Henri Bounameaux

Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report

BACKGROUNDnWe update recommendations on 12 topics that were in the 9th edition of these guidelines, and address 3 new topics.nnnMETHODSnWe generate strong (Grade 1) and weak (Grade 2) recommendations based on high- (Grade A), moderate- (Grade B), and low- (Grade C) quality evidence.nnnRESULTSnFor VTE and no cancer, as long-term anticoagulant therapy, we suggest dabigatran (Grade 2B), rivaroxaban (Grade 2B), apixaban (Grade 2B), or edoxaban (Grade 2B) over vitamin K antagonist (VKA) therapy, and suggest VKA therapy over low-molecular-weight heparin (LMWH; Grade 2C). For VTE and cancer, we suggest LMWH over VKA (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). We have not changed recommendations for who should stop anticoagulation at 3xa0months or receive extended therapy. For VTE treated with anticoagulants, we recommend against an inferior vena cava filter (Grade 1B). For DVT, we suggest not using compression stockings routinely to prevent PTS (Grade 2B). For subsegmental pulmonary embolism and no proximal DVT, we suggest clinical surveillance over anticoagulation with a low risk of recurrent VTE (Grade 2C), and anticoagulation over clinical surveillance with a high risk (Grade 2C). We suggest thrombolytic therapy for pulmonary embolism with hypotension (Grade 2B), and systemic therapy over catheter-directed thrombolysis (Grade 2C). For recurrent VTE on a non-LMWH anticoagulant, we suggest LMWH (Grade 2C); for recurrent VTE on LMWH, we suggest increasing the LMWH dose (Grade 2C).nnnCONCLUSIONSnOf 54 recommendations included in the 30 statements, 20 were strong and none was based on high-quality evidence, highlighting the need for further research.

International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer

Summary.u2002 Background:u2002Guidelines addressing the management of venous thromboembolism (VTE) in cancer patients are heterogeneous and their implementation has been suboptimal worldwide. Objectives:u2002To establish a common international consensus addressing practical, clinically relevant questions in this setting. Methods:u2002An international consensus working group of experts was set up to develop guidelines according to an evidence‐based medicine approach, using the GRADE system. Results:u2002For the initial treatment of established VTE: low‐molecular‐weight heparin (LMWH) is recommended [1B]; fondaparinux and unfractionated heparin (UFH) can be also used [2D]; thrombolysis may only be considered on a case‐by‐case basis [Best clinical practice (Guidance)]; vena cava filters (VCF) may be considered if contraindication to anticoagulation or pulmonary embolism recurrence under optimal anticoagulation; periodic reassessment of contraindications to anticoagulation is recommended and anticoagulation should be resumed when safe; VCF are not recommended for primary VTE prophylaxis in cancer patients [Guidance]. For the early maintenance (10u2003days to 3u2003months) and long‐term (beyond 3u2003months) treatment of established VTE, LMWH for a minimum of 3u2003months is preferred over vitamin K antagonists (VKA) [1A]; idraparinux is not recommended [2C]; after 3–6u2003months, LMWH or VKA continuation should be based on individual evaluation of the benefit‐risk ratio, tolerability, patient preference and cancer activity [Guidance]. For the treatment of VTE recurrence in cancer patients under anticoagulation, three options can be considered: (i) switch from VKA to LMWH when treated with VKA; (ii) increase in LMWH dose when treated with LMWH, and (iii) VCF insertion [Guidance]. For the prophylaxis of postoperative VTE in surgical cancer patients, use of LMWH o.d. or low dose of UFH t.i.d. is recommended; pharmacological prophylaxis should be started 12–2u2003h preoperatively and continued for at least 7–10u2003days; there are no data allowing conclusion that one type of LMWH is superior to another [1A]; there is no evidence to support fondaparinux as an alternative to LMWH [2C]; use of the highest prophylactic dose of LMWH is recommended [1A]; extended prophylaxis (4u2003weeks) after major laparotomy may be indicated in cancer patients with a high risk of VTE and low risk of bleeding [2B]; the use of LMWH for VTE prevention in cancer patients undergoing laparoscopic surgery may be recommended as for laparotomy [Guidance]; mechanical methods are not recommended as monotherapy except when pharmacological methods are contraindicated [2C]. For the prophylaxis of VTE in hospitalized medical patients with cancer and reduced mobility, we recommend prophylaxis with LMWH, UFH or fondaparinux [1B]; for children and adults with acute lymphocytic leukemia treated with l‐asparaginase, depending on local policy and patient characteristics, prophylaxis may be considered in some patients [Guidance]; in patients receiving chemotherapy, prophylaxis is not recommended routinely [1B]; primary pharmacological prophylaxis of VTE may be indicated in patients with locally advanced or metastatic pancreatic [1B] or lung [2B] cancer treated with chemotherapy and having a low risk of bleeding; in patients treated with thalidomide or lenalidomide combined with steroids and/or chemotherapy, VTE prophylaxis is recommended; in this setting, VKA at low or therapeutic doses, LMWH at prophylactic doses and low‐dose aspirin have shown similar effects; however, the efficacy of these regimens remains unclear [2C]. Special situations include brain tumors, severe renal failure (CrClu2003<u200330u2003mLu2003min−1), thrombocytopenia and pregnancy. Guidances are provided in these contexts. Conclusions:u2002Dissemination and implementation of good clinical practice for the management of VTE, the second cause of death in cancer patients, is a major public health priority.

International clinical practice guidelines for the treatment and prophylaxis of thrombosis associated with central venous catheters in patients with cancer

Summary.u2002 Background:u2002Although long‐term indwelling central venous catheters (CVCs) may lead to pulmonary embolism (PE) and loss of the CVC, there is lack of consensus on management of CVC‐related thrombosis (CRT) in cancer patients and heterogeneity in clinical practices worldwide. Objectives:u2002To establish common international Good Clinical Practices Guidelines (GCPG) for the management of CRT in cancer patients. Methods:u2002An international working group of experts was set up to develop GCPG according to an evidence‐based medicine approach, using the GRADE system. Results:u2002For the treatment of established CRT in cancer patients, we found no prospective randomized studies, two non‐randomized prospective studies and one retrospective study examining the efficacy and safety of low‐molecular‐weight heparin (LMWH) plus vitamin K antagonists (VKAs). One retrospective study evaluated the benefit of CVC removal and two small retrospective studies were on thrombolytic drugs. For the treatment of symptomatic CRT, anticoagulant treatment (AC) is recommended for a minimum of 3u2003months; in this setting, LMWHs are suggested. VKAs can also be used, in the absence of direct comparisons of these two types of anticoagulants in this setting [Guidance]. The CVC can be kept in place if it is functional, well‐positioned and non‐infected and there is good resolution under close surveillance; whether the CVC is kept or removed, no standard approach in terms of AC duration has been established [Guidance]. For the prophylaxis of CRT in cancer patients, we found six randomized studies investigating the efficacy and safety of VKA vs. placebo or no treatment, one on the efficacy and safety of unfractionnated heparin, six on the value of LMWH, one double‐blind randomized and one non randomized study on thrombolytic drugs and six meta‐analyses of AC and CVC thromboprophylaxis. Type of catheter (open‐ended like the Hickman® catheter vs. closed‐ended catheter with a valve like the Groshong® catheter), its position (above, below or at the junction of the superior vena cava and the right atrium) and method of placement may influence the onset of CRT on the basis of six retrospective trials, four prospective non‐randomized trials, three randomized trials and one meta‐analysis. In light of these data: use of AC for routine prophylaxis of CRT is not recommended [1A]; a CVC should be inserted on the right side, in the jugular vein, and distal extremity of the CVC should be located at the junction of the superior vena cava and the right atrium [1A]. Conclusion:u2002Dissemination and implementation of these international GCPG for the prevention and treatment of CRT in cancer patients at each national level is a major public health priority, needing worldwide collaboration.

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism

BACKGROUND Although many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full‐ or lower‐intensity anticoagulation therapy or aspirin. METHODS In this randomized, double‐blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once‐daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding. RESULTS A total of 3365 patients were included in the intention‐to‐treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups. CONCLUSIONS Among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439.)

Characterization of endothelial-like cells derived from human mesenchymal stem cells.

Summary.u2002 Background:u2002 Blood‐derived endothelial progenitor cells (EPC) have been used to treat ischemic disease. However, the number of EPC that can be obtained from adult blood is limited.

Cardiac biomarkers for risk stratification in non-massive pulmonary embolism: a multicenter prospective study

Summary.u2002 Background: Troponins (cTnI and cTnT), N‐terminal pro‐Brain Natriuretic Peptide (NT‐proBNP), myoglobin, heart‐type fatty acid‐binding protein (H‐FABP) and fibrin D‐Dimer are emergent candidates for risk stratification in pulmonary embolism (PE). Objective: To compare the respective prognostic values of biomarker with non‐massive PE to predict an adverse outcome at 3u2003months. Patients/Methods: One hundred and forty‐six consecutive patients with non‐massive PE were included in this multicenter prospective study. The combined outcome consisted of intensive care monitoring on admission, death or hospitalization attributable to either a PE‐related complication [defined by PE/deep vein thrombosis (DVT) relapse or major bleeding under anticoagulation] or to dyspnoea with or without chest pain during follow‐up. Results: The outcome was met in 12% of patients. In univariate analysis, a NT‐proBNP level above 300u2003pg/ml was the strongest predictor of unfavorable outcome with an odds ratio (OR) of 15.8 [95% confidence interval (CI): 2.05–122). ORs for the other variables were: 8.0 for D‐dimer >2000u2003ng/ml (95% CI: 1.1–64), 4.7 for H‐FABP >6ng/ml (95% CI:1.5–14.8), 3.5 for cTnI >0.09u2003ng/ml (95% CI:1.2–9.7), 3.4 for myoglobin >70u2003ng/ml (95% CI:0.9–12.2). Receiver operating curve (ROC) analysis indicated that NT‐proBNP was the best predictor [area under the curve (AUC) 0.84; 95%CI: 0.76–0.92; Pu2003<u20030.0001] with a negative predictive value of 100% (95% CI: 91–100) at 300u2003pg/ml. At that cut‐off, the true negative rate for NT‐proBNP was 40%. In multivariate analysis, NT‐proBNP was the only significant independent predictors. Conclusions: NT‐proBNP appears to be a good risk stratification marker in identifying low‐risk patients with non‐massive PE who could be treated in an outpatient setting.

International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer

Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. These patients are at an increased risk of developing VTE and are more likely to have a recurrence of VTE and bleeding while taking anticoagulants. Management of VTE in patients with cancer is a major therapeutic challenge and remains suboptimal worldwide. In 2013, the International Initiative on Thrombosis and Cancer (ITAC-CME), established to reduce the global burden of VTE in patients with cancer, published international guidelines for the treatment and prophylaxis of VTE and central venous catheter-associated thrombosis. The rapid global adoption of direct oral anticoagulants for management of VTE in patients with cancer is an emerging treatment trend that needs to be addressed based on the current level of evidence. In this Review, we provide an update of the ITAC-CME consensus recommendations based on a systematic review of the literature ranked according to the Grading of Recommendations Assessment, Development, and Evaluation scale. These guidelines aim to address in-hospital and outpatient cancer-associated VTE in specific subgroups of patients with cancer.

D-dimer, factor VIII coagulant activity, low-intensity warfarin and the risk of recurrent venous thromboembolism.

Summary.u2002 Background:u2002Elevated plasma D‐dimer and factor VIII coagulant activity (FVIIIc) may be associated with the risk of recurrent venous thromboembolism (VTE). Objectives:u2002To evaluate D‐dimer and FVIIIc as risk factors for recurrent VTE and assess the efficacy of extended low‐intensity warfarin (target International Normalized Ratio 1.5–2.0) in preventing recurrence by biomarker level. Patients and methods:u2002In the Prevention of Recurrent Venous Thromboembolism trial, 508 idiopathic VTE patients treated for ≥u20033u2003months with full‐intensity warfarin, and who had stopped warfarin for 7u2003weeks on average, were randomized to low‐intensity warfarin or placebo and followed for 2.1u2003years for recurrent VTE. Prerandomization blood samples were analysed for D‐dimer and FVIIIc. Results:u2002One‐third of participants had elevated baseline D‐dimer (≥u2003500u2003ngu2003mL−1) and one‐fourth, elevated FVIIIc (≥u2003150u2003IUu2003dL−1). Adjusting for other risk factors, the hazard ratios (HRs) for recurrent VTE with elevated D‐dimer or FVIIIc were 2.0 [95% confidence interval (CI) 1.2–3.4] and 1.5 (95% CI 0.8–2.8), respectively. The association of elevated D‐dimer with recurrence was larger among patients with one prior VTE (HR 3.2, 95% CI 1.3–8.0) than in patients with more than one event (HR 1.4, 95% CI 0.7–2.2). For patients with one prior VTE on placebo, the annual recurrence incidence was 10.9% with elevated D‐dimer and 2.9% with normal values. Low‐intensity warfarin was equally effective in recurrence risk reduction in those with normal or elevated biomarkers. Conclusions:u2002Among patients with idiopathic VTE, measurement of D‐dimer, but not FVIIIc, might be useful for risk stratification. The efficacy of extended low‐intensity warfarin therapy did not vary by biomarker level.

Challenges in the Diagnosis Acute Pulmonary Embolism

The state of the art of diagnostic evaluation of hemodynamically stable patients with suspected acute pulmonary embolism was reviewed. Diagnostic evaluation should begin with clinical assessment using a validated prediction rule in combination with measurement of D-dimer when appropriate. Imaging should follow only when necessary. Although with 4-slice computed tomography (CT) and 16-slice CT, the sensitivity for detection of pulmonary embolism was increased by combining CT angiography with CT venography, it is not known whether CT venography increases the sensitivity of 64-slice CT angiography. Methods to reduce the radiation exposure of CT venography include imaging only the proximal leg veins (excluding the pelvis) and obtaining discontinuous images. Compression ultrasound can be used instead. In young women, radiation of the breasts produces the greatest risk of radiation-induced cancer. It may be that scintigraphy is the imaging test of choice in such patients, but this pathway should be tested prospectively. A patient-specific approach to the diagnosis of pulmonary embolism can be taken safely in hemodynamically stable patients to increase efficiency and decrease cost and exposure to radiation.

Swiss Atherothrombosis Survey : a field report on the occurrence of symptomatic and asymptomatic peripheral arterial disease

Objectives.u2002 To investigate the Ankle/Brachial Pressure Index (ABI) for its suitability in daily practice to identify patients at atherothrombotic risk. To collect data on the prevalence of atherothrombotic events [coronary artery disease (CAD), stroke/transient ischaemic attack (TIA)], of ‘hidden’ (asymptomatic) versus ‘known’ (symptomatic) peripheral arterial disease (PAD) and treatment in the general practice population.