Role of Direct Oral Anticoagulants in the Management of Anticoagulation.

For decades, vitamin K antagonists (VKAs) have been the oral treatment of choice for many thromboembolic conditions. The limitations of VKAs include the need for monitoring through blood testing, drug interactions, and narrow therapeutic windows. These shortcomings have led to the development of direct oral anticoagulants. These new oral agents act on specific targets in the coagulation cascade (eg, factor Xa, thrombin) and negate some of the shortcomings of VKAs. This article reviews the roles of dabigatran, rivaroxaban, apixaban, and edoxaban in stroke prevention in nonvalvular atrial fibrillation, for prevention of venous thromboembolism after orthopedic surgery, and in the treatment of venous thromboembolism. Direct oral anticoagulants are at least as efficacious and safe as traditional anticoagulation therapy.

Differences in galectin-3, a biomarker of fibrosis, between participants with peripheral artery disease and participants with normal ankle-brachial index.

The aim of this study was to determine if galectin-3 levels were different between participants with peripheral artery disease (PAD) and controls, and to describe its relationship with markers of early atherosclerosis. Sixty participants were recruited into two groups: a PAD group (n=31), ankle-brachial index (ABI) ⩽0.90 and a normal ABI group (n=29), ABI 1.0-1.4. PAD participants were older (68.6 vs 61.8 years, p=0.037), more commonly men (68% vs 38%, p=0.02), and with more cardiovascular risk factors (p<0.001). Galectin-3 was 22% higher in PAD participants (mean±SD: 17.6±4.7 vs 14.4±4.1 ng/mL, p<0.01). The odds ratio for galectin-3 in PAD to be 1 ng/mL higher than the participants with normal ABI was 1.19, after adjusting by age and gender (p=0.014). High-sensitivity C-reactive protein (hs-CRP) and homeostatic model assessment (HOMA) were positively associated with galectin-3 in the age- and gender-adjusted model, while arterial elasticity and microalbuminuria were not. In conclusion, galectin-3 levels were higher in participants with PAD.

Endovascular therapy for advanced post-thrombotic syndrome: Proceedings from a multidisciplinary consensus panel.

Patients with advanced post-thrombotic syndrome (PTS) and chronic iliac vein obstruction suffer major physical limitations and impairment of health-related quality of life. Currently there is a lack of evidence-based treatment options for these patients. Early studies suggest that imaging-guided, catheter-based endovascular therapy can eliminate iliac vein obstruction and saphenous venous valvular reflux, resulting in reduced PTS severity; however, these observations have not been rigorously validated. A multidisciplinary expert panel meeting was convened to plan a multicenter randomized controlled clinical trial to evaluate endovascular therapy for the treatment of advanced PTS. This article summarizes the findings of the panel, and is expected to assist in developing a National Institutes of Health-sponsored clinical trial and other studies to improve the care of patients with advanced PTS.

Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial.

BACKGROUND: Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, single-centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS. METHODS: We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsberg's criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials.gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751. FINDINGS: From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73-1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings. INTERPRETATION: ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT. FUNDING: Canadian Institutes of Health Research.

Primary venous thromboembolism prophylaxis in patients with solid tumors: a meta-analysis.

Venous thromboembolism (VTE) is a leading cause of death among outpatient chemotherapy patients. However the VTE preventive measures for outpatients are not widely advocated. We did a meta-analysis to evaluate the outpatient VTE prevention's effectiveness and safety. We searched electronic databases until the end of December 2012 and reviewed the abstracts and manuscripts following the PRISMA guidelines. Occurrence of first VTE event was the efficacy outcome. The safety end point was major bleeding. We calculated Q statistic and a homogeneity formal test. The odds ratio (OR) estimates were pooled by using the Mantel-Haenszel fixed-effects method in the absence of heterogeneity. Data were analyzed using the R META package). We identified 1,485 articles and reviewed 37 articles based on initial screening. The number of patients included in 11 selected trials was 7,805. The odds of VTE was lower in the prophylaxis group (OR 0.56; 95% CI 0.45-0.71) and improved when heparin-based prevention was analyzed (OR 0.53; 95% CI 0.41-0.70). We found strong prevention among patients with lung cancer (OR 0.46; 95% CI 0.29-0.74) and pancreatic cancer (OR 0.33; 95% CI 0.16-0.67). Major bleeding events were frequent in the intervention group (OR 1.65; 95% CI 1.12-2.44). Thromboprophylaxis reduced VTE episodes. The VTE events were reduced by 47% in heparin-based prophylaxis trials compared to placebo. The patients receiving heparin-based prophylaxis had a 60% increase in bleeding events. Improving risk stratification tools to personalize prevention strategies may enhance the VTE prevention applicability in cancer patients.

Effectiveness of foam sclerotherapy for the treatment of varicose veins.

Varicose veins (VVs) are associated with lifestyle-limiting symptoms and complications. Patients who fail compression therapy are candidates for more invasive treatments. This study evaluates the efficacy and safety of endovenous foam sclerotherapy (EFS) for the treatment of VVs in a US academic center. We reviewed medical records of a consecutive cohort of patients who underwent EFS over a 2-year period. The primary outcome measure was obliteration of VVs. The secondary outcome measures were symptomatic improvement, ulcer healing, recurrence, and adverse events. A total of 166 patients (217 legs) underwent EFS for pain (81%), pruritus (41%), swelling (17%), ulcerations (17%), thrombophlebitis (14%), and varix rupture (3%). Complete (65%) or near-complete (34%) obliteration was achieved in 215 (99%) legs after one injection. Additional injections achieved complete obliteration in 39 of 53 legs. Ninety-three percent (27/29) of active ulcers healed or were decreasing in size. Five ulcers and 11 VVs recurred. Common adverse events included pain and hyperpigmentation. Thrombosis, hematoma, skin necrosis, and neurologic events were rare. In conclusion, EFS appears to be a safe and effective outpatient therapy for the treatment of symptomatic and complicated VVs.

June 2008 is Oklahoma DVT Awareness Month.

A concurrent resolution recognizing the importance of raising public awareness of deep-vein thrombosis (DVT) was passed by the state legislature and signed on February 12, 2008, declaring June 4, 2008, Oklahoma DVT Awareness Day and June 2008, Oklohoma DVTAwareness Month. As part of this effort, the Oklahoma State Medical Association is actively involved in the education of health professionals about DVT. This resolution was co-authored by State Senator Johnnie Crutchfield, and State Representatives Greg Piatt and Dr. Doug Cox.

Exclusion of first-episode deep-vein thrombosis after-hours using D-dimer.

The objective of this study was to test the safety of withholding anticoagulant treatment and additional call-back diagnostic testing with ultrasound in patients who have a negative D-dimer at presentation. Patients with signs and symptoms of deep-vein thrombosis who presented to the emergency department after regular hours and on weekends underwent D-dimer testing using the STA-Liatest D-di. In patients with negative D-dimer results, heparin therapy was withheld, and no further diagnostic testing for deep-vein thrombosis was done as part of the initial evaluation. Patients with positive D-dimer results underwent compression ultrasonography. The primary outcome measure was a diagnosis of new symptomatic venous thromboembolism confirmed by diagnostic testing during the 3-month follow-up period. Of the 260 eligible patients, 81 (31%) had a negative D-dimer and 179 (69%) had a positive D-dimer. No patient with a negative D-dimer at presentation had confirmed venous thromboembolism at 3-month follow-up. Three patients died: one by intracranial hemorrhage secondary to cerebrovascular accident; and two deaths of indeterminate cause almost 3 months after entry. The automated assay for D-dimer, the STA-Liatest D-di, seems to provide a simple method with high clinical utility for excluding acute first-episode deep-vein thrombosis in symptomatic patients who present to the emergency room after regular hours.

Medical Treatment for Postthrombotic Syndrome.

Deep vein thrombosis (DVT) is a prevalent disease. About 20 to 30% of patients with DVT will develop postthrombotic syndrome (PTS) within months after the initial diagnosis of DVT. There is no gold standard for diagnosis of PTS, but clinical signs include pitting edema, hyperpigmentation, phlebectatic crown, venous eczema, and varicose veins. Several scoring systems have been developed for diagnostic evaluation. Conservative treatment includes compression therapy, medications, lifestyle modification, and exercise. Compression therapy, the mainstay and most proven noninvasive therapy for patients with PTS, can be prescribed as compression stockings, bandaging, adjustable compression wrap devices, and intermittent pneumatic compression. Medications may be used to both prevent and treat PTS and include anticoagulation, anti-inflammatories, vasoactive drugs, antibiotics, and diuretics. Exercise, weight loss, smoking cessation, and leg elevation are also recommended. Areas of further research include the duration, compliance, and strength of compression stockings in the prevention of PTS after DVT; the use of intermittent compression devices; the optimal medical anticoagulant regimen after endovascular therapy; and the role of newer anticoagulants as anti-inflammatory agents.

Program requirements for fellowship education in venous and lymphatic medicine.

Background In every field of medicine, comprehensive education should be delivered at the graduate level. Currently, no single specialty routinely provides a standardized comprehensive curriculum in venous and lymphatic disease. Method The American Board of Venous & Lymphatic Medicine formed a task force, made up of experts from the specialties of dermatology, family practice, interventional radiology, interventional cardiology, phlebology, vascular medicine, and vascular surgery, to develop a consensus document describing the program requirements for fellowship medical education in venous and lymphatic medicine. Result The Program Requirements for Fellowship Education in Venous and Lymphatic Medicine identify the knowledge and skills that physicians must master through the course of fellowship training in venous and lymphatic medicine. They also specify the requirements for venous and lymphatic training programs. The document is based on the Core Content for Training in Venous and Lymphatic Medicine and follows the ACGME format that all subspecialties in the United States use to specify the requirements for training program accreditation. The American Board of Venous & Lymphatic Medicine Board of Directors approved this document in May 2016. Conclusion The pathway to a vein practice is diverse, and there is no standardized format available for physician education and training. The Program Requirements for Fellowship Education in Venous and Lymphatic Medicine establishes educational standards for teaching programs in venous and lymphatic medicine and will facilitate graduation of physicians who have had comprehensive training in the field.

Sensitivity and specificity of ultrasonography in the diagnosis of upper extremity deep vein thrombosis: a systematic review.

OBJECTIVES: To determine the sensitivity and specificity of ultrasonography in the diagnosis of upper extremity deep vein thrombosis and to determine the safety of withholding anticoagulant therapy in patients with negative ultrasonographic results. DATA SOURCES: The MEDLINE database was searched for literature published from January 1, 1980, to December 31, 2000, that evaluated ultrasonography for the diagnosis of upper extremity deep vein thrombosis. Bibliographies of the retrieved articles were cross-checked to identify additional studies. STUDY SELECTION: All prospective English-language studies were selected. Retrospective studies, review articles, and case reports were excluded. DATA EXTRACTION: Two of us (B.O.M. and S.W.R.) used predefined criteria to independently assess each study. Data on sensitivity and specificity and the associated 95% confidence intervals were recorded when available. DATA SYNTHESIS: Only one study met all of the predefined criteria for adequately evaluating sensitivity and specificity. The sensitivity of duplex ultrasonography ranged from 56% to 100%, and the specificity ranged from 94% to 100%. No study evaluated the safety of withholding anticoagulant therapy without additional testing in patients with negative ultrasonographic results. CONCLUSION: The safety of withholding anticoagulant treatment in a patient with suspected upper extremity deep vein thrombosis and negative ultrasonographic results is uncertain.

Negative D-dimer result to exclude recurrent deep venous thrombosis: a management trial.

BACKGROUND: All of the available diagnostic tests for deep venous thrombosis (DVT) have limitations for excluding acute recurrent DVT. Measurement of plasma d-dimer by using an automated quantitative assay may be useful as a rapid exclusion test in patients with suspected recurrent DVT. OBJECTIVE: To test the safety of withholding additional diagnostic testing and heparin treatment in patients who have a negative d-dimer result at presentation (using the automated quantitative assay STA-Liatest D-di), regardless of their symptoms. DESIGN: Prospective cohort study. SETTING: Academic medical center in the United States. PATIENTS: 300 consecutive patients with suspected recurrent DVT. INTERVENTION: Patients underwent d-dimer testing at presentation. In patients with negative D-dimer results, heparin therapy was withheld, and no further diagnostic testing for DVT was done as part of the initial evaluation. Patients with positive D-dimer results underwent compression ultrasonography. MEASUREMENTS: The primary outcome measure was a diagnosis of new symptomatic venous thromboembolism confirmed by diagnostic testing during the 3-month follow-up period. RESULTS: Of the 300 study patients, the d-dimer result was negative at presentation in 134 patients (45%; negative cohort) and positive at presentation in 166 patients. Of the 166 patients, compression ultrasonography documented new DVT in 54 patients. Compression ultrasonography findings were normal in 79 patients and were inconclusive in 33 patients. After 3 months of follow-up, 1 of 134 patients in the negative cohort had confirmed venous thromboembolism (0.75% [95% CI, 0.02% to 4.09%]). Venous thromboembolism on follow-up could not be definitively excluded in 5 patients with recurrent leg symptoms and in 1 patient who died. If these patients are considered to have venous thromboembolism, the incidence during the 3-month follow-up period would be 6.0% (CI, 2.6% to 11.4%) (8 of 134 patients). LIMITATIONS: There is no accepted diagnostic reference standard for recurrent DVT. The precision of the estimate of the incidence of venous thromboembolism on follow-up and the generalizability to settings other than an academic health center should be evaluated. CONCLUSIONS: Measurement of plasma d-dimer by using the automated quantitative assay STA-Liatest D-di seems to provide a simple method for excluding acute recurrent DVT in symptomatic patients.

Comparison of methods to determine rivaroxaban anti-factor Xa activity.

BACKGROUND AND OBJECTIVES: Rivaroxaban, a new oral anti-Xa agent, has been approved for use without routine monitoring, but the lack of a predictable drug level measurement may hinder the management of anticoagulated patients. The aims of the project were to correlate a Anti-Factor Xa assay using commercial calibrators and controls (Riva Activity) with serum drug levels analyzed by HPLC-MS/MS (Riva MS) in patients currently receiving rivaroxaban, and secondly, to correlate the PT/PTT, thrombin generation (CAT assay) and Thromboelastograph (TEG) with the Riva activity and Riva MS. METHODS: Recruited patients receiving rivaroxaban prospectively had a total of 3 blood samples taken at least 2 hours apart. Plasma was divided for measurement of PT/PTT, Riva activity, rivaroxaban HPCL-MS/MS, and thrombin generation. TEG activity was measured at one random time point for each patient. Correlation and linear regression evaluations were used to compare the different assays. RESULTS: The cases were 22 patients on rivaroxaban, age 56+12.6, and 10 healthy controls. There was a strong correlation between Riva activity compared to serum Riva MS (r=0.99). We found a statistically significant correlation between PT/INR compared to serum measurements of Riva MS (r=0.68) and anti-Xa activity (r=0.69). The peak (r=-0.50) and lag time (r=0.57) CAT correlated with Riva MS measurements. There was no correlation between Riva MS and PTT, TEG R, TEG MA, Endogenous Thrombin potential. CONCLUSION: Riva anti-factor Xa activity assay measured with commercial calibrators and controls provides a reliable assessment of rivaroxaban serum levels for patients requiring measurement of anticoagulant activity. Correlation with other coagulation tests is not sufficiently strong to be used clinically.

Clinical utility of D-dimer in patients with suspected pulmonary embolism and nondiagnostic lung scans or negative CT findings.

BACKGROUND: The diagnosis of pulmonary embolism is difficult because the clinical diagnosis is nonspecific and all of the objective tests have limitations. The assay for plasma d-dimer may be useful as an exclusion test if results are negative. We conducted a prospective cohort study that evaluated the clinical utility (usefulness) of an automated quantitative d-dimer test in the diagnosis of patients with suspected pulmonary embolism. METHODS: Consecutive eligible patients who had clinically suspected PE with nondiagnostic lung scans or negative helical CT scan of the chest results underwent d-dimer testing. RESULTS: The d-dimer results were negative in 11 of 103 inpatients (10.6%, 95% confidence interval [CI], 5.5 to 18.3%) and 7 of 22 outpatients (31.8%, 95% CI, 13.9 to 54.9%; p = 0.02). CONCLUSIONS: Measurement of plasma d-dimer is of limited clinical utility for inpatients with clinically suspected pulmonary embolism and nondiagnostic lung scans or negative helical CT results at a US academic health center.

Core content for training in venous and lymphatic medicine.

The major venous societies in the United States share a common mission to improve the standards of medical practitioners, the educational goals for teaching and training programs in venous disease, and the quality of patient care related to the treatment of venous disorders. With these important goals in mind, a task force made up of experts from the specialties of dermatology, interventional radiology, phlebology, vascular medicine, and vascular surgery was formed to develop a consensus document describing the Core Content for venous and lymphatic medicine and to develop a core educational content outline for training. This outline describes the areas of knowledge considered essential for practice in the field, which encompasses the study, diagnosis, and treatment of patients with acute and chronic venous and lymphatic disorders. The American Venous Forum and the American College of Phlebology have endorsed the Core Content.

Clinical significance of ankle systolic blood pressure following exercise in assessing calf muscle tissue ischemia in peripheral artery disease.

Our primary objective assessed whether a decline in ankle systolic blood pressure (SBP) to less than 50 mm Hg after treadmill exercise is associated with lower extremity ischemia, as measured by calf muscle hemoglobin oxygen saturation (StO(2)). Eighty-four patients with peripheral artery disease (PAD) completed a treadmill test. Ankle SBP <50 mm Hg following exercise was observed in only 49% (group 1), whereas 51% had ankle SBP ≥50 mm Hg (group 2). No group differences were observed for the decline in calf muscle StO(2) to a minimum value (group 1: 18 ± 21%, group 2: 20 ± 20%; P = .60) and for the time to reach minimum StO(2) (group 1: 224 ± 251 seconds, group 2: 284 ± 283 seconds; P = .30). Requirement of ankle SBP to decrease below 50 mm Hg after exercise has little clinical significance for assessing ischemia in calf muscle of patients with PAD limited by intermittent claudication.

Treatment of varicose veins.

Varicose veins (VVs) are the most common manifestation of chronic venous insufficiency, affecting 25% of women and 15% of men. Reticular veins and telangiectasias (spider veins) are found in more than 80% of the general population. VVs produce symptoms of pain, swelling, heaviness, fatigue, and pruritus and predispose patients to complications including bleeding, superficial thrombophlebitis, and ulcerations that interfere with activities of daily living and result in lost time from work. Current treatments for VVs include conservative measures, and when these are unsuccessful, more invasive surgical and endovenous interventions primarily aimed at reducing venous hypertension and preventing progression to chronic inflammation and ulcerations. Surgical procedures including saphenous vein stripping, ligation of the saphenofemoral junction, and ambulatory phlebectomy are effective in the treatment of VVs but are associated with a high complication rate and recovery time. Emerging endovenous therapies, including endovenous laser therapy, radiofrequency ablation, and endovenous foam sclerotherapy, have shown similar efficacy in the treatment of VVs compared with more invasive surgical procedures, with lower complication rates and less time lost from work.

Venous thromboembolism in women.

The risk of venous thromboembolism (VTE) varies throughout a woman's life and is associated primarily with underlying hormonal exposure. Alteration in hemostatic mechanisms, including resistance to activated protein C, may explain this altered risk. Initially, development of VTE with the use of contraception in young adulthood may reveal inherited thrombophilia. Pregnancy, and particularly the post-partum period, likely confer the greatest risk of VTE, but the absolute risk is small. Guidelines for prevention of VTE during pregnancy are based on personal or family history of VTE, and known inherited thrombophilia. Use of hormone replacement therapy later in life is associated with increased risk of VTE, and may be safest if given as an estrogen-only preparation to young postmenopausal women for less than 5 years. Universal screening for thrombophilia prior to pregnancy or initiating hormonal therapy is not recommended; however, selected testing in high-risk groups may be warranted. The lack of firm recommendations for the prevention of VTE in women highlights the need for future investigation aimed at identifying high-risk groups and evaluating the efficacy of prophylactic measures.