Months Of Anticoagulant Therapy Research Articles

Guidelines on oral anticoagulation (warfarin): third edition – 2005 update

The British Committee for Standards in Haematology (BCSH) published its third edition of Guidelines on Oral Anticoagulation in 1998 (British Committee for Standards in Haematology, 1998). Most of the recommendations made in 1998 remain unchanged and a fourth edition of the guideline is considered unnecessary at the time of writing (June 2005). However, we draw attention to those areas where new informative data have been published. As in the original guideline, the term ‘oral anticoagulant’ used in this update refers to oral vitamin K antagonists (VKA), such as warfarin. New oral non-VKA are currently being evaluated in clinical trials but are not yet licensed for use in the UK. When these drugs become available new guidance will be issued specifically for the use of those drugs. The guideline group was selected to be representative of UKbased medical experts. The drafting group met and communicated by email. MEDLINE was searched systematically for publications in English from 1998. The writing group convenor (T. Baglin) produced the draft guidelines which were subsequently revised by consensus. The guideline was reviewed by a multidisciplinary sounding board, the BCSH and the British Society for Haematology (BSH) and comments incorporated where appropriate. Criteria used to quote levels and grades of evidence are as in Appendix 3 of the Procedure for Guidelines Commissioned by the BCSH (http://www.bcshguidelines.com/process1.asp#App3). The target audience for this guideline is healthcare professionals involved in the management of patients receiving oral anticoagulant therapy.

Secondary Prevention of Venous Thromboembolism with the Oral Direct Thrombin Inhibitor Ximelagatran

The authors conducted a study to determine the effects of oral ximelagatran for the extended prevention of venous thromboembolism because the protection of anticoagulation therapy does not extend beyond six months owing to the risk of major bleeding. Patients with venous thromboembolism who had undergone six months of anticoagulant therapy were randomized to treatment with 24 mg ximelagatran (twice daily) (612 patients) or placebo (611 patients). The regimen lasted 18 months during which time coagulation was not monitored. Symptomatic recurrent venous thromboembolism occurred in 12 patients on the ximelagatran regimen and 71 patients in placebo. In the ximelagatran group, 6.4% of patients had transient elevation of alanine aminotransferase level to more than three times compared with 1.2% in the placebo group. The authors concluded that oral ximelagatran was superior to placebo for the extended prevention of venous thromboembolism.

Elevated plasma factor VIII and D-dimer levels as predictors of poor outcomes of thrombosis in children.

Elevated levels of plasma factor VIII and D-dimer predict recurrent venous thromboembolism in adults. We sought to determine whether an elevation of factor VIII, D-dimer, or both at diagnosis and persistence of the laboratory abnormality after three to six months of anticoagulant therapy correlate with poor outcomes of thrombosis in children. We evaluated levels of factor VIII and D-dimer and additional components of an extensive laboratory thrombophilia (i.e., hypercoagulability) panel at the time of diagnosis in 144 children with a radiologically confirmed acute thrombotic event. All patients were treated initially with heparin and then with either warfarin or low-molecular-weight heparin for at least three to six months, according to the current standard of care. Patients were examined at follow-up visits 3, 6, and 12 months after diagnosis and then annually, at which times testing was repeated in children with previously abnormal factor VIII and D-dimer test results and a uniform evaluation for the post-thrombotic syndrome was performed. Among 82 children for whom complete data were available regarding laboratory test results at diagnosis and thrombotic outcomes during follow-up, 67 percent had factor VIII levels above the cutoff value of 150 IU per deciliter, D-dimer levels above 500 ng per milliliter, or both at diagnosis, and at least one of the two laboratory values was persistently elevated in 43 percent of the 75 patients in whom testing was performed after three to six months of anticoagulant therapy. Fifty-one percent of the 82 patients had a poor outcome (i.e., a lack of thrombus resolution, recurrent thrombosis, or the post-thrombotic syndrome) during a median follow-up of 12 months (range, 3 months to 5 years). Elevated levels of factor VIII, D-dimer, or both at diagnosis were highly predictive of a poor outcome (odds ratio, 6.1; P=0.008), as was the persistence of at least one laboratory abnormality at three to six months (odds ratio, 4.7; P=0.002). The combination of a factor VIII level above 150 IU per deciliter and a D-dimer level above 500 ng per milliliter at diagnosis was 91 percent specific for a poor outcome, and after three to six months of standard anticoagulation, the combination was 88 percent specific. Elevated levels of plasma factor VIII, D-dimer, or both at diagnosis and a persistent elevation of at least one of these factors after standard-duration anticoagulant therapy predict a poor outcome in children with thrombosis.

Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor

The risk of recurrence is lower after treatment of an episode of venous thromboembolism associated with a transient risk factor, such as recent surgery, than after an episode associated with a permanent, or no, risk factor. Retrospective analyses suggest that 1 month of anticoagulation is adequate for patients whose venous thromboembolic event was provoked by a transient risk factor. In this double-blind study, patients who had completed 1 month of anticoagulant therapy for a first episode of venous thromboembolism provoked by a transient risk factor were randomly assigned to continue warfarin or to placebo for an additional 2 months. Our goal was to determine if the duration of treatment could be reduced without increasing the rate of recurrent venous thromboembolism during 11 months of follow-up. Of 84 patients assigned to placebo, five (6.0%) had recurrent venous thromboembolism, compared with three of 81 (3.7%) assigned to warfarin, resulting in an absolute risk difference of 2.3%[95% confidence interval (CI) - 5.2, 10.0]. The incidence of recurrent venous thromboembolism after discontinuation of warfarin was 6.8% per patient-year in those who received warfarin for 1 month and 3.2% per patient-year in those who received warfarin for 3 months (rate difference of 3.6% per patient-year; 95% CI - 3.8, 11.0). There were no major bleeds in either group. Duration of anticoagulant therapy for venous thromboembolism provoked by a transient risk factor should not be reduced from 3 months to 1 month as this is likely to increase recurrent venous thromboembolism without achieving a clinically important decrease in bleeding.

A Potentially Better Means of Preventing Recurrent Venous Thromboembolism Is on the Horizon

Synopsis: In patients with venous thromboembolism, treatment with long-term ximelagatran following 6 months of anticoagulant therapy may safely and effectively reduce the risk of recurrent thromboembolic events. Source: Schulman S et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med. 2003;349:1713–1721.

Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis

A small proportion of patients with deep vein thrombosis develop recurrent venous thromboembolic complications or bleeding during anticoagulant treatment. These complications may occur more frequently if these patients have concomitant cancer. This prospective follow-up study sought to determine whether in thrombosis patients those with cancer have a higher risk for recurrent venous thromboembolism or bleeding during anticoagulant treatment than those without cancer. Of the 842 included patients, 181 had known cancer at entry. The 12-month cumulative incidence of recurrent thromboembolism in cancer patients was 20.7% (95% CI, 15.6%-25.8%) versus 6.8% (95% CI, 3.9%- 9.7%) in patients without cancer, for a hazard ratio of 3.2 (95% CI, 1.9-5.4) The 12-month cumulative incidence of major bleeding was 12.4% (95% CI, 6.5%-18.2%) in patients with cancer and 4.9% (95% CI, 2.5%-7.4%) in patients without cancer, for a hazard ratio of 2.2 (95% CI, 1.2-4.1). Recurrence and bleeding were both related to cancer severity and occurred predominantly during the first month of anticoagulant therapy but could not be explained by sub- or overanticoagulation. Cancer patients with venous thrombosis are more likely to develop recurrent thromboembolic complications and major bleeding during anticoagulant treatment than those without malignancy. These risks correlate with the extent of cancer. Possibilities for improvement using the current paradigms of anticoagulation seem limited and new treatment strategies should be developed.

Does the location of thrombosis determine the risk of disease recurrence in patients with proximal deep vein thrombosis?

PURPOSE: To determine if the location of deep vein thrombosis is a predictor of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. METHODS: The study population consisted of 1,149 consecutive patients with symptomatic proximal deep vein thrombosis. In all patients, deep vein thrombosis was confirmed by Duplex ultrasound or venography and was classified as popliteal, femoral, or iliofemoral. Patients received initial treatment with unfractionated heparin, enoxaparin, or reviparin for least 4 days, as well as a coumarin derivative, with a target international normalized ratio of 2.0 to 3.0, starting on the 1st or 2nd day of treatment. All patients were followed for 3 months, and all episodes of recurrent venous thromboembolism were confirmed with objective diagnostic tests. RESULTS: The overall rate of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy was 5.5% (63/1,149). The rate of recurrence in patients with popliteal vein thrombosis was 5.1% (23/453); in patients with femoral vein thrombosis, it was 5.3% (34/645); and in patients with iliofemoral vein thrombosis, it was 11.8% (6/51). Two clinical risk factors were associated with an increased risk of recurrent venous thromboembolism: iliofemoral vein thrombosis (odds ratio [OR] = 2.4; 95% confidence interval [CI]: 0.95, 5.9), and cancer (OR = 2.6; 95% CI: 1.5, 4.4). CONCLUSIONS: Patients with extensive iliofemoral vein thrombosis who receive conventional anticoagulant therapy have a greater than twofold higher risk of developing recurrent venous thromboembolism than patients without iliac vein involvement (i.e., 11.8% vs. 5.2%). Prospective studies are needed to determine whether alternative antithrombotic strategies are warranted in such patients.

Anticoagulant Therapy Modifies Fibrinolytic Dysfunction in Chronic Atrial Fibrillation

Objective: We evaluated the changes in fibrinolytic activation markers before starting anticoagulation, at 1 and 6 months following the introduction of anticoagulant therapy. Design and Methods: Tissue plasminogen activator (t-PA), its endothelial inhibitor (PAI-1), plasmin:antiplasmin complexes (PAPc), modified antithrombin III (ATM), D dimer (D-D) and fibrinogen (FIB) were measured in 36 patients with chronic atrial fibrillation. Fifteen of them had rheumatic mitral stenosis and 21 had nonrheumatic atrial fibrillation. Basal levels were compared with a sex- and age-matched healthy control group. Results: At baseline, patients with atrial fibrillation showed significantly higher plasma levels of PAI-1, ATM, D-D and FIB levels (p < 0.05) than controls, and no differences in t-PA and PAPc concentrations. Levels of t-PA, PAI-1, ATM and D-D decreased significantly under anticoagulant therapy, whereas FIB levels were not significantly modified. PAPc levels were significantly increased at 6 months in the rheumatic group but did not differ significantly in the nonrheumatic group. Conclusions: Patients with chronic atrial fibrillation show a hypercoagulant state and a relatively low fibrinolytic function. After 6 months of anticoagulant therapy, an improvement in fibrinolytic function markers was detected.

Clinical Risk Factors and Timing of Recurrent Venous Thromboembolism During the Initial 3 Months of Anticoagulant Therapy

In patients with venous thromboembolism (VTE), identifying clinical risk factors for recurrence during the initial 3 months of anticoagulant therapy and knowledge of the time course of recurrence may help clinicians decide about the frequency of clinical surveillance and the appropriateness of outpatient treatment. Analysis of a randomized controlled trial database involving 1021 patients with VTE (750 with deep vein thrombosis [DVT] and 271 with pulmonary embolism [PE]) who were followed up for 3 months after the start of anticoagulant therapy. All patients received initial treatment with unfractionated heparin or a low-molecular-weight heparin (reviparin) and a coumarin derivative starting the first or second day of treatment, with a target international normalized ratio of 2.0 to 3.0. Four independent clinical risk factors for recurrent VTE were identified: (1) cancer (odds ratio [OR], 2.72; 95% confidence interval [CI], 1. 39-5.32), (2) chronic cardiovascular disease (OR, 2.27; 95% CI, 1. 08-4.97), (3) chronic respiratory disease (OR, 1.91; 95% CI, 0.85-4. 26), and (4) other clinically significant medical disease (OR, 1.79; 95% CI, 1.00-3.21). Older age was associated with a decreased risk for recurrent VTE (OR, 0.76; 95% CI, 0.64-0.92). Previous VTE, sex, and idiopathic VTE were not risk factors for recurrence. In patients with DVT or PE, there was no significant difference in the rates of recurrent nonfatal VTE (4.8% vs 4.1%; P =.62), major bleeding (2.9% vs 2.2%; P =.53), and non-VTE death (6.4% vs 7.8%; P =.45), but recurrent fatal PE was more frequent in patients with PE than DVT (2. 2% vs 0%; P<.01). There was a clustering of recurrent VTE episodes during the initial 2 to 3 weeks after the start of treatment. During the initial 3 months of anticoagulant therapy, recurrent VTE is more likely to occur in patients with cancer, chronic cardiovascular disease, chronic respiratory disease, or other clinically significant medical disease. Patients with PE are as likely to develop recurrent VTE as those with DVT; however, recurrence is more likely to be fatal in patients who initially present with PE. Arch Intern Med. 2000;160:3431-3436.

F10The sonographic diagnosis of uterine venous plexus thrombosis made by transvaginal B‐mode and color Doppler scanning: two case reports

BackgroundTransvaginal sonography (TVS) enables a close imaging of the pelvic organs providing a clear imaging of the pelvic vessels. To the best of our knowledge – this is the first report of the diagnosis of uterine venous plexus thrombosis using this technique.Case reports 1st case: 38‐year‐old patient diagnosed as having a left tubal ectopic pregnancy in the 7th week of gestation. On TVS examination the ipsilateral uterine plexus thrombosis was found. The blood clots were demonstrated as elongated echogenic structures within the dilated veins. The thrombi showed swinging movements caused by the surrounding blood flow. This effect could also be provoked by gentle transducer pressure. On the transverse view of the affected veins the thrombi appeared as free round structures in the lumen. The blood flow around the thrombi was seen on color Doppler. 2nd case: 36‐year‐old patient with fetal death in the 19th week of gestation. Two days after the induced labor the patient experienced excessive vaginal bleeding. A placental residue was confirmed by TVS. Upon examination the engorged uterine venous plexuses were seen with a thrombus on the right side. The sonographic description of the clot was as in the first case.There were no signs of thromboembolic disease in both cases. The deep leg veins and iliac veins were studied and found to be normal. The uterine plexus thrombi could not be detected by transabdominal sonography and were only seen by TVS. Over 3 months of anticoagulation therapy the clots gradually disappeared in both cases.ConclusionsIn both patients the transvaginal sonographic diagnosis of uterine venous plexus thrombosis was accidental. There is not enough data in the medical literature to determine the evidence based approach to such cases. Nevertheless, focusing on the pelvic veins may reveal important findings with significant clinical implications.

Mejoría de la función fibrinolítica tras el tratamiento anticoagulante en la fibrilación auricular reumática crónica

Patients with rheumatic atrial fibrillation are considered at high risk of systemic embolism and require oral anticoagulation. Fibrinolytic function has been little studied. We evaluated fibrinolytic activation markers before starting anticoagulation, at 1 and 6 months following the introduction of oral anticoagulation therapy. We analyzed the relationship with left atrial diameter and mitral area. Tissue plasminogen activator (tPA), its inhibitor (PAI-1), plasmin-antiplasmin complexes (PAP) and D-dimer were measured in 13 patients with rheumatic atrial fibrillation. Basal levels were compared with those found in plasma of 20 healthy subjects matched by sex and age. Transthoracic echocardiography was made. A significant increase for PAI-1 and D-dimer levels were detected in patients with atrial fibrillation group (p < 0.05), with no differences in tPA and PAP concentrations. Significant correlation between left atrial diameter and basal t-PA levels was found. Levels of t-PA, PAI-1 and D-dimer decreased significantly under anticoagulation therapy, whereas PAP levels were significantly increased. Patients with rheumatic atrial fibrillation show a relative hypofibrinolytic state due to elevated PAI-1 levels with no increase in PAP concentration. At six months of anticoagulation therapy, an improvement of fibrinolytic function markers was observed. This is consistent with the prophylactic effect of oral anticoagulants therapy against thromboembolic risk.

Stent implantation versus balloon angioplasty in chronic coronary occlusions: results from the GISSOC trial

Objectives. In this multicenter, randomized trial we evaluated whether stent implantation after successful recanalization of a chronic coronary occlusion reduced the incidence of restenosis.Background. Percutaneous transluminal coronary angioplasty (PTCA) in chronic total occlusions is associated with a higher rate of angiographic restenosis and reocclusion than PTCA in subtotal stenoses. Preliminary reports have suggested a decreased restenosis rate after stent implantation in coronary total occlusions.Methods. We randomly assigned 110 patients with recanalized total occlusion to Palmaz-Schatz stent implantation, followed by 1 month of anticoagulant therapy versus no other treatment. The primary end point was the minimal lumen diameter (MLD) of the treated segment at follow-up, as determined by quantitative angiography at a core laboratory.Results. Repeat coronary angiography was performed 9 months after the procedure in 88% of patients. The MLD (mean ± SD) at follow-up was 1.74 ± 0.88 mm in patients assigned to stent implantation and 0.85 ± .75 mm in patients assigned to PTCA (p < 0.001). Stent implantation was associated with a lower incidence of restenosis (defined as diameter stenosis ≥50% at follow-up) (32% vs. 68%, p < 0.001) and reocclusion (8% vs. 34%, p = 0.003) than balloon PTCA. Likewise, stent-treated patients had less recurrent ischemia (14% vs. 46%, p = 0.002) and target lesion revascularization (5.3% vs. 22%, p = 0.038), but experienced a longer hospital stay.Conclusions. Palmaz-Schatz stent implantation after successful balloon PTCA of chronic total occlusions improves the midterm angiographic and clinical outcome and could be the preferred treatment option in selected patients with occluded vessels.

Duration of Anticoagulant Therapy After First Episode of Venous Thrombosis in Patients With Inherited Thrombophilia

PATIENTS WITH acute venous thrombosis or pulmonary embolism (PE) (venous thromboembolism [VTE]) are at high risk of recurrence unless they are treated with an adequate course of anticoagulants.^1,2Anticoagulant therapy is very effective for the treatment of VTE but is associated with bleeding.³The risk of recurrence is highest early after the acute episode and then declines over time. Ideally, treatment should be continued until the benefits of treatment are offset by the risks, but this optimal duration is uncertain because both the risk of recurrence after discontinuing treatment and the risk of bleeding during anticoagulation therapy are not easily predicted in individual patients. For most patients, the benefits of 3 to 6 months of anticoagulant therapy greatly outweigh the risks.^1,4In addition, some patients, for example those with familial thrombophilia, remain at high risk for recurrence even after completing such a course of anticoagulants^5,6; consequently,

Les luxations rétro-sternales de la clavicule: A propos de quatre cas traités chirurgicalement par plaque antérieure vissée provisoire et revue de la littérature

The authors report 4 new cases of retrosternal dislocation of the clavicle operated by capsular and ligament restoration, and temporary stabilization by anterior plating. The 4 patients were men with a mean age of 17.5 years. The lesion was caused by a sports injury (football, rugby) in 3 out of 4 cases and was related to an indirect mechanism. Clinical examination allowed the diagnosis, was related to based on painful palpation of a dip over the joint, supported by radiology and computed tomography. CT did not reveal the epiphyseal separation present in two cases. Complications were frequent: 1 case of tracheal compression, 2 cases of temporary paresthesia of the upper limb, 2 cases of venous compression with one case of subclavian and medial jugularis venous thrombosis, 1 hemopneumothorax. Surgical reduction was performed in all 4 cases after 2 failures of attempted orthopedic treatment under general anesthesia. All patients recovered a full range of movement, a painless shoulder and no recurrence has been observed. All complications resolved after reduction. Venous thrombosis responded favourably after 6 months of anticoagulant therapy. One plate breakage was observed with no clinical implications. On the basis of an extensive review of the literature, the authors discuss the epidemiology, pathology and the importance of associated injuries, which are frequent and sometimes serious, justifying urgent reduction. Computed tomography is the most useful radiologic modality, both for diagnosis and for investigation of complications. Orthopedic treatment must be attempted first (especially in children) according to a well systematized technique. One third of attempts fail, and cases of delayed diagnosis and serious vascular complications, then require surgical treatment. The costoclavicular ligament is repaired either by Burrows's ligamentoplasty or by bone suture; the clavicle is stabilized by bone suture or by anterior plating. The authors do not advocate either joint fixation by Kirschner wire, or resection of the medial end of the clavicle.

Evaluation of a new treatment strategy for Paget-Schroetter syndrome: Spontaneous thrombosis of the axillary-subclavian vein

Purpose: The purpose of this study was to evaluate the efficacy of a staged, multimodal algorithm of therapy for durable correction of Paget-Schroetter syndrome.Methods: Fifty consecutive patients were entered into a sequential treatment program for spontaneous axillary-subclavian vein thrombosis. Forty-three had initial thrombolytic or anticoagulant treatment followed by longer-term warfarin sodium therapy. Thirty-six (72%) underwent surgical correction of the underlying structural abnormality, and nine patients had postoperative balloon angioplasty.Results: At the time of final evaluation, 93% of patients with a patent vein and 64% of those with an occluded vein were essentially free of symptoms. After surgical correction there were no episodes of recurrent thrombosis in a mean follow-up period of 3.1 years. Urokinase was the most effective pharmacologic agent for clot lysis (p = 0.003), and restoration of initial patency was the most significant factor in establishing final venous patency determined venographically (p = 0.003).Conclusions: It was concluded that a staged, multimodal approach to the Paget-Schroetter syndrome can effectively restore venous patency, reduce rethrombosis, and return normal function. The most effective sequence included transcatheter thrombolytic therapy, 3 months of anticoagulation therapy with warfarin sodium, and transaxillary first rib resection and decompression, followed by balloon angioplasty in cases of residual stricture.

The relative contributions of antithrombin iii during heparin treatment, and of clinically recognisable risk factors, to early recurrence of venous thromboembolism.

The influence of antithrombin III (ATIII) level and ATIII activity, measured during intravenous heparin treatment for venous thromboembolism (VTE), on 'heparin requirement' (the heparin dose required to prolong the activated partial thromboplastin time (APTT) into its designated therapeutic range), and on the likelihood of recurrent VTE during the first month of anticoagulant therapy, were examined in a prospective study of 232 patients with VTE treated according to a standard protocol. 15 patients with recurrent VTE (6.5%) had a lower mean APTT during heparin treatment than patients without recurrence; a finding due partly to their heparin requirement. However, there was no measurable relationship between ATIII level or ATIII activity and either heparin requirement or recurrence of VTE. By contrast, both the presence of disseminated malignancy and the development of heparin induced thrombocytopenia were powerful, clinically recognisable, risk factors for recurrence during or soon after heparin therapy.