a new class of anticoagulant drugs, the direct, selective inhibitors of Factor Xa. The EINSTEIN-Extension study compared rivaroxaban with placebo in patients who completed their standard treatment course after venous thromboembolism (VTE), in whom there was equipoise with respect to the need for continued anticoagulation. After 6–12 months of treatment, rivaroxaban significantly reduced the risk of recurrent VTE at the cost of a moderate increase in bleeding complications. Overall, these results suggest that rivaroxaban can be a valid alternative to warfarin for patients requiring long-term secondary prevention of VTE. However, additional data are needed for special populations including the elderly, patients with cancer, renally impaired patients and morbidly obese patients, all of whom were scarcely represented in this trial.

Prognostic clinical prediction rules to identify a low-risk pulmonary embolism: a systematic review and meta-analysis.

Summary.  Background:  Prognostic assessment is important for the management of patients with a pulmonary embolism (PE). A number of clinical prediction rules (CPRs) have been proposed for stratifying PE mortality risk. The aim of this systematic review was to assess the performance of prognostic CPRs in identifying a low‐risk PE.

Retrievable vena cava filters: a clinical review

Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism (PE), is a major cause of morbidity and mortality. Parenteral anticoagulant treatment with full-dose unfractioned heparin, low-molecular-weight-heparin, or fondaparinux, followed by oral treatment with the vitamin K antagonists, is recommended for the majority of patients. However, in the presence of contraindications to anticoagulant treatment, bleeding complications during antithrombotic treatment, or VTE recurrences despite optimal anticoagulation, interruption of the inferior vena cava with a filter is a potential option aimed to prevent life-threatening PE. Currently, the vast majority of filters implanted worldwide are of the permanent type, but their use is associated with a number of long term complications. Non-permanent filters represent an important alternative, and in particular retrievable filters are an attractive option because they may be either left in place permanently or safely retrieved after a quite long period when they become unnecessary. In this review, we summarize the currently available literature regarding retrievable vena cava filters and we discuss current evidences on their efficacy and safety. Moreover, the appropriate indications for their use in daily clinical practice are reviewed.

Clinical approach to splanchnic vein thrombosis: risk factors and treatment.

Splanchnic vein thrombosis (SVT) is an unusual manifestation of venous thromboembolism which involves one or more abdominal veins (portal, splenic, mesenteric and supra-hepatic veins). SVT may be associated with different underlying disorders, either local (abdominal cancer, liver cirrhosis, intra-abdominal inflammation or surgery) or systemic (hormonal treatment, thrombophilic conditions). In the last decades, myeloproliferative neoplasm (MPN) emerged as the leading systemic cause of SVT. JAK2 mutation, even in the absence of known MPN, showed a strong association with the development of SVT, and SVT was suggested to be the first clinical manifestation of MPN. Recently, an association between SVT, in particular supra-hepatic vein thrombosis, and paroxysmal nocturnal hemoglobinuria has also been reported. SVT occurs with heterogeneous clinical presentations, ranging from incidentally detected events to extensive thrombosis associated with overt gastrointestinal bleeding, thus representing a clinical challenge for treatment decisions. In the absence of major contraindications, anticoagulant therapy is generally recommended for all patients presenting with acute symptomatic SVT, but there is no consensus about the use of anticoagulant drugs in chronic or incidentally detected SVT. High quality evidence on the acute and long-term management is substantially lacking and the risk to benefit-ratio of anticoagulant therapy in SVT still needs to be better assessed.

Epidemiology and pathophysiology of venous thromboembolism: similarities with atherothrombosis and the role of inflammation

Venous thromboembolism (VTE) is a multifactorial disease. Major provoking factors (e. g. surgery, cancer, major trauma, and immobilisation) are identified in 50-60 % of patients, while the remaining cases are classified as unprovoked. However, minor predisposing conditions may be detectable in these patients, possibly concurring to the pathophysiology of the disease, especially when co-existing. In recent years, the role of chronic inflammatory disorders, infectious diseases and traditional cardiovascular risk factors has been extensively investigated. Inflammation, with its underlying prothrombotic state, could be the potential link between these risk factors, as well as the explanation for the reported association between arterial and venous thromboembolic events.

Optimal treatment duration of venous thrombosis

Randomized controlled trials have shown that patients with venous thromboembolism benefit from a minimum of three months of anticoagulant therapy. After this period, it was suggested that patients with an expected annual recurrence rate of < 5% could safely discontinue treatment. Using a population‐based approach for stratification, these patients are those with major transient risk factors, and represent the minority. For all other patients, including those with previous episodes of venous thromboembolism, cancer, or unprovoked events, this treatment duration may not be sufficiently protective. Because extending anticoagulation for additional three to nine months does not result in further, long‐term reduction of recurrences, indefinite treatment duration should be considered. However, case‐fatality rate for major bleeding in patients taking warfarin for more than three months is higher than case‐fatality rate of recurrent venous thromboembolism. Thus, an individual patient approach to improve and increase the identification of those who can safely discontinue treatment at three months becomes necessary. Clinical prediction rules or management strategies based on D‐dimer levels or residual vein thrombosis have been proposed and need further refinement and validation. Specific bleeding scores are lacking. Meanwhile, the oral direct inhibitors have been proposed as potential alternatives to the vitamin K antagonists, and aspirin may provide some benefit in selected patients who discontinue anticoagulation. Deep vein thrombosis in unusual sites is associated with less, but potentially more severe recurrences, in particular in patients with splanchnic vein thrombosis who also face an increased risk of bleeding complications while on treatment.

Splanchnic vein thrombosis: new risk factors and management

Splanchnic vein thrombosis (SVT) is a rather heterogeneous disease which involve one or more abdominal veins draining from different organs, including small and large bowel, liver, spleen and pancreas, and it may be associated with a wide spectrum of underlying disorders, either local or systemic. The role of new risk factors for SVT, including the JAK2 V617F mutation and the paroxysmal nocturnal hemoglobinuria clone, has been highlighted in recent years. The clinical presentations of SVT are variable and, not uncommonly, may include the concomitant presence of extensive thrombosis and gastrointestinal bleeding, thus representing a clinical challenge for treatment decisions. High quality evidence on the acute and long-term management is substantially lacking, thus requiring further research on SVT.

Management of Bleeding in Patients Receiving Conventional or New Anticoagulants

Anticoagulant drugs are highly effective for the prevention and treatment of venous and arterial thromboembolism. However, their use is also associated with an increased risk for bleeding, with an associated ~10% case-fatality rate. Appropriate strategies for the management and reversal of anticoagulant-associated bleeding are clinically important and, ideally, should be standardized. These include general resuscitation, and diagnosis and local treatment of the bleeding source, and one or more of the following interventions: transfusion of red cells; transfusion of clotting factor replacements; and administration of anticoagulant antidotes and other prohaemostatic agents. Reversal strategies for the ‘conventional’ anticoagulants are based largely on clinical evidence, whereas evidence to guide the management of bleeding associated with ‘new’ anticoagulants is emerging. This review provides an evidence-based, but practical, patient-focused approach for the management of bleeding associated with the old and new anticoagulants.