G. Pernod

Six Months vs Extended Oral Anticoagulation After a First Episode of Pulmonary Embolism: The PADIS-PE Randomized Clinical Trial

IMPORTANCE The optimal duration of anticoagulation after a first episode of unprovoked pulmonary embolism is uncertain. OBJECTIVES To determine the benefits and harms of an additional 18-month treatment with warfarin vs placebo, after an initial 6-month nonrandomized treatment period on a vitamin K antagonist. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind trial (treatment period, 18 months; median follow-up, 24 months); 371 adult patients who had experienced a first episode of symptomatic unprovoked pulmonary embolism (ie, with no major risk factor for thrombosis) and had been treated initially for 6 uninterrupted months with a vitamin K antagonist were randomized and followed up between July 2007 and September 2014 in 14 French centers. INTERVENTIONS Warfarin or placebo for 18 months. MAIN OUTCOMES AND MEASURES The primary outcome was the composite of recurrent venous thromboembolism or major bleeding at 18 months after randomization. Secondary outcomes were the composite at 42 months (treatment period plus 24-month follow-up), as well as each component of the composite, and death unrelated to pulmonary embolism or major bleeding, at 18 and 42 months. RESULTS After randomization, 4 patients were lost to follow-up, all after month 18, and 1 withdrew due to an adverse event. During the 18-month treatment period, the primary outcome occurred in 6 of 184 patients (3.3%) in the warfarin group and in 25 of 187 (13.5%) in the placebo group (hazard ratio [HR], 0.22; 95% CI, 0.09-0.55; P = .001). Recurrent venous thromboembolism occurred in 3 patients in the warfarin group and 25 patients in the placebo group (HR, 0.15; 95% CI, 0.05-0.43); major bleeding occurred in 4 patients in the warfarin group and in 1 patient in the placebo group (HR, 3.96; 95% CI, 0.44 to 35.89). During the 42-month entire study period (including the study treatment and follow-up periods), the composite outcome occurred in 33 patients (20.8%) in the warfarin group and in 42 (24.0%) in the placebo group (HR, 0.75; 95% CI, 0.47-1.18). Rates of recurrent venous thromboembolism, major bleeding, and unrelated death did not differ between groups. CONCLUSIONS AND RELEVANCE Among patients with a first episode of unprovoked pulmonary embolism who received 6 months of anticoagulant treatment, an additional 18 months of treatment with warfarin reduced the composite outcome of recurrent venous thrombosis and major bleeding compared with placebo. However, benefit was not maintained after discontinuation of anticoagulation therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00740883.

Incidence and predictors of venous thromboembolism recurrence after a first isolated distal deep vein thrombosis

Isolated distal deep vein thrombosis (iDDVT) (i.e. without proximal DVT or pulmonary embolism) represents half of all cases of lower limb DVT. Its clinical significance and management are controversial. Data on long‐term follow‐up are scarce, especially concerning risk and predictors of venous thromboembolism (VTE) recurrence.

Long-term risk of venous thromboembolism recurrence after isolated superficial vein thrombosis

Essentials Long‐term risk of recurrence of isolated superficial vein thrombosis (SVT) is under‐studied. We analyzed data from a cohort of first SVT and proximal deep vein thrombosis (DVT) without cancer. The risk of recurrence as DVT or pulmonary embolism is twice lower in SVT patients. However, overall risk of recurrence is similar between SVT and proximal DVT patients.

Risk factors for recurrent venous thromboembolism after unprovoked pulmonary embolism: the PADIS-PE randomised trial

We aimed to identify risk factors for recurrent venous thromboembolism (VTE) after unprovoked pulmonary embolism. Analyses were based on the double-blind randomised PADIS-PE trial, which included 371 patients with a first unprovoked pulmonary embolism initially treated during 6 months who were randomised to receive an additional 18 months of warfarin or placebo and followed up for 2 years after study treatment discontinuation. All patients had ventilation/perfusion lung scan at inclusion (i.e. at 6 months of anticoagulation). During a median follow-up of 41 months, recurrent VTE occurred in 67 out of 371 patients (6.8 events per 100 person-years). In main multivariate analysis, the hazard ratio for recurrence was 3.65 (95% CI 1.33–9.99) for age 50–65 years, 4.70 (95% CI 1.78–12.40) for age >65 years, 2.06 (95% CI 1.14–3.72) for patients with pulmonary vascular obstruction index (PVOI) ≥5% at 6 months and 2.38 (95% CI 1.15–4.89) for patients with antiphospholipid antibodies. When considering that PVOI at 6 months would not be available in practice, PVOI ≥40% at pulmonary embolism diagnosis (present in 40% of patients) was also associated with a 2-fold increased risk of recurrence. After a first unprovoked pulmonary embolism, age, PVOI at pulmonary embolism diagnosis or after 6 months of anticoagulation and antiphospholipid antibodies were found to be independent predictors for recurrence. Residual pulmonary embolism is an independent predictor for recurrence after unprovoked pulmonary embolism http://ow.ly/jf0X30fQQGf

[Management of pulmonary embolism: A 2015 update].

Pulmonary embolism (PE) is a frequent, serious and multifactorial disease, the incidence of which increases with advanced age. In the absence of pathognomonic clinical signs or symptoms, diagnostic management lies in the evaluation of clinical pre-test probability followed by a laboratory or an imaging test. So far, multidetector computed tomography angiography is the diagnostic test of choice to make a positive diagnosis of PE. Anticoagulants at therapeutic dose for at least 3 months constitute the cornerstones of PE therapeutic management. Duration of anticoagulant treatment is modulated according to the presence of transient (surgery, plaster immobilization, bed rest/hospitalization) and chronic/persistent (age, cancer, clinical or biological thrombophilia…) risk factors of PE. Thrombolysis is usually prescribed only for cases of severe PE with arterial hypotension. Arrival of new oral anticoagulants, which have recently been shown to be as effective and as safe as vitamin K antagonist, should simplify and ease ambulatory management of PE and favor more prolonged treatments with anticoagulant for cases of unprovoked PE or PE provoked by a chronic/persistent risk factor.

More on: incorrect use of thromboprophylaxis for venous thromboembolism in medical and surgical patients: results of a multicentric, observational, and cross-sectional study in Brazil.

Dorner F, Rieger M. Nonneutralizing IgM and IgG antibodies to von Willebrand factor-cleaving protease (ADAMTS-13) in a patient with thrombotic thrombocytopenic purpura. Blood 2003; 102: 3241–3. 41 George JN. The role of ADAMTS13 in the pathogenesis of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clin Adv Hematol Oncol 2005; 3: 627–32. 42 Rodas RA, Fenstermaker RA, McKeever PE, Blaivas M, Dickinson LD, Papadopoulos SM, Hoff JT, Hopkins LN, Duffy-Fronckowiak M, Greenberg HS. Correlation of intraluminal thrombosis in brain tumor vessels with postoperative thrombotic complications: a preliminary report. J Neurosurg 1998; 89: 200–5. 43 Sawaya R, Zuccarello M, Elkalliny M, Nishiyama H. Postoperative venous thromboembolism and brain tumors: Part I. Clinical profile. J Neurooncol 1992; 14: 119–25. 44 Sawaya R, Highsmith RF. Postoperative venous thromboembolism and brain tumors: Part III. Biochemical profile. J Neurooncol 1992; 14: 113–8. 45 Ruff RL, Posner JB. Incidence and treatment of peripheral venous thrombosis in patients with glioma. Ann Neurol 1983; 13: 334–6. 46 Liu F, Feys HB, Dong N, Zhao Y, Ruan C. Alteration of ADAMTS13 antigen levels in patients with idiopathic thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura and systemic lupus erythematosus. Thromb Haemost 2006; 95: 749–50. 47 Rieger M, Ferrari S, Kremer Hovinga JA, Konetschny C, Herzog A, Koller L, Weber A, Remuzzi G, Dockal M, Plaimauer B, Scheiflinger F. Relation between ADAMTS13 activity and ADAMTS13 antigen levels in healthy donors and patients with thrombotic microangiopathies (TMA). Thromb Haemost 2006; 95: 212–20. 48 Shelat SG, Smith P, Ai J, Zheng XL. Inhibitory autoantibodies against ADAMTS-13 in patients with thrombotic thrombocytopenic purpura bind ADAMTS-13 protease and may accelerate its clearance in vivo. J Thromb Haemost 2006; 4: 1707–17.

More on: a survey of thrombosis prophylaxis use in patients undergoing arthroscopic surgery

We have read with a great interest the recently published paper byAgeno et al. [1] on the use of thromboprophylaxis in patients undergoing arthroscopic surgery, and the commentary of Dahl [2] on the geographical opinions on prophylaxis use among surgeons. In a surgical situation in which consensus is not completely established [3,4], Ageno et al. reported that nearly all Italian orthopedic surgeons prescribed pharmacological antithrombotic prophylaxis, although the thrombosis risk was not clearly established and considered as low [5,6]. By contrast, Dahl [2] reported, in the same issue, an opposite point of view from North-American surgeons who prefer to focus on groups at high risk of thrombosis. These two approaches underline the regional divergent view and practice regarding the use of thromboprophylaxis. Beyond this geographical aspect, we observed such a discrepancy in the use of thromboprophylaxis in a same homogenous region, and related to medical institution and specialist in charge of the patients. A few years ago, we have conducted a prospective multicenter study in 16 centers (hospital, university or general, or private clinics) of the Region Rhône-Alpes in France [7]. Our aim was to evaluate the medical practice regarding the thromboprophylaxis, after hip (n 1⁄4 396) or knee (n 1⁄4 109) arthroplasty, a well-defined risk major orthopedic surgery in which consensus indicated the need of optimal thromboprophylaxis. All (100%) patients received a pharmacological antithrombotic prophylaxis, 130 (23%) a non-fractioned heparin and 375 (77%) a low molecular weight heparin respectively. The majority of patients (86%) received the drug postoperatively. However, in 181 patients (36%), the dose was not adequate because of the lower than recommended dosage in such surgical situations. Interestingly in this practice, the rate of heparin prescription varied depending on the specialist in charge. In this series, thromboprophylaxis was prescribed by the anesthesiologists (57%), the surgeon (23%) or a vascular physician (20%). The prescription was inadequate for 15% of vascular physicians, 30% for anesthesiologist and up to 61% for orthopedic surgeons (P < 0.01). Moreover, the applicability of consensus varied between the institutions. In hospital (university and general) the rate of non-conform prescription was higher (47% vs. 32%, P 1⁄4 0.01). In this group, prescription was made by anesthesiologist in 75% of cases (41% non-conform), or by surgeons in 24% of cases (54% non-conform). In private clinics, prescription was made by anesthesiologist in 49% of cases (24% non-conform), by vascular physicians in 27% of cases (16% non-conform) and by surgeons in 24% of cases (64% non-conform). Curiously, the conformity of the prescription was related neither to patients’ individual patterns nor surgery or anesthesiology characteristics. The global prevalence of detected deep vein thrombosis (DVT) by venous ultrasound was 14% (range 11–17%) (proximal 4.2% and distal 9.9%). Interestingly, the risk of having DVT was higher in patients receiving low dosage of heparin (prevalence 19% vs. 11%, RR 1.7, P 1⁄4 0.01). Although this study was conducted 6 years ago, it is totally in agreement with the recently debate on the compliance with recommended prophylaxis for venous thromboembolism [8]. Our data suggest that in our country, specialists in charge of patients undergoing major orthopedic surgery have developed a great attention to the occurrence of DVT, as mentioned by Ageno et al. [1]. In fact, the use of pharmacological prophylaxis (100%) was better than the 70–80% of patients previously reported [9]. However, a great discrepancy subsists in the application of thromboprophylaxis consensus. The geographical practices variation was already described, but the physicians and environment-related factors were also recently debated [8]. In our series, the non-respect of guidelines within a same homogenous region seems to be more related to the specificity of prescriber rather than to the patients’ characteristics. The perception of the risk of thrombosis or bleeding among clinicians could probably explain the discrepancy in the adhesion to the recommendations. However, as DVT prevalence was directly related to respect of consensus, this might have a negative impact in terms of quality care. For this reason, strategies must be encouraged in attempts to improve both practical recommendations and compliance with guidelines. Evaluation of guideline application is also necessary to be sure that it is effective in medical practice. Correspondence: G. Pernod, DBPC, Haemostasis Unit, CHU Grenoble, F-38043 Grenoble Cx 9, France. Tel.: +33 4 76 76 54 87; fax +33 4 76 76 59 35; e-mail: gpernod@ chu-grenoble.fr

Long-term outcomes of isolated superficial vein thrombosis in patients with active cancer

BACKGROUND Cancer patients who develop a deep-vein thrombosis (DVT) or a pulmonary embolism (PE) are at higher risk of death than similar cancer patients who do not develop DVT or PE. The impact of isolated superficial venous thrombosis (SVT) (i.e. without DVT or PE) on the prognosis of cancer patients is unknown. METHODS Data from the OPTIMEV, multicentre, observational study, to compare at 3 years the incidences of death, DVT-PE recurrence and bleeding of cancer patients with objectively confirmed SVT vs. cancer patients with DVT (matched 1:2 on age, sex, cancer stage) and vs. patients with SVT without cancer (matched 1:3 on age and sex). RESULTS Cancer patients with SVT (n = 34) had a high risk of death (23.2%patient-year(PY)), that was similar to that of cancer patients with DVT (aHR = 1.0[0.6-1.9]) and higher to that of SVT patients without cancer (aHR = 9.0[3.5-23.1]). Cancer patients with SVT received anticoagulants for a median duration of 45 days and had a high risk of DVT-PE recurrence (6.0%PY), similar to that of cancer patients with DVT (adjusted cause-specific HR (aCHR) = 1.5[0.4-5.8]) and higher to that of SVT patients without cancer (aCHR = 2.9[0.7-11.9]). In our population, venous thrombosis on varicose veins was associated with a lower risk of death (aHR = 0.6[0.3-1.0]) and DVT-PE recurrence (aCHR = 0.6[0.2-1.7]). CONCLUSION Our results suggest that cancer patients with SVT have a poor prognosis, similar to that of patients with cancer-related DVT. The high rate of DVT-PE recurrence suggests that such patients may need longer duration of anticoagulant treatment.

Aide à l’arrêt d’un traitement anticoagulant (maladie thromboembolique veineuse) : présentation des réunions de concertation organisées par un réseau ville-hôpital

anticoagulant, le bilan de thrombophilie, la thrombose et le cancer, la femme enceinte. . . La visioconférence permet de mettre en relation visuelle et sonore un groupe d’individus situés à des endroits distincts par le biais de lignes de communication. Cette mise en relation est pour le moment uniquement possible au CH de Saint Quentin par l’utilisation de stations dédiées situées dans des lieux fixes. L’initialisation d’une visioconférence demande l’intervention d’un technicien pour l’activation des liens de télécommunication entre les points qui doivent communiquer. Au sein d’une même plateforme régionale, le nombre de sites n’occasionne aucun problème technique, c’est plus en termes de « confort » visuel et sonore et d’organisation que les questions se posent. La situation est plus complexe si on interconnecte plusieurs plateformes régionales (ex. Rouen et Amiens). Sur le plan pratique, les salles de visioconférence sont situées au sein de chaque hôpital, elles disposent d’un micro, d’une caméra, d’une télévision ou comme sur Amiens d’un grand écran de vidéo projection. Le technicien est prévenu à l’avance de l’horaire de la réunion. À l’heure dite, nous n’avons plus qu’à nous installer devant l’écran et activer la télécommande d’ouverture du son. Dès qu’un membre prend la parole, il apparaît sur l’écran de ses correspondants. À partir d’exemples concrets, ces échanges par visioconférence améliorent l’expertise du praticien des hôpitaux généraux, celuici n’ayant pas forcément la possibilité physique d’assister aux colloques organisés par les CHU. Ces visioconférences sont le prolongement logique de la collaboration des laboratoires des hôpitaux généraux avec ceux des centres plus spécialisés. Grâce à cette organisation, le praticien des hôpitaux généraux devient le référent de proximité vis-à-vis du patient qu’il a pris en charge. Par cette réflexion collégiale interactive et facile d’accès, il devient possible de répondre rapidement, au mieux de nos connaissances actuelles, aux besoins du patient et avec le maximum de sécurité. doi:10.1016/j.jmv.2010.12.119

Maladie thromboembolique veineuse : questions et controverses. Séminaire pédagogique du DESC de médecine vasculaire (22 novembre 2007)

Rapid advances has been made in the diagnosis and treatment of venous thromboembolic disease, but many questions or controversies remain. In this review, we present a progress report on various concepts still open to discussion. New epidemiologic data from the French epidemiology study, Optimev, are presented. Widespread use of multidetector CT scan for the diagnostic work-up of pulmonary embolism has had considerable impact on clinical practices. We discuss indications and use of the various imaging methods. The review ends with a report on constitutional or acquired thrombophilia, particularly cancer-associated venous thromboembolic disease, which remains a daily preoccupation with various approaches still under debate. This review was the topic of the French vascular medicine teaching seminary in November2007.