Search

Background Splanchnic vein thrombosis (SVT) is a common complication in patients with liver cirrhosis. The aim of this study was to evaluate the efficacy and safety of anticoagulant therapy for SVT in cirrhotic patients. Methods In this systematic review and meta-analysis, studies reporting on SVT recanalization and progression, recurrent venous thromboembolism (VTE), major bleeding, and overall mortality were searched in MEDLINE, EMBASE, and ClinicalTrial.gov up to December 2019. Pooled proportions and risk ratios (RRs) with corresponding 95% confidence intervals (CIs) were calculated. Results A total of 1,475 patients were included in 26 studies (23 observational and 3 randomized controlled trials). In patients receiving anticoagulant therapy, SVT recanalization occurred in 68% (95% CI, 62–74; 571/842 patients; 22 studies), SVT progression in 6% (95% CI, 4–9; 25/748 patients; 22 studies), recurrent VTE in 10% (95% CI, 4–22; 48/399 patients; 7 studies), major bleeding in 6% (95% CI, 4–10; 58/785 patients; 18 studies), and overall mortality in 9% (95% CI, 6–14; 68/787 patients; 17 studies). Anticoagulant treatment was associated with higher SVT recanalization (RR 3.19; 95% CI, 1.42–7.17), lower thrombosis progression (RR 0.28; 95% CI, 0.15–0.52), major bleeding (RR 0.52; 95% CI, 0.28–0.97), and overall mortality (RR 0.42; 95% CI, 0.24–0.73) compared with no treatment. Conclusion Anticoagulant therapy seems to improve vein recanalization and to reduce SVT progression, major bleeding, and overall mortality in cirrhotic patients with SVT. The incidence of recurrent VTE during anticoagulation remains substantial.

Background Direct oral anticoagulants are recommended for the treatment of cancer-associated thrombosis (CAT) as an alternative to low-molecular-weight heparin (LMWH), but an increased bleeding risk in patients with gastrointestinal cancer was reported. The Caravaggio study compared apixaban and dalteparin for the treatment of patients with CAT. Here we describe sites of bleeding, associated cancer sites, clinical presentation, and course of major bleeding in patients included in the Caravaggio study. Methods The Caravaggio study was a multinational, randomized, open-label, noninferiority study. Bleeding events and the severity of major bleedings were adjudicated by a committee unaware of treatment allocation using predefined criteria; for the purpose of this analysis, data were analyzed in the safety population. Results Major bleeding occurred in 22 of 576 patients on apixaban (3.8%) and in 23 of 579 patients on dalteparin (4.0%). The sites of major bleeding and their distribution according to the type of cancer were similar between the two treatment groups. Major bleeding occurred in nine patients with gastrointestinal cancer in each treatment group. The clinical presentation of major bleeding was severe or fatal in 6 patients on apixaban and in 5 patients on dalteparin, while the clinical course was severe in 5 patients on apixaban and in 7 patients on dalteparin. Conclusion Apixaban is a safe alternative to LMWH for the treatment in patients with CAT. No excess in gastrointestinal bleeding was observed in patients who received apixaban, including those with gastrointestinal cancer.

Venous thromboembolism (VTE) remains a major cause of morbidity and mortality in hospitalized medically ill patients. These patients constitute a heterogeneous population, whose VTE risk is dependent upon the acute medical illness, immobility status, and patient-specific risk factors that have been incorporated into individualized VTE risk assessment models. Randomized placebo-controlled trials (RCTs) have shown both efficacy and net clinical benefit of in-hospital thromboprophylaxis, which is supported by guideline recommendations. The data for extended posthospital discharge thromboprophylaxis are more nuanced. RCTs comparing standardized duration low-molecular weight heparin versus extended duration direct oral anticoagulants, such as betrixaban and rivaroxaban, have shown efficacy and net clinical benefit in select groups of high VTE and low-bleed risk populations of hospitalized medically ill patients. These oral agents are now approved for both in-hospital and extended thromboprophylaxis. However, the most recent guidelines do not recommend routine use of these agents for extended thromboprophylaxis. Longitudinal studies in medically ill patients have shown that the majority of VTE events occur in the posthospital discharge setting within 6 weeks of hospitalization. This, coupled with the short hospital length-of-stay and lack of routine postdischarge thromboprophylaxis in U.S. health care settings, has dampened quality improvement efforts aimed at reducing hospital-acquired VTE. The aim of this multidisciplinary document is to provide an evidence-based framework to guide clinicians in assessing VTE and bleeding risk in hospitalized medically ill patients using an individualized, risk-adapted, and patient-centered approach, with the aim of providing clinical pathways toward the use of appropriate type and duration of available thromboprophylactic agents.

Background Bleeding risk is highly relevant for treatment decisions in cancer-associated thrombosis (CAT). Several risk scores exist, but have never been validated in patients with CAT and are not recommended for practice. Objectives To compare methods of estimating clinically relevant (major and clinically relevant nonmajor) bleeding risk in patients with CAT: (1) existing risk scores for bleeding in venous thromboembolism, (2) pragmatic classification based on cancer type, and (3) new prediction model. Methods In a posthoc analysis of the Hokusai VTE Cancer study, a randomized trial comparing edoxaban with dalteparin for treatment of CAT, seven bleeding risk scores were externally validated (ACCP-VTE, HAS-BLED, Hokusai, Kuijer, Martinez, RIETE, and VTE-BLEED). The predictive performance of these scores was compared with a pragmatic classification based on cancer type (gastrointestinal; genitourinary; other) and a newly derived competing risk-adjusted prediction model based on clinical predictors for clinically relevant bleeding within 6 months after CAT diagnosis with nonbleeding-related mortality as the competing event (“CAT-BLEED”). Results Data of 1,046 patients (149 events) were analyzed. Predictive performance of existing risk scores was poor to moderate (C-statistics: 0.50–0.57; poor calibration). Internal validation of the pragmatic classification and “CAT-BLEED” showed moderate performance (respective C-statistics: 0.61; 95% confidence interval [CI]: 0.56–0.66, and 0.63; 95% CI 0.58–0.68; good calibration). Conclusion Existing risk scores for bleeding perform poorly after CAT. Pragmatic classification based on cancer type provides marginally better estimates of clinically relevant bleeding risk. Further improvement may be achieved with “CAT-BLEED,” but this requires external validation in practice-based settings and with other DOACs and its clinical usefulness is yet to be demonstrated.

Coronavirus disease 2019 (COVID-19), currently a worldwide pandemic, is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The suspected contribution of thrombotic events to morbidity and mortality in COVID-19 patients has prompted a search for novel potential options for preventing COVID-19-associated thrombotic disease. In this article by the Global COVID-19 Thrombosis Collaborative Group, we describe novel dosing approaches for commonly used antithrombotic agents (especially heparin-based regimens) and the potential use of less widely used antithrombotic drugs in the absence of confirmed thrombosis. Although these therapies may have direct antithrombotic effects, other mechanisms of action, including anti-inflammatory or antiviral effects, have been postulated. Based on survey results from this group of authors, we suggest research priorities for specific agents and subgroups of patients with COVID-19. Further, we review other agents, including immunomodulators, that may have antithrombotic properties. It is our hope that the present document will encourage and stimulate future prospective studies and randomized trials to study the safety, efficacy, and optimal use of these agents for prevention or management of thrombosis in COVID-19.

Direct oral anticoagulants (DOACs) facilitate the outpatient treatment of venous thromboembolism (VTE). However, the pivotal trials of DOACs have not reported outcomes separately for patients managed either as outpatients or in the hospital. We performed a subgroup analysis of the Hokusai-VTE study comparing efficacy and safety of edoxaban with warfarin in 8,292 patients with acute VTE. Patients received initial therapy with open-label enoxaparin or unfractionated heparin for ≥5 days in the hospital or as an outpatient at the discretion of the treating physician. Edoxaban or warfarin was then given for 3 to 12 months. The primary efficacy outcome was the cumulative incidence of symptomatic recurrent VTE at 12 months. The principal safety outcome was the incidence of clinically relevant bleeding (composite of major or clinically relevant non-major bleeding). Of the 5,223 consecutively enrolled patients with recorded hospital status and length of stay, 1,414 patients (27.1%) were managed as outpatients and 3,809 were managed in hospital. Among the outpatients, initial presentation was symptomatic deep-vein thrombosis (DVT) in 1,183 patients (83.7%) and pulmonary embolism (PE) in 231 patients (16.3%). Among the outpatients with DVT, recurrent VTE occurred in 18 (3.0%) given edoxaban and in 21 (3.6%) given warfarin (risk difference: −0.61, 95% confidence interval [CI]: −2.6 to 1.4). The principal safety outcome in outpatients occurred in 46 edoxaban patients (7.7%) and in 48 warfarin patients (8.3%; risk difference: −0.59, 95% CI: −3.7 to 2.5). Most outpatients had symptomatic DVT at presentation. In these patients, initial heparin followed by edoxaban had similar efficacy and safety to standard therapy with heparin and warfarin.

SummaryLittle information is available on the incidence of splanchnic vein thrombosis and on mortality rates during the acute phase of the disease. We performed a large epidemiologic study on hospital admissions for portal vein thrombosis (PVT) and the Budd-Chiari syndrome (BCS) between 2002 and 2012 in Northwestern Italy. Primary and secondary discharge diagnoses of PVT and BCS were identified using the 9th edition International Classification of Diseases codes 453.0, 572.1 and 452. Hospitalisations for recurrent events were not included. Information was collected on age and gender, vital status at discharge, duration of hospitalisation, and up to five secondary discharge diagnoses. Comorbidity was evaluated using the Charlson comorbidity index (CCI). A total of 3535 patients with PVT and 287 with BCS were hospitalized. The overall gender-specific incidence rates for PVT were 3.78 per 100,000 inhabitants in males and 1.73 per 100,000 inhabitants in females; for BCS 2.0 and 2.2 per million inhabitants, respectively. In-hospital case fatality was 7.3 % in patients with PVT and 4.9 % in patients with BCS. Age, non-abdominal solid cancer, and CCI were independently associated with in-hospital mortality in both PVT and BCS after stepwise regression analysis, male gender and haematologic cancer were associated with mortality in BCS patients only. In this large study we confirmed the low incidence of BCS and we found an incidence of PVT higher than previously reported. This incidence was stable during the period of observation. In-hospital mortality is not negligible, in particular in PVT patients.

SummaryPulmonary embolism (PE) is a common disorder with high mortality and morbidity rates. However, population-based information on its incidence and prognosis remains limited. We conducted a large epidemiology study collecting data on hospitalisation for PE (from 2002 to 2012) in a population of about 13 million people in Northwestern Italy. Patients were identified using the ICD-9-CM codes: 415.11, 415.19; gender and age specific incidence rate of PE during the study period were estimated using the resident population for each year of the study. Furthermore, time trends in the in-hospital PE-related mortality and case fatality rate were calculated. Results were adjusted for possible confounders. A total of 60,853 patients (mean age 72.8 years, ± 14.1, 59.6 % females) with PE were included; the overall crude incidence rate for the entire study period was 55.4 and 40.6 events per year per 100,000 inhabitants for women and men, respectively (p < 0.001). However, this difference was completely lost after standardisation for age. The incidence of PE significantly increased in both genders during the study period. In-hospital case fatality rate significantly decreased throughout the study period (p < 0.001) in women (from 15.6 % to 10.2 %) and in men (from 17.6 % to 10.1 %). The observed decrease of the in-hospital case-fatality throughout the study period remained significant also after adjustment for possible confounders. In conclusion, time trends over an 11-year period show an increasing incidence of PE, but a significant reduction in mortality during hospitalisation. Reduction in the case fatality rate remained significant after adjustment for these possible confounders.Supplementary Material to this article is available online at www.thrombosis-online.com.

SummaryVenous thromboembolism (VTE), comprising both deep-vein thrombosis (DVT) and pulmonary embolism (PE), is a serious and common cardiovascular disease associated with the risk of chronic complications, recurrent VTE events and even death. The treatment landscape has, in recent years, seen a paradigm shift from the use of traditional anticoagulants (low-molecular-weight heparin [LMWH] overlapping with and followed by a vitamin K antagonist [VKA]) to non-VKA oral anticoagulants (NOACs). This class of agents, encompassing direct factor Xa inhibitors and direct thrombin inhibitors have shown non-inferior efficacy and better safety to standard of care in randomised controlled trials (RCTs). The direct, oral factor Xa inhibitor rivaroxaban was the first to be approved for treatment of acute DVT and PE and secondary prevention of recurrent VTE events based on data from EINSTEIN DVT and EINSTEIN PE, respectively. Real-world evidence now helps to further support data from RCTs, and also bridges the gap for physicians regarding any areas of clinical uncertainty that may not be addressed by RCTs. XA inhibition with rivaroxaban for Long-term and Initial Anticoagulation in venous thromboembolism (XALIA) was the first large, prospective, observational, real-world study that has investigated the safety and effectiveness profile of rivaroxaban in patients with DVT and PE associated with DVT in routine clinical practice. This article will present the key clinical outcomes from this important global non-interventional study, and will discuss remaining questions to be addressed in Phase IV studies.

SummaryDirect oral anticoagulants simplify venous thromboembolism (VTE) treatment by obviating the need for coagulation monitoring. Nonetheless, renal function, body weight and P-glycoprotein inhibitors influence drug levels. The objective of this analysis was to determine whether reduction in edoxaban dose based on clinical criteria avoids excess drug exposure and preserves efficacy and safety in the Hokusai-VTE study. After initial heparin, patients received edoxaban or warfarin for 3-12 months. Edoxaban was given once daily at a dose of 60 mg, which was reduced to 30 mg in patients with a creatinine clearance of 30–50 ml/minute, body weight ≤60 kg or receiving certain P-glycoprotein inhibitors. The primary efficacy outcome was recurrent VTE and the principal safety outcome was major or clinically relevant non-major bleeding. A total of 8292 patients with acute VTE were randomised, 733 and 719 patients in the edoxaban and warfarin groups met the criteria for dose reduction. These patients were older, more often female or Asian and had more extensive VTE. Edoxaban levels were lower in the 30 mg edoxaban group. Rates of recurrent VTE and bleeding with the 30 mg and 60 mg edoxaban dose were comparable: VTE rates were 3.0 % and 3.2 % and clinically relevant bleeding rates were 7.9 % and 8.6 %, respectively. Rates of recurrent VTE and bleeding in the warfarin-treated patients meeting the criteria for dose reduction were 4.2 % and 12.8 %, respectively. The reduced dose edoxaban regimen maintained efficacy and safety compared with the 60 mg dose but was safer than warfarin in patients meeting the criteria for dose reduction.Supplementary Material to this article is available online at www.thrombosis-online.com.

SummaryVenous 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.

SummaryThe prevention and treatment of venous thromboembolism (VTE) remains a clinical challenge, primarily owing to drawbacks associated with the use of heparins and vitamin K antagonists (VKAs). These and other factors, including a growing elderly population, mean that VTE presents a continuing burden to patients and physicians. Anticoagulant therapy is a fundamental approach for VTE management. Non- VKA oral anticoagulants, including the factor Xa inhibitors apixaban, edoxaban and rivaroxaban, and the thrombin inhibitor dabigatran, have been studied in phase III trials across a spectrum of thromboembolic disorders. These agents offer simplified care, with similar or improved efficacy and safety outcomes compared with heparins and vitamin K antagonists. There are several factors a physician must consider when prescribing an anticoagulant. An important consideration with all anticoagulant use is bleeding risk, especially in high-risk groups such as the elderly or those with renal impairment or cancer. In orthopaedic patients, other risks include a need for surgical revision or blood transfusion, or wound complications. Therefore, the clinical benefits of an anticoagulant should ideally be balanced with any risks associated with the therapy. Quantitative benefit–risk assessments are lacking, and owing to differences in trial design the non-VKA oral anticoagulants cannot be compared directly. Based on trial and “reallife” data, this review will summarise the clinical data for the non-VKA oral anticoagulants in the prevention and treatment of VTE, focusing on the balance between the benefits and risks of anticoagulation with these drugs, and their potential impact on VTE management.

Efficacy and safety of patent foramen ovale closure in patients with a cryptogenic stroke: Systematic review and meta-analysis

SummaryVenous thromboembolism (VTE) is a frequent complication in the acute setting after spinal cord injury (SCI). Less is known about the long-term risk of VTE in these patients. It was the aim of this study to prospectively evaluate the short- and long-term risk of VTE in a cohort of patients after acute SCI and during rehabilitation and post-rehabilitation follow-up period. From January 2003 to November 2007 all consecutive adult patients admitted to a Spinal Rehabilitation Unit (RU) after surgical treatment in three Neurosurgical Units for SCI, were enrolled. After an accurate evaluation of their neurosurgical medical records the patients were prospectively evaluated for VTE occurrence. Ninety-four patients (80 males; mean age 40.3 years, SD 15.9) were recruited. All the patients received thromboprophylaxis with low-molecular-weight heparin combined with compressive stockings during hospitalization (median duration 7 months, IQR 4.5–8.8). Over a median follow-up period of 36.3 months (IQR 4.4–48) after SCI, VTE was diagnosed in 22 patients (23.4%) The majority of VTE events were recorded during the first three months of follow-up (34.4 VTE events/100 patient-years in the first 3 months and 0.3 VTE events/100 patient-years thereafter); age over 45 years (HR 8.4, 95% CI 3–23.5), previous VTE (HR 6.0, 95% CI 1.6–23.3) and paraplegia (HR 4.7, 95% CI 1.6–13.7) were independently associated with the occurrence of VTE. In conclusion, the risk of VTE in patients suffering from SCI is high despite the use of thromboprophylaxis, in particular in some patients categories. However, this risk appears to be limited to the first 3 months after the index event.

Location of venous thrombosis in patients with FVL or prothrombin G20210A mutations: Systematic review and meta-analysis

SummaryThe therapeutic management of venous thromboembolism (VTE) is rapidly evolving. Following the positive results of pivotal large-scale randomised trials, the non-vitamin K antagonist oral anticoagulants (NOACs) represent an important alternative to standard anticoagulation. In phase III studies, dabigatran was as effective as, and significantly safer than warfarin. Additional information on real-world data of dabigatran is now warranted. RE-COVERY DVT/PE is a multi-centre, international, observational (i. e. non-interventional) study enrolling patients with acute DVT and/or PE within 30 days after objective diagnosis. The study is designed with two phases. Phase 1 has a cross-sectional design, enrolling approximately 6000 patients independently of treatment choice, with the aim of providing a contemporary picture of the management of VTE worldwide. Phase 2 has a prospective cohort design, with follow-up of one year, enrolling 8000 patients treated with dabigatran or vitamin K antagonists (VKAs) with the aim of comparing their safety, defined by the occurrence of major bleeding, and effectiveness, defined by the occurrence of symptomatic recurrent VTE. RE-COVERY DVT/PE will complement both the results of other observational studies in this field and the results of phase III studies with dabigatran, in particular by assessing its clinical benefit in various patient subgroups treated in routine clinical practice.

SummaryAnticoagulation therapy for the prevention of venous thromboembolic events is indicated in patients after major orthopaedic surgery and in hospitalised acutely ill medical patients, who have a high or moderate risk of venous thromboembolism (VTE), respectively. Clinical trials have clearly demonstrated that short-term anticoagulation reduces the risk of VTE in these patient groups and that longer-term anticoagulation is beneficial for some indications. Evidence-based guidelines for throm-boprophylaxis have been developed based on these studies. However, despite these guidelines, thromboprophylaxis is still underused, or used suboptimally, in many patients. This is, in part, because of the limitations of traditional anticoagulants such as unfractionated heparin, lowmolecular-weight heparin, synthetic pentasaccharides, and vitamin K antagonists. Newer oral anticoagulants, such as rivaroxaban, apixaban, and dabigatran etexilate, have certain advantages over traditional agents. They can be administered orally at a fixed dose without routine coagulation monitoring and have minimal food and drug interactions. These characteristics may result in better adherence to guidelines and improved patient outcomes. This review provides an overview of phase III clinical trial data for these newer anticoagulants in major orthopaedic surgery and in hospitalised acutely ill medical patients, and discusses their potential for extended use in the post-hospital discharge setting. All three newer oral anticoagulants are approved in many countries for the prevention of VTE after hip replacement or knee replacement surgery in adult patients, and it is likely that these drugs will contribute considerably towards reducing the substantial healthcare burden associated with VTE.

SummaryThe management of acute pulmonary embolism (PE) is often challenging and requires specific medical expertise, diagnostic techniques and therapeutic options that may not be available in all hospitals throughout the entire week. The aim of our study was to evaluate whether or not an association exists between weekday or weekend admission and mortality for patients hospitalised with acute PE. Using routinely collected hospital administrative data, we examined patients discharged with a diagnosis of PE from the hospitals of the Emilia- Romagna Region in Italy (January 1999-December 2009). The risk of inhospital death was calculated for admissions at the weekend and compared to weekday admissions. Of a total of 26,560 PEs, 6,788 (25.6%) had been admitted during weekends. PE admissions were most frequent on Mondays (15.8%) and less frequent on Saturdays and Sun- days/holidays (12.8%) (p

SummaryStatins have important pleiotropic effects and have been shown to reduce vascular inflammation. Some evidence suggests that statins may have a role in the primary prevention of atrial fibrillation (AF), whereas little is know on the role of statins in patients with existing AF. We performed a meta-analysis of the literature to assess the effect of statins on the recurrence of AF after electrical cardioversion or ablation. MEDLINE and EMBASE databases were searched up to January 2010. Relative risks (RR) and 95% confidence intervals (CIs) were then calculated and pooled using a random-effects model. Statistical heterogeneity was evaluated through the use of I2 statistics. Sixteen studies were included in our systematic review. Statins did not reduce the risk of AF recurrence after ablation (four studies including 750 patients; RR, 1.04; 95% CI, 0.85–1.28, p=0.71; I2 = 34%). Conversely, the use of statins was associated with a significantly reduced risk of AF recurrence after electrical cardioversion (12 studies including 1790 patients; RR, 0.78; 95% CI, 0.67–0.90, p=0.0003; I2 = 34%). This reduction was not statistically significant when the analysis was restricted to randomised controlled trials (RCTs) only (five studies, 458 patients, RR, 0.76; 95% CI, 0.48–1.20). In conclusion, statins may lower the risk of AF recurrence after electrical cardioversion, but not ablation. However, this finding should be considered with caution, and larger RCTs are warranted to confirm our preliminary results.

SummaryUnanticipated elevation of the INR is common in patients receiving warfarin. We performed a prospective cohort study of 107 warfarintreated patients with INR values of more than 10 who received a single 2.5 mg dose of oral vitamin K. During the first week, one patient experienced major bleeding, and one died. In the first 90 days after enrolment four patients had major bleeding (3.7%, 1.0% to 9.3%), eight patients (7.5%, 3.3% to 14.2%) died and two had objectively confirmed thromboembolism. Based on our low rate of observed major bleeding we conclude that 2.5 mg of oral vitamin K is a reasonable treatment for patients with INR values of more than 10 who are not actively bleeding.

SummarySeveral small series have suggested the efficacy of thrombolysis in patients with cerebral vein thrombosis (CVT). However, since no randomised controlled trials have compared the use of thrombolysis with anticoagulant treatment in these patients, the risk to benefit ratio of this approach remains uncertain. The aim of this study is therefore to assess the safety of thrombolysis in CVT estimating mortality and major bleeding complications. MEDLINE and EMBASE databases were searched up to June 2010. Two reviewers performed study selection independently. Studies providing data on mortality and/or on the incidence of major bleeding complications were potentially eligible for the study. Two reviewers independently extracted data on study and population characteristics, type, dose and administration route of thrombolytic treatment; use and dose of concomitant heparin. Weighted mean proportion of the mortality rate and of the rate of major and non-major bleeding complications were calculated. Fifteen studies for a total of 156 patients were included. Twelve patients died after thrombolysis (weighted mean 9.2%; 95% CI 4.3, 15.7%) and 15 patients had a major bleeding complication (weighted mean 9.8%; 95% CI 5.3, 15.6%). Twelve haemorrhages were intracranial (weighted mean 7.6%; 95% CI 3.5, 13.1%), and seven of these patients died (58.3%; 95% CI 32.0, 80.7%). Our results suggest that thrombolysis is associated with a nonnegligible incidence of major bleeding complications, including intracranial bleeding potentially affecting patients outcome. Future studies are necessary to evaluate the safety of thrombolysis in comparison to more conservative strategies.

SummaryOptimal timing for restarting anticoagulant therapy after intracranial bleeding is a critical issue. The purpose of this systematic review is to summarize published studies on the management of oral anticoagulant therapy after intracranial bleeding secondary to the use of vitamin K antagonists in patients with a mechanical heart valve. A computer-assisted search of the MEDLINE and EMBASE electronic databases till January 2008 was performed. Two investigators independently performed study selection and completed a predefined quality assessment and data extraction form. Main inclusion criterion was the enrolment of patients with a mechanical heart valve and intracranial haemorrhage during oral anticoagulant treatment. Any randomised controlled trial, observational cohort study, case series and reports was included. No randomised controlled trials were identified. Six observational cohort studies were included in the final analysis. All studies were of low quality. A total of 120 patients were enrolled. Anticoagulation was restarted within a broad time range (2 days to 3 months). Four ischaemic strokes and two recurrent cerebral haemorrhages occurred after anticoagulation was restarted after a mean follow-up of 7.9 months. Eighteen patients were described in the selected case reports. Anticoagulant therapy was restarted within four days to eight weeks. Two patients had a recurrent haemorrhagic event, and no ischaemic events were reported. In conclusion, restarting oral anticoagulant therapy few days and, indirectly, stopping anticoagulant therapy for a few days (even for 7–14 days) after the occurrence of cerebral haemorrhage are both safe. However, well-designed studies are strongly recommended to provide better evidence.

The 8th American College of Chest Physicians Guidelines – A perspective on venous thromboembolism guidelines

Risk factors for suboptimal efficacy of 3-factor prothrombin complex concentrates in emergency VKA anticoagulation reversal

SummaryPost-thrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT). Little is known about prognostic factors that might identify patients at high risk for the development of PTS. Body mass index (BMI) has been previously reported to be associated to the development of PTS. The aim of this study was to assess the association between BMI and other anthropometric parameters and PTS in a general population of DVT patients.In a prospective cohort study, 83 consecutive patients with objective diagnosis of DVT underwent physical examination. BMI was recorded at baseline and at 12 months, and waist circumference was recorded at 12 months to assess individual patterns of body fat distribution. The presence of PTS at 12 months was ascertained using a validated clinical scale. Sixty-three patients (75.9%) were overweight or obese at 12 months, 60 (72.3%) had a weight gain over 1 year. Twenty patients developed PTS (24.1%). Mean BMI was significantly higher in patients who developed PTS than in patients who did not (29.6 and 27.2 Kg/m2, respectively, p = 0.022). A BMI of > 28 Kg/m2 predicted early onset of PTS (OR 3.54, 95% CI 1.07-12.08, p = 0.017). Neither patterns of fat distribution nor weight gain in 1 year were correlated with PTS (p = 0.918 and p = 0.775, respectively).BMI is significantly correlated with the development of PTS. Patients with DVT should be encouraged to avoid weight gain. Reducing patient weight might be an important strategy to prevent PTS.

New insights on the role of direct thrombin inhibitors for the prevention of venous thromboembolism after major orthopaedic surgery

Haemost 2014; 112: 692-699. Historically, hospital-related venous thromboembolism (VTE) has been thought to mainly occur in surgical patients (1). Several phase III randomised controlled trials (RCTs) have investigated benefits and harms of pharmacologic thromboprophylaxis in this setting (1). Subsequently, acutely ill hospitalised medical patients have been recognised to be at increased risk of VTE, with approximately 75% of all VTE-related deaths diagnosed in autopsy studies occurring in non-surgical patients (2). Based on such compelling evidence, a number of RCTs have been carried out which consistently shown the clinical benefit of pharmacologic thromboprophylaxis also in medical inpatients (3, 4). Conversely, 3 phase III RCTs, i.e. EXCLAIM, ADOPT, and MAGELLAN studies, have subsequently failed to support the extended use of thromboprohylaxis beyond the first two weeks of treatment in this setting due to an excess in bleeding rates (5-7). The results of these trials have raised again concerns on the true clinical benefit of anticoagulant prophylaxis in a population that is mainly represented by fragile, elderly patients (8). The widespread existence of these concerns is confirmed by the fact that despite high-quality evidence supporting in-hospital prophylaxis and recommendations from international guidelines, thromboprophylaxis in acutely ill medical inpatients remains substantially underused (9-11). Appropriate patient selection remains a major issue and a number of pitfalls in proposed strategies have been identified. First, the group-specific thromboembolic risk assessment used in the RCTs, that is based on the diagnosis of admission, does not sufficiently take into account the heterogeneity of medical diseases and the role of concomitant patient-specific risk factors; second, immobilisation per se does not represent a sufficient condition for recommending pharmacologic thromboprophylaxis; third, patient bleeding risk has not been adequately addressed and, therefore, used for patient selection (12). The 9th edition of the American College of Chest Physicians (ACCP) guidelines for the first time introduced a new approach to patient selection, based on the application of risk assessment models (RAM) (3). The concept behind RAMs is that VTE risk factors are generally cumulative and the majority of patients hospitalised in medical wards harbour more than one risk factor. The proposed RAM to assess VTE risk for the medical population was the PADUA score, which combines patient specific risk factors (e.g. advanced age, obesity, known thrombophilia, previous VTE) and disease specific risk factors (e.g. cancer, heart failure, respiratory failure, reduced mobility) (13). Although there was no validated RAM to assess the individual risk of bleeding, the guidelines panel proposed to consider the IMPROVE bleeding risk score, yet acknowledging this score is complex and not validated, and therefore suggesting to consider patients to have an excessive risk of bleeding if they had multiple risk factors or one risk factor with the strongest association with bleeding (14). Unfortunately, none of available RAM has been extensively and adequately validated till recently (15). Indeed, the model performance in validation studies is often worse than in development studies (12). In this issue of Thrombosis and Haemostasis, Mahan et al. published the first external validation of any appropriately evidence-derived RAM in acutely ill medical patients (16). They used a large database of 41,486 inpatients from three acute care hospitals to validate the IMPROVE RAM. The seven included VTE risk factors and the assigned points can be summarised by the acronym Im1P3A1C2T2-I1LL2: Immobilisation ≥ 7 days, Previous VTE, Age > 60 years, Cancer, known Thrombophilia, Intensive care / coronary care unit stay, Lower Limb paralysis. In the derivation cohort, a score of 0 to 1 placed patients at low risk of symptomatic VTE (less than 1%), a score of 2 to 3 at moderate VTE risk (1 to 2%), and a score of 4 or more at high VTE risk (> 4.8%) (17). In this study, the incidence of VTE was 0.20% (95% confidence interval [CI] 0.18-0.22), 1.04% (95% CI 0.88-1.25) and 4.15% (95% CI 2.79-8.12) in the low, moderate, and high VTE risk groups, respectively (16). The proportion of patients classified at low, moderate and high VTE risk was 63.3%, 31.1%, and 5.5%, respectively. As the receiver-operating curve was 0.77, we may conclude that another step forward for the correct stratification of VTE risk in medical inpatients has been made. We are only at the beginning of a new era in VTE prevention. As correctly acknowledged by the authors, this external validation study demonstrates a level 2 of evidence for the validation of a RAM, according to McGinn scale (18). An impact analysis remains necessary in order to reach a level 1 of evidence and to use a RAM in a wide variety of settings with confidence that its use can change clinical behaviour and improve patient outcomes. Concomitantly, it is important to perform Invited Editorial Focus

Presence of residual thromboemboli at least six months after a first episode of symptomatic pulmonary embolism: Do perfusion scintigraphy and angio-computed tomography agree?

Duration of anticoagulant treatment and recurrence of venous thromboembolism in patients with and without thrombophilic abnormalities

Antithrombin levels and the risk of a first episode of venous thromboembolism. A case-control study

SummaryVitamin K antagonists (VKA) therapy is increasingly used in elderly for prevention of venous thromboembolism (VTE) and of stroke in atrial fibrillation (AF). Glomerular filtration rate (GFR), usually estimated from different equations, decreases progressively with age and it is a risk factor for bleeding. In the frame of the EPICA study, a multicentre prospective observational study including 4,093 patients ≥80 years naïve to VKA treated for AF or after VTE, we performed this ancillary study to evaluate the prevalence of chronic kidney diseases (CKD) by estimated GFR (eGFR). Incidence of bleedings was recorded and bleeding risk was evaluated in relation to eGFR calculated by Cockroft-Gault (C-G); Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas. In addition, the agreement among the three eGFR formulas was evaluated. We recorded 179 major bleedings (rate 1.87 x100 patient-years [py]), 26 fatal (rate 0.27 x100 py). Moderate CKD was detected in 69.3%, 59.3% and 47.0% and severe CKD in 5.8%, 7.4% and 10.0% of cases by C-G, MDRD and CKD-EPI, respectively. Bleeding risk was higher in patients with severe CKD irrespective of the applied equation. This study confirms that CKD represents an independent risk factor for bleeding and that a wide proportion of elderly on VKA had severe or moderate CKD, suggesting the need for frequent monitoring. Although the different available equations yield different eGFR, all appear to similarly predict the risk of major bleeding.

SummaryMany studies showed that the occurrence of cardiovascular and cerebrovascular events exhibits a seasonal and monthly variation. Evidences of a seasonal and monthly variation in the incidence of venous thromboembolism (VTE) are more conflicting. We conducted a systematic review and a meta-analysis of the literature to assess the presence of an infradian rhythm of this disease. MEDLINE and EMBASE databases were searched up to January 2010. Monthly and seasonal variation in the incidence of VTE were analysed. We included studies analysing seasonal or monthly aggregation in the incidence of deep-vein thrombosis (DVT) and/or pulmonary embolism (PE) with an objective diagnosis of VTE. Two authors independently reviewed and extracted data. Seventeen studies for a total of about 35,000 patients were included. Twelve studies analysed the seasonal variation and 10 studies the monthly variation of VTE. Our results showed a significantly increased incidence of VTE in winter (chi-square 146.04, p

SummarySome studies have suggested that high levels of total white blood cell (WBC) count and C-reactive protein (CRP) may be considered as independent prognostic factors in patients with acute coronary syndromes (ACS) and/or after cardiac revascularisation by percutaneous coronary intervention or coronary artery bypass grafting surgery. Evidence on the role of neutrophils in cardiovascular disease is less compelling. Therefore, we conducted a systematic review of the literature with the aim of identifying all the available evidence to clarify the role of neutrophils (absolute or relative count, neutrophil/lymphocyte ratio) as a prognostic risk factor in patients with ACS and/or cardiac revascularisation. All published studies evaluating the role of neutrophils as a risk factor for clinical outcomes were assessed using the MEDLINE and EMBASE databases. Study selection, data extraction and validity assessment was performed independently by two reviewers. Twenty-one studies (17 of which had positive results) for a total of more than 34,000 patients were included. Ten of 13 studies in ACS patients found that neutrophils measured on-admission are related to mortality rate and/or to major adverse clinical events. A predictive value of neutrophils after cardiac revascularisation procedures was reported in seven out of eight studies. Most of the studies showed that neutrophils were independent predictors of cardiovascular outcomes when analysed concomitantly with other markers of inflammation (WBC, CRP). The findings of our systematic review highlight the potential application of this inexpensive and readily available inflammatory marker for risk stratification in patients with ACS and/or cardiac revascularisation.

SummaryProthrombin complex concentrates (PCCs) are recommended as the treatment of choice in warfarin-related coagulopathy. However, the risk of thromboembolic complications associated with their use is not well defined. We performed a meta-analysis to estimate the rate of thromboembolic complications in patients receiving vitamin K antagonists (VKAs) treated with PCCs for bleeding or before urgent surgery. Medline and Embase databases were searched. Two reviewers performed study selection and extracted data independently. Studies providing data on incidence of thromboembolic complications in VKA-treated patients were eligible for the study. Weighted mean proportion of the rate of thromboembolic complications and the mortality rate were calculated. Twenty-seven studies (1,032 patients) were included. Seven studies used 3-factor, and 20 4-factor PCCs. Twelve patients had a thromboembolic complication (weighted mean 1.4%; 95% CI 0.8–2.1), of which two were fatal. The incidence of thromboembolic events was 1.8% (95% CI 1.0–3.0) in patients treated with 4-factor PCCs, and 0.7% (95% CI 0.0–2.4) in patients treated with 3-factor PCCs. Total mortality rate was 10.6% (95% CI 5.9–16.6). In conclusion, our results suggest there is a low but quantifiable risk of thromboembolism in VKA-treated patients receiving PCCs for anticoagulation reversal. These findings should be confirmed in randomised, controlled trials.

Walter Ageno1; Francesco Dentali1; Alessandro Squizzato1; Trevor Baglin2; James Douketis3; Martin Lansberg4; Maurizio Paciaroni5; Gualtiero Palareti6 1Department of Clinical Medicine, University of Insubria, Varese, Italy; 2Department of Hematology, Cambridge University, Cambridge, UK; 3Department of Medicine, McMaster University, Hamilton, Canada; 4Stanford Stroke Center, Stanford University Medical Center, Palo Alto, USA; 5Department of Vascular Medicine and Stroke Unit, University of Perugia, Perugia, Italy; 6Department of Angiology, University of Bologna, Bologna, Italy

Hospitalised medical patients are at increased risk of venous thromboembolism (VTE), but the incidence of hospitalisation-related VTE in unselected medical inpatients has not been extensively studied, and uncertainties remain about the optimal use of thromboprophylaxis in this setting. Aims of our prospective, observational study were to assess the prevalence of VTE and the incidence of symptomatic, hospitalisation-related events in a cohort of consecutive patients admitted to 27 Internal Medicine Departments, and to evaluate clinical factors associated with the use of thromboprophylaxis. Between March and September 2006, a total of 4,846 patients were included in the study. Symptomatic VTE with onset of symptoms later than 48 hours after admission ("hospital-acquired" events, primary study end-point) occurred in 26 patients (0.55%), while the overall prevalence of VTE (including diagnosis prior to or at admission) was 3.65%. During hospital stay antithrombotic prophylaxis was administered in 41.6% of patients, and in 58.7% of those for whom prophylaxis was recommended according to the 2004 Guidelines of the American College of Chest Physicians. The choice of administering thromboprophylaxis or not appeared qualitatively adherent to indications from randomised clinical trials and international guidelines, and bed rest was the strongest determinant of the use of prophylaxis. Data from our real-world study confirm that VTE is a relevant complication in patients admitted to Internal Medicine Departments, and recommended tromboprophylaxis is still under-used, in particular in some patients groups. Further efforts are needed to better define risk profile and to optimise prophylaxis in the heterogeneous setting of medical inpatients.

SummaryInherited thrombophilic abnormalities may have a role in the development of portal vein thrombosis (PVT).However, the prevalence of these factors in patients with PVT has been evaluated only in small studies with non-conclusive results. It was the purpose of this study to assess the risk of PVT associated with factorV Leiden (FVL) and G20210A prothrombin mutation (PTM). The MEDLINE, EMBASE, Cochrane Library databases, reference lists of retrieved articles and contact with content experts were used. Studies carried out in Western Europe comparing the prevalence of prothrombotic abnormalities in patients with PVT and in controls without a history of thromboembolic disease were included. Two reviewers independently selected studies and extracted study characteristics, quality and outcomes. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each trial and pooled using a fixed and random-effects model. Statistical heterogeneity was evaluated using the I2 statistic. Sensitivity analyses were performed examining separately studies according to the etiology of PVT and to control population. Twelve studies involving more than 3,000 patients were included. The pooled OR for PVT was 1.90 (95%CI: 1.25, 2.90) in patients with FVL and 4.48 (95%CI: 3.10, 6.48) in patients with PTM. In conclusion, PVT is associated with the presence of FVL and PTM in Western Europe.

SummaryResidual venous obstruction (RVO) in patients with previous deep vein thrombosis (DVT) of the lower limbs has been suggested as an independent risk factor for recurrent venous thromboembolism (VTE).RVO could be a marker of a persistent prothrombotic state. We have compared the rate of RVO in patients with DVT and a personal history of at least one previous episode of VTE to the rate of RVO among patients with a first episode of DVT. All patients underwent compression ultrasonography (CUS) of the lower limbs 1 year after index DVT. RVO was arbitrarily defined as a thrombus occupying, at maximal compressibility, more than 20% of the vein area in the absence of compression. 50 consecutive patients with recurrent DVT and 50 age and sex-matched patients with a single episode of DVT were enrolled. The index event was idiopathic in 62% of patients with recurrent DVT and in 60% of patients with a single episode. In 74% of patients with recurrent DVT the index event occurred in either the contralateral leg or in a different segment of the ipsilateral leg. RVO was detected in 50% of patients with a single episode of DVT and in 88% of patients with recurrent DVT (p

Post-thrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT). Little is known about prognostic factors that might identify patients at high risk for the development of PTS. Body mass index (BMI) has been previously reported to be associated to the development of PTS. The aim of this study was to assess the association between BMI and other anthropometric parameters and PTS in a general population of DVT patients. In a prospective cohort study, 83 consecutive patients with objective diagnosis of DVT underwent physical examination. BMI was recorded at baseline and at 12 months, and waist circumference was recorded at 12 months to assess individual patterns of body fat distribution. The presence of PTS at 12 months was ascertained using a validated clinical scale. Sixty-three patients (75.9%) were overweight or obese at 12 months, 60 (72.3%) had a weight gain over 1 year. Twenty patients developed PTS (24.1%). Mean BMI was significantly higher in patients who developed PTS than in patients who did not (29.6 and 27.2 Kg/m(2), respectively, p = 0.022). A BMI of28 Kg/m(2) predicted early onset of PTS (OR 3.54, 95% CI 1.07-12.08, p = 0.017). Neither patterns of fat distribution nor weight gain in 1 year were correlated with PTS (p = 0.918 and p = 0.775, respectively). BMI is significantly correlated with the development of PTS. Patients with DVT should be encouraged to avoid weight gain. Reducing patient weight might be an important strategy to prevent PTS.

SummaryLow dose oral vitamin K rapidly reverses warfarin-associated coagulopathy. Its effect in patients receiving acenocoumarol is uncertain. We compared the effect of withholding acenocoumarol and administering 1 mg oral vitamin K with simply withholding acenocoumarol in asymptomatic patients presenting with INR values between 4.5 and 10.0. The primary end-point of the study was the INR value on the day following randomisation. We found that patients receiving oral vitamin K had more sub-therapeutic INR levels than controls (36.6% and 13.3%, respectively; RR 1.83, 95% confidence interval 1.16, 2.89) and a lower, but non-significant, proportion of INR values in range (50% and 66.6%, respectively) on the day following randomisation. After 5 ± 1 days, there were more patients with an INR value in range in the vitamin K group than in controls (74.1% and 44.8%, respectively). There were no clinical events during 1 month follow-up. We conclude that the omission of a single dose of acenocoumarol is associated with an effective reduction of the INR in asymptomatic patients presenting with an INR value of 4.5 to 10.0. Furthermore, the use of a 1 mg dose of oral vitamin K results in an excessive risk of overreversal of the INR.

SummaryThere is an increasing use of computer-based dosage programs to monitor oral anticoagulant therapy in outpatients. DAWN AC INDUCTION by 4S, UK, is a computer generated system to initiate oral anticoagulant therapy providing fast access to the maintenance program. This method of initiation of anticoagulant therapy has not been validated. We therefore randomized 50 hospitalized patients starting oral anticoagulation to control by the computer and 51 by manual dosing using a dosing schedule based on a locally defined algorithm. After a 7 days follow up, the daily mean INR was 2.09 and 2.07 and the proportion of dose adjustments was 48% and 45% in the computer and manually controlled groups respectively. Twenty-eight % of the patients monitored by the computer system required at least one manual overriding. DAWN AC INDUCTION provided a simple and accurate organization of the data, with an overall quality comparable to that of the manual system. Furthermore, the induction programme provided simple access to the maintenance programme. Although it required careful monitoring, the programme resulted in a significant saving in personnel time.