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Effectiveness, safety and costs of thromboembolic prevention in patients with non-valvular atrial fibrillation: phase I ESC-FA protocol study and baseline characteristics of a cohort from a primary care electronic database.
Giner-Soriano, M, Vedia Urgell, C, Roso-Llorach, A, Morros, R, Capellà, D, Castells, X, Ferreira-González, I, Troncoso Mariño, A, Diògene, E, Elorza, JM, et al
BMJ open. 2016;(1):e010144
Abstract
PURPOSE Atrial fibrillation is the most common arrhythmia. Its management aims to reduce symptoms and to prevent complications through rate and rhythm control, management of concomitant cardiac diseases and prevention of related complications, mainly stroke. The main objective of Effectiveness, Safety and Costs in Atrial Fibrillation (ESC-FA) study is to analyse the drugs used for the management of the disease in real-use conditions, particularly the antithrombotic agents for stroke prevention. The aim of this work is to present the study protocol of phase I of the ESC-FA study and the baseline characteristics of newly diagnosed patients with atrial fibrillation in Catalonia, Spain. PARTICIPANTS The data source is System for the Improvement of Research in Primary Care (SIDIAP) database. The population included are all patients with non-valvular atrial fibrillation diagnosis registered in the electronic health records during 2007-2012. FINDINGS TO DATE A total of 22,585 patients with non-valvular atrial fibrillation were included in the baseline description. Their mean age was 72.8 years and 51.6% were men. The most commonly prescribed antithrombotics were vitamin K antagonists (40.1% of patients) and platelet aggregation inhibitors (32.9%); 25.3% had not been prescribed antithrombotic treatment. Age, gender, comorbidities and co-medication at baseline were similar to those reported for previous studies. FUTURE PLANS The next phase in the ESC-FA study will involve assessing the effectiveness and safety of antithrombotic treatments, analysing stroke events and bleeding episodes' rates in our patients (rest of phase I), describing the current management of the disease and its costs in our setting, and assessing how the introduction of new oral anticoagulants changes the stroke prevention in non-valvular atrial fibrillation.
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Evaluation of oral anticoagulation therapy: rationale and design of the thrombEVAL study programme.
Prochaska, JH, Coldewey, M, Göbel, S, Keller, K, Hendelmeier, M, Konstantinides, S, Münzel, T, Wild, PS, ,
European journal of preventive cardiology. 2015;(5):622-8
Abstract
BACKGROUND Since decades, oral anticoagulation (OAC) with vitamin K antagonists (VKA) is an established therapy for both prevention and treatment of thromboembolism in daily clinical routine. Increasing life expectancy, demographic changes, and novel oral anticoagulants have led to an increasing complexity of medical therapy. However, data on quality and management of VKA therapy with phenprocoumon in current medical care are limited. Our aim is to investigate the quality of OAC with VKA in current health care and to evaluate the potential for improvements. STUDY DESIGN The investigator-initiated thrombEVAL study programme comprises two cohorts of patients treated with vitamin K antagonists for oral anticoagulation therapy in real-life settings: a multicentre cohort of patients in regular medical care and a multilocal, single-centre cohort of patients in a telemedicine-based coagulation service. The study programme is expected to enrol a total number of approximately 2000 to 2500 patients. Both cohorts will build on a detailed clinical assessment of participants and anticoagulation therapy at study enrolment. Subsequently active and passive follow-up investigations are carried out to document and validate complications of the treatment. The primary short-term outcome is the distribution of time in therapeutic range; the primary long-term outcome comprises the composite of stroke, systemic embolism, myocardial infarction, major and clinically relevant bleeding, and death. CONCLUSIONS The thrombEVAL project will provide a large prospective observational cohort of patients predominantly treated with phenprocoumon. It will evaluate the quality of oral anticoagulation in regular medical care and a telemedicine-based coagulation service.
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SAfety of Fondaparinux in transoesophageal echocardiography-guided Electric cardioversion of Atrial Fibrillation (SAFE-AF) study: a pilot study.
Cohen, A, Stellbrink, C, Le Heuzey, JY, Faber, T, Aliot, E, Banik, N, Kropff, S, Omran, H, ,
Archives of cardiovascular diseases. 2015;(2):122-31
Abstract
BACKGROUND Current guidelines recommend unfractionated heparin (UFH) or low-molecular-weight heparin plus an oral anticoagulant for the prevention of thromboembolism in patients undergoing electric cardioversion of atrial fibrillation (AF). Selective factor Xa inhibitors, such as fondaparinux, which has a favourable benefit-risk profile in the prevention and treatment of venous thromboembolism and the management of acute coronary syndromes, have not been systematically evaluated in this setting. AIM: To evaluate the efficacy and safety of fondaparinux versus standard treatment in patients undergoing echocardiographically-guided cardioversion of AF. METHODS In this multicentre, randomized, open-label, controlled, two-parallel-group, phase II pilot study, patients with AF undergoing electric cardioversion following transoesophageal echocardiography (TEE) were randomized to fondaparinux or standard therapy (UFH plus vitamin K antagonist [VKA]). Patients showing an atrial thrombus in the first TEE (clot-positive) were randomized to treatment with fondaparinux or standard care for 4 weeks before cardioversion. RESULTS The primary endpoint (combined rate of cerebral neurological events, systemic thromboembolism, all-cause death and major bleeding events) occurred in 3 of 174 (1.7%) patients on fondaparinux and 2 of 170 (1.2%) patients on UFH+VKA. The rate of thrombus disappearance among clot-positive patients was higher in the fondaparinux arm (11 of 14; 78.6%) than in the UFH+VKA arm (7 of 14; 50.0%). Incidences of adverse events were similar (45.4% with fondaparinux and 46.5% with UFH+VKA). CONCLUSION In this pilot study in patients with TEE-guided cardioversion, the use of fondaparinux appeared to be well tolerated, with similar efficacy to UFH+VKA. Furthermore, a trend to greater thrombus resolution was observed.
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Net Clinical Benefit of Non-vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Phase III Atrial Fibrillation Trials.
Renda, G, di Nicola, M, De Caterina, R
The American journal of medicine. 2015;(9):1007-14.e2
Abstract
OBJECTIVES The evaluation of the "net clinical benefit" allows an integrated assessment of both the anti-ischemic and the prohemorrhagic effects of non-vitamin K antagonist oral anticoagulants compared with warfarin, and—in the absence of direct comparisons—may inform clinical decisions. We estimated the net clinical benefit of non-vitamin K antagonist oral anticoagulants versus warfarin across the 4 phase III clinical trials performed in patients with atrial fibrillation. METHODS We considered various composites of the main ischemic and hemorrhagic events, estimating the rate ratio of all treatment groups versus warfarin for each composite outcome. Because the clinical relevance of the various ischemic or hemorrhagic events is not identical, we then attributed to each of them a weight, according to its impact on death, as derived from previous studies. We evaluated a weighed net clinical benefit of each non-vitamin K antagonist oral anticoagulant compared with warfarin in the 4 trials. RESULTS The composite outcome of ischemic + hemorrhagic stroke was reduced by dabigatran 150 mg and apixaban. The composite of disabling stroke + life-threatening bleeding was reduced by all non-vitamin K antagonist oral anticoagulants. The composite of ischemic stroke + systemic embolism + myocardial infarction + hemorrhagic stroke + major bleeding was reduced by apixaban and edoxaban at both doses. By attributing weights to these events according to their impact on mortality, all non-vitamin K antagonist oral anticoagulants featured a favorable net clinical benefit compared with warfarin, albeit to a quantitatively different extent. CONCLUSIONS The choice of the proper antithrombotic treatment in patients with atrial fibrillation has to consider the net clinical benefit of each drug. However, all non-vitamin K antagonist oral anticoagulants have a better efficacy/safety profile than warfarin in patients with atrial fibrillation.
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Low molecular weight heparin (LMWH) increases the efficacy of cisplatinum plus gemcitabine combination in advanced pancreatic cancer.
Icli, F, Akbulut, H, Utkan, G, Yalcin, B, Dincol, D, Isikdogan, A, Demirkazik, A, Onur, H, Cay, F, Büyükcelik, A
Journal of surgical oncology. 2007;(6):507-12
Abstract
BACKGROUND In this non-randomized study we aimed to assess the efficacy of the addition of low molecular weight heparin (LMWH) to gemcitabine (GEM) plus cisplatinum (CDDP) combination chemotherapy on survival by prevention of thromboembolic complications in patients with advanced pancreatic cancer (APC). PATIENTS AND METHODS Between November 1999 and February 2004, 69 consecutive patients with APC were treated with GEM (800 mg/m2, day 1, day 8) plus CDDP (35 mg/m2, day 1, day 8) every 21 days +/-LMWH (nadroparine calcium, 2,850 IU/day until disease progression). Ten out of 35 patients in LMWH group and 10 out of 34 patients in chemotherapy alone group had primary inoperable locally advanced disease and the rest of the patients had metastatic disease. RESULTS Total response rate was 58.8% (11.7% CR) for the patients treated with LMWH and 12.1% for those treated without LMWH (P = 0.0001). LMWH group had a better median time to progression (TTP) and survival when compared to control group (7.3 vs. 4.0 months, P = 0.0001; 13.0 vs. 5.5 months, P = 0.0001). The toxicity was similar and acceptable in both groups. CONCLUSION Addition of LMWH to GEM plus CDDP combination significantly improved the response and survival in patients with APC and the current schedule deserves to be tested in phase III trials.
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Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran.
Schulman, S, Wåhlander, K, Lundström, T, Clason, SB, Eriksson, H, ,
The New England journal of medicine. 2003;(18):1713-21
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Abstract
BACKGROUND For many patients with venous thromboembolism, secondary prevention with vitamin K antagonists is not extended beyond six months, since the risk of recurrence may be outweighed by the risk of major bleeding. METHODS In a double-blind, multicenter trial, we randomly assigned 1233 patients with venous thromboembolism who had undergone six months of anticoagulant therapy to extended secondary prevention with the oral direct thrombin inhibitor ximelagatran (24 mg) or placebo, taken twice daily, for 18 months without monitoring of coagulation. At base line, bilateral ultrasonography of the legs and perfusion lung scanning were performed. RESULTS Data from 612 patients in the ximelagatran group and 611 in the placebo group were analyzed. The occurrence of the primary end point, symptomatic recurrent venous thromboembolism, was confirmed in 12 patients assigned to ximelagatran and 71 patients assigned to placebo (hazard ratio, 0.16; 95 percent confidence interval, 0.09 to 0.30; P<0.001). Death from any cause occurred in 6 patients in the ximelagatran group and 7 patients in the placebo group, and bleeding occurred in 134 patients and 111 patients, respectively (hazard ratio, 1.19; 95 percent confidence interval, 0.93 to 1.53; P=0.17). The incidence of major hemorrhage was low (six events in the ximelagatran group and five in the placebo group), and none of these hemorrhages were fatal. The cumulative risk of a transient elevation of the alanine aminotransferase level to more than three times the upper limit of normal was 6.4 percent in the ximelagatran group, as compared with 1.2 percent in the placebo group (P<0.001). CONCLUSIONS Oral ximelagatran was superior to placebo for the extended prevention of venous thromboembolism. There was no significant increase in the frequency of bleeding complications, but there was an increase in the number of patients with a transient elevation in the alanine aminotransferase level.
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Potential association of thyrotoxicosis with vitamin B and folate deficiencies, resulting in risk for hyperhomocysteinemia and subsequent thromboembolic events.
Colleran, KM, Ratliff, DM, Burge, MR
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2003;(4):290-5
Abstract
OBJECTIVE To describe a patient with severe thyrotoxicosis attributable to Graves' disease who had a thrombotic cerebrovascular accident and hyperhomocysteinuria, which resolved on correction of the thyrotoxicosis, and to present findings in a pilot study undertaken to investigate the relationship among thyrotoxicosis, homocysteine, folate, and vitamin B(12). METHODS We present a case report of the index case, with clinical and laboratory details. For the investigative analysis, 21 patients who were 18 to 50 years old and had newly diagnosed, untreated Graves' disease and 10 age-and sex-matched euthyroid control subjects were studied. Of the patients with Graves' disease, 11 underwent studies both at diagnosis and after treatment. Fasting blood tests were performed for thyrotropin, free thyroxine, homocys-teine, vitamin B(12), folate, and methylmalonic acid, a marker of vitamin B(12) deficiency. RESULTS Vitamin B(12), folate, homocysteine, and methylmalonic acid levels were not significantly different between the thyrotoxic and control or posttreatment groups. In patients with thyrotoxicosis, however, free thyroxine was positively correlated with both homocysteine (r = 0.67; P = 0.03) and methylmalonic acid (r = 0.89; P = 0.003). CONCLUSION The positive correlation between free thyroxine levels and both homocysteine and methylmalonic acid suggests that thyrotoxicosis may be associated with functional vitamin B(12) deficiency. Such a deficiency may result in clinically important hyperhomocysteine-mia.
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Postpartum bone mineral density in women treated for thromboprophylaxis with unfractionated heparin or LMW heparin.
Pettilä, V, Leinonen, P, Markkola, A, Hiilesmaa, V, Kaaja, R
Thrombosis and haemostasis. 2002;(2):182-6
Abstract
Venous thromboembolism remains an important cause of maternal mortality. In a randomised open study, 44 pregnant women with confirmed previous or current thromboembolism were randomised to receive either low-molecular-weight heparin, dalteparin (N = 21) once daily subcutaneously or unfractionated sodium heparin (UF heparin, N = 23) twice daily subcutaneously for thromboprophylaxis during pregnancy and puerperium. Bone mineral density (BMD) in the lumbosacral spine was measured with dual X-ray absorptiometry (DEXA) 1, 6, 16, 52 weeks and, if possible, 3 years after delivery. BMD values were also compared with those of healthy, delivered women (N = 19). Mean BMD of the lumbar spine was significantly lower in the unfractionated heparin group compared with the dalteparin and with the control groups (repeated measures ANOVA p = 0.02). BMD in the dalteparin group did not differ from BMD of healthy delivered women. Multiple logistic regression analysis revealed that therapy was the only independent factor influencing BMD at weeks 16 and 52. Therefore we recommend use of dalteparin instead of UF heparin for long-term thromboprophylaxis during and after pregnancy.
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[Thromboembolic prophylaxis after major abdominal surgery].
Celebi, F, Balik, AA, Yildirgan, MI, Başoğlu, M, Adigüzel, H, Oren, D
Ulusal travma dergisi = Turkish journal of trauma & emergency surgery : TJTES. 2001;(1):44-8
Abstract
PURPOSE To investigate the efficacy of prophylaxis modalities after major abdominal surgery. PATIENTS AND METHODS Patients who underwent major abdominal surgery between October 1998 and October 1999 were randomly divided into 3 groups. The patients in Group 1 received compression stockings, in Group 2 0.3 ml low-molecular weight heparin (nadroparine calcium 0.3 ml, 2850 IU AXa LMWH) subcutaneously and in Group 3 compression stockings and 0.3 ml LMWH. All symptomless patients evaluated with low extremity deep venous Doppler ultrasonography (DUSG), and patients who had pulmonary embolus (PE) suspicion evaluated with pulmonary scintigraphy. RESULTS There were 91 patients in Group 1, 91 patients in Group 2 and 92 patients in Group 3. The mean age was 57.25 +/- 13.12, 54.53 +/- 13.54, and 53.65 +/- 13.28 respectively. Male/female ratio was 51/38, 56/35 and 62/30, in Group 1, 2 and 3 respectively. Twenty-seven patients in Group 1, 26 patients in Group 2 and 37 patients in Group 3 had risk factors. DUSG showed deep venous thrombosis (DVT) on the 7th postoperative day in 10 patients in Group 1, in 8 patients in Group 2 and in 3 patients in Group 3. Pulmonary scintigraphy showed PE suspicion in 6 patients in Group 1, 1 patient in Group 2 and 1 patients in Group 3. Wound hematoma and hemorrhage from abdominal drains were developed in 1/0, 8/2 and 3/1 patients in Groups 1, 2 and 3 respectively. Four patients in Group 1 and 2 patients in Group 2 died during the treatment (2.2%). Satistical analysis showed significant differences in PE and wound hematoma between Groups 1 and 2, in DVT and PE between Groups 1 and 3, in risk factors between Groups 2 and 3 (p < 0.05). The differences in DVT and PE and hematoma between group 2 and 3 were not significant. CONCLUSION All treatment modalities could not prevent all thromboembolic complications. In our study combined treatment was the most effective one.
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Abrupt versus gradual withdrawal of vitamin K antagonist treatment in patients with venous thromboembolic disease: assessment of hypercoagulability and clinical outcome.
de Groot, MR, Njo, TL, van Marwijk Kooy, M, Büller, HR
Clinical laboratory. 2000;(11-12):575-81
Abstract
BACKGROUND It is yet unclear whether vitamin K antagonist treatment should be stopped abruptly or gradually after an episode of venous thromboembolism. The mode of withdrawal might influence a potential development of a hypercoagulable state, which could influence the risk for recurrent disease. METHODS We prospectively studied 37 consecutive patients in whom acenocoumarol was discontinued either abrupt (18) or gradually (19) (2/3 and 1/3 of the initial dose for one week). Blood sampling was performed at various time points up to 18 days after complete withdrawal and was analysed for INR, prothrombin fragment F1 + 2 and D-dimer. All patients were clinically followed-up for the assessment of the association between hypercoagulability and occurrence of disease such as recurrent venous thromboembolism or malignancy. RESULTS An approximately fourfold increase was observed (median increase from 0.3 to 1.3 nmol/l) in the F1 + 2 levels after both abrupt and gradual withdrawal and in the D-dimer concentrations in the abrupt withdrawal group (0.10 to 0.44 mg/l), while those in whom acenocoumarol was discontinued gradually showed a less pronounced increase of the D-dimer levels (0.11 to 0.29 mg/L) (not significant). During follow-up one recurrent venous thromboembolic event occurred in each group, and a diagnosis of cancer was made four times. All these patients had the highest D-dimer concentrations measured in the entire study group. CONCLUSIONS This study indicates the potential for a hypercoagulable state after acenocoumarol discontinuation, which was not prevented by tapering the acenocoumarol dose. D-dimer, measured 2 to 3 weeks after acenocoumarol withdrawal, might be an important tool to identify patients at risk for recurrent venous thromboembolism and/or for the presence of an underlying malignancy.