Effect of RRR-α-tocopherol supplementation on serum of breastfeeding women up to 60 days after delivery: a randomised controlled trial.

BACKGROUND: Maternal supplementation is a viable strategy to combat vitamin E deficiency in newborns, although a protocol for maternal vitamin E supplementation has not been defined. The present study assessed the effect of maternal supplementation in a single dose on the serum of postpartum women up to 60 days after delivery. METHODOLOGY: Fifty healthy breastfeeding women were recruited at two maternity hospitals both located in Natal, RN, Brazil. The participants were randomly allocated to a control group and a treatment group in a 1 : 1 ratio. Serum was collected 1, 20, 30 and 60 days after delivery. Immediately after the first collection, the treatment group received a single dose of 400 IU of RRR-α-tocopherol. α-Tocopherol was quantified by high-performance liquid chromatography. The usual dietary vitamin E intake was determined using four 24-h recalls, and intake adequacy was assessed based on the estimated average requirements for lactating women (16 mg day-1 ). RESULTS: The mean dietary vitamin E intakes of the both groups were similar (P > 0.05) and inadequate. The serum levels of α-tocopherol assessed at 1, 20, 30 and 60 days indicated adequate vitamin E status in both the control group (1194.6, 907.7, 910 and 748.6 µg dL-1 , respectively) and treatment group (1183.7, 956.0, 935.9 and 766.4 µg dL-1 , respectively). The comparison at each day showed no difference between treatments (P > 0.05). CONCLUSIONS: A single vitamin E supplement did not change the mean serum level of α-tocopherol in breastfeeding women; thus, it does not improve their vitamin E status in the first 60 days after delivery.

Evaluation of a new PT-INR monitoring system in patients with the antiphospholipid syndrome.

INTRODUCTION: Patients on anticoagulant therapy with vitamin K antagonists (VKA) need frequent INR monitoring. Reliability of point-of-care (POC) devices for measuring INR needs rigorous evaluation, particularly in patient with the antiphospholipid syndrome (APS). The aim of this study was to evaluate the accuracy of the ProTime InRhythm(™) System (here called device) for INR measurement in patients with APS on VKA. METHODS: We compared the device INR vs. the laboratory INR measurement for blood samples from 29 APS-positive and 31 APS-negative patients consecutively enrolled. APS was confirmed by positive serological and/or phospholipid-dependent coagulation tests. Chromogenic factor X assay was used to evaluate anticoagulation. Bland-Altman difference plot for paired INR (POC vs. laboratory) was used to evaluate agreement between the device and the laboratory. The device INR relationship with factor X chromogenic assay was evaluated by orthogonal regression analysis. RESULTS: Overall, 97% of the device INR measurements were similar to laboratory INR values with an absolute difference less than 0.4 units. Correlation coefficient for the device INR vs. factor X was -0.69 (P < 0.0001, CI 95% -0.80 to -0.52). CONCLUSIONS: The ProTime InRhythm System(™) is an accurate point-of-care device for measuring INR also in patients with and without APS.

New oral anticoagulants in thrombotic antiphospholipid syndrome.

A main goal in clinical management of patients with antiphospholipid syndrome (APS) is to prevent thrombotic recurrences and/or miscarriages. For many decades, the only available oral anticoagulant drugs have been vitamin K antagonists (VKA), which are still the cornerstone of long-term treatment of thromboembolism. However, the limits of VKA treatment are well known: narrow therapeutic window and high patient-to-patient variability of response. Moreover, in some patients with APS a higher international normalized ratio (INR) therapeutic target was suggested, and INR inaccuracy due to antiphospholipid antibodies was reported. Therefore, VKA management in APS patients is frequently cumbersome, requires close INR monitoring and may affect patient's quality of life. A new class of oral anticoagulant agents has been developed, the Direct Oral Anticoagulants (DOA), which directly inhibit a single enzyme of the coagulation cascade. Compared with VKA, they have more stable pharmacokinetic and pharmacodynamic profiles, little interaction with food or drugs with a predictable anticoagulation effect, they can thus be prescribed in a fixed dose, without requiring frequent laboratory monitoring. The efficacy and safety of DOA has been shown in large phase III clinical trials. Unfortunately, translating these good results to APS patients is not straightforward: currently, at least three randomized controlled clinical trials are ongoing.

Phase III studies on novel oral anticoagulants for stroke prevention in atrial fibrillation: a look beyond the excellent results.

In this overview we address the three phase III studies that compared new oral anticoagulants (dabigatran, rivaroxaban and apixaban) with warfarin in the setting of stroke prevention in atrial fibrillation. Strengths and weaknesses of the studies were examined in detail through indirect comparison. We analyze and comment the inclusion and exclusion criteria, the characteristics of randomized patients, the primary efficacy and safety end points and side effects. All new oral anticoagulants resulted in being non-inferior to vitamin K antagonists in reducing stroke or systemic embolism in patients with atrial fibrillation. Dabigatran 150 mg and apixaban were superior to vitamin K antagonists. Importantly, new oral anticoagulants significantly reduced hemorrhagic stroke in all three studies. Major differences among new oral anticoagulants include the way they are eliminated and side effects. Both dabigatran and apixaban were tested in low- to moderate-risk patients (mean CHADS2 [Congestive heart failure, Hypertension, Age, Diabetes, Stroke] score = 2.1-2.2) whereas rivaroxaban was tested in high-risk patients (mean CHADS2 score = 3.48) and at variance with dabigatran and apixaban was administered once daily. Apixaban significantly reduced mortality from any cause. The choice of a new oral anticoagulant should take into account these and other differences between the new drugs.

Risk factors for catheter-related thrombosis (CRT) in cancer patients: a patient-level data (IPD) meta-analysis of clinical trials and prospective studies.

BACKGROUND: Knowledge of independent, baseline risk factors for catheter-related thrombosis (CRT) may help select adult cancer patients who are at high risk to receive thromboprophylaxis. OBJECTIVES: We conducted a meta-analysis of individual patient-level data to identify these baseline risk factors. PATIENTS/METHODS: MEDLINE, EMBASE, CINAHL, CENTRAL, DARE and the Grey literature databases were searched in all languages from 1995 to 2008. Prospective studies and randomized controlled trials (RCTs) were eligible. Studies were included if original patient-level data were provided by the investigators and if CRT was objectively confirmed with valid imaging. Multivariate logistic regression analysis of 17 prespecified baseline characteristics was conducted. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. RESULTS: A total sample of 5636 subjects from five RCTs and seven prospective studies was included in the analysis. Among these subjects, 425 CRT events were observed. In multivariate logistic regression, the use of implanted ports as compared with peripherally implanted central venous catheters (PICCs), decreased CRT risk (OR, 0.43; 95% CI, 0.23-0.80), whereas past history of deep vein thrombosis (DVT) (OR, 2.03; 95% CI, 1.05-3.92), subclavian venipuncture insertion technique (OR, 2.16; 95% CI, 1.07-4.34) and improper catheter tip location (OR, 1.92; 95% CI, 1.22-3.02), increased CRT risk. CONCLUSIONS: CRT risk is increased with use of PICCs, previous history of DVT, subclavian venipuncture insertion technique and improper positioning of the catheter tip. These factors may be useful for risk stratifying patients to select those for thromboprophylaxis. Prospective studies are needed to validate these findings.

The cost-effectiveness of computer-assisted anticoagulant dosage: results from the European Action on Anticoagulation (EAA) multicentre study.

BACKGROUND: Increased demand for oral anticoagulation has resulted in wider adoption of computer-assisted dosing in anticoagulant clinics. An economic evaluation has been performed to investigate the cost-effectiveness of computer-assisted dosing in comparison with manual dosing in patients on oral anticoagulant therapy. METHODS: A trial-based cost-effectiveness analysis was conducted as part of the EAA randomized study of computer-assisted dosage vs. manual dosing. The 4.5-year multinational trial was conducted in 32 centres with 13 219 anticoagulation patients randomized to manual or computer-assisted dosage. The main outcome measures were total health care costs, clinical event rates and cost-saving per clinical event prevented by computer dosing compared with manual dosing. RESULTS: Mean dosing costs per patient were lower (difference: euro47) for computer-assisted dosing, but with little difference in clinical event costs. Total overall costs were euro51 lower in the computer-assisted dosing arm. There were a larger number of clinical events in the manual dosing arm. The overall difference between trial arms was not significant (difference in clinical events, -0.003; 95% CI, -0.010-0.004) but there was a significant reduction in events with DVT/PE, suggesting computer-assisted dosage with the two study programs (dawn ac or parma 5) was at least as effective clinically as manual dosage. The cost-effectiveness analysis indicated that computer-assisted dosing is less costly than manual dosing. CONCLUSIONS: Results indicate that computer-assisted dosage with the two programs (dawn ac and parma 5) is cheaper than manual dosage and is at least as effective clinically, indicating that investment in this technology represents value for money.

Do Italian vascular centers look for isolated calf deep vein thrombosis? Analysis of isolated calf deep vein thromboses included in the ''Master'' Registry.

AIM: Two diagnostic imaging strategies for suspected deep venous thrombosis (DVT) in symptomatic patients are currently used: a serial compression ultrasound examination of proximal veins, or a single complete ultrasound investigation of proximal and distal veins. These strategies lead to different results since only the latter allows diagnosis of isolated calf DVT (ICDVT). METHODS: We analyzed the approach of Italian centers in looking for ICDVT using the observational MASTER registry which prospectively collected information on patients with acute symptomatic venous thromboembolism. RESULTS: ICDVT was diagnosed in 170 of the 1772 patients with leg DVT (9.6%). The rate of diagnosed ICDVT vs total DVT differed between centers from 0% to 24%. Patients with ICDVT were younger (P<0.0001); diagnosis was more frequently delayed (P<0.0001), temporary risk factors were more frequent, cancer was less frequent (P<0.001), and pulmonary embolism (PE) was more frequent at presentation (P<0.05). More ICDVT patients received LMWH only, not followed by oral anticoagulation (P<0.001). CONCLUSIONS: The diagnostic strategy for suspected leg DVT differs greatly among Italian centers. A relatively high rate of PE was recorded in patients with ICDVT for reasons which are open to debate. Prospective, well designed studies on the clinical risks and the need for diagnosing ICDVT, and the advantages/disadvantages of the two diagnostic procedures are urgently needed.

An international multicenter randomized study of computer-assisted oral anticoagulant dosage vs. medical staff dosage.

BACKGROUND: Increased demand for oral anticoagulants is overwhelming facilities worldwide, resulting in increasing use of computer assistance. A multicenter clinical endpoint study has been performed to compare the safety and effectiveness of computer-assisted dosage with dosage by experienced medical staff at the same centers. METHODS: A randomized study of dosage of two commercial computer-assisted dosage programs (PARMA 5 and DAWN AC) vs. manual dosage at 32 centers with an established interest in oral anticoagulation in 13 countries. The aim was to recruit a minimum of 16,000 patient-years randomized to medical staff or computer-assisted dosage. In total, 13,219 patients participated, 6503 patients being randomized to medical staff and 6716 to computer-assisted dosage. The safety and effectiveness of computer-assisted dosage were compared with those of medical staff dosage. RESULTS: In total, 13,052 patients were recruited (18,617 patient-years). International Normalized Ratio (INR) tests numbered 193 890 with manual dosage and 193,424 with computer-assisted dosage. The number of clinical events with computer-assisted dosage was lower (P = 0.1), but in the 3209 patients with deep vein thrombosis/pulmonary embolism, they were reduced by 37 (24%, P = 0.001). Time in target INR range was significantly improved by computer assistance as compared with medical staff dosage at the majority of centers (P < 0.001). CONCLUSIONS: The safety and effectiveness of computer-assisted dosage has been demonstrated using two different marketed programs in comparison with experienced medical staff dosage at the centers with established interest in anticoagulation. Significant prevention of clinical events in patients with deep vein thrombosis/pulmonary embolism and the achievement of target INR in all clinical groups has been observed. The reliability and safety of other marketed computer-assisted dosage programs need to be established.

The first ambulatory screening on thromboembolism: a multicentre, cross-sectional, observational study on risk factors for venous thromboembolism.

OBJECTIVES: To assess the prevalence of risk factors for venous thromboembolism (VTE) and the prevalence of recent (<1 year) VTE [including superficial vein thrombosis (SVT), deep vein thrombosis (DVT) and pulmonary embolism (PE)] amongst patients attending general practitioner (GP) surgeries. DESIGN: Multicentre, cross-sectional, observational study. SETTING: A total of 1536 GP surgeries. PARTICIPANTS: A total of 15 180 adult, co-operative subjects, who had consulted their GP for a health disorder and signed the informed consent form. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Prevalence of known VTE risk factors graded according to importance and prevalence of recent (<1 year) VTE events (including SVT), based on interviews. RESULTS: About 1:5 patients had at least one strong risk factor and about 1:20 had at least two risk factors, with no difference between sexes. The prevalence of strong risk factors increased with age. Most were related to medical conditions: history of SVT and/or DVT/PE, heart failure and malignancy. About 3:4 women and 2:3 men had at least one moderate to weak risk factor; nearly 1:2 women and 1:3 men had at least two moderate to weak risk factors. The most common were: history of VTE, smoking, history of miscarriage, estrogen therapy, obesity, and varicose veins. Overall, 80% women and 67% men had at least one risk factor, and 50% women and 35% men had at least two risk factors. The prevalence of recent (<1 year) VTE was 3.4% in women and 2.4% in men, and increased with age. The majority of cases were SVT in both sexes (2.5% in women and 1.5% in men). CONCLUSIONS: The prevalence of risk factors for VTE amongst patients attending GP surgeries is high. GPs should bear this in mind during their daily practice.

Central venous catheter-related complications in patients with hematological malignancies: a retrospective analysis of risk factors and prophylactic measures.

UNLABELLED: We retrospectively analyzed the incidence of thrombotic and infectious complications in relation with the use of central venous catheters (CVCs), in a series of patients with hematological malignancies and low platelet and leucocyte counts. PATIENTS AND METHODS: 126 patients with hematological malignancies were analyzed. A total of 207 CVCs were implanted: 137 centrally (CICCs) and 70 peripherally (PICCs). The median duration of the CVCs was 19 days for a total of 4051 catheter-days. Antithrombotic prophylaxis was unfractionated heparin (UFH), 2,500 IU daily by 24 h continuous infusion in 169 CVCs, low molecular weight heparin (LMWH), 3,800 IU daily by single bolus intravenous injection (i.v.) in 21 and warfarin in one. No prophylaxis was given in 16 CVCs. Thrombotic complications developed in 15.5% of the CVCs (7.9 events/1000 catheter days), and the frequency of infectious complications was 10.6% (5.2 events/1000 catheter days). On multivariate analysis thromboses were more frequent and earlier with PICCs than CICCs (p = 0.0001), and in patients on UFH (16.6%) than in LMWH prophylaxis (4.7%), but the last difference was not statistically significant. In conclusions the incidence of thrombotic complications in our series was comparable to that observed in non-thrombocytopenic patients and was significantly higher in those carrying PICC than CICC (p = 0.0001). There were fewer thrombotic events in the patients receiving i.v. LMWH prophylaxis than in those receiving i.v. UFH. The use of anticoagulants was safe and not associated with hemorrhages.

Prevention of venous thrombosis with elastic stockings during long-haul flights: the LONFLIT 5 JAP study.

The aim of this study was to evaluate deep venous thrombosis (DVT) prophylaxis with specific elastic stockings in long-haul flights (11-13 hours), in high-risk subjects. A group of 300 subjects was included; 76 were excluded for several problems including concomitant treatments; 224 were randomized into two groups (stockings vs. controls) to evaluate prophylaxis with below-knee stockings. An exercise program was used in both groups. Scholl (UK) Flight Socks (14-17 mmHg of pressure at the ankle) were used. DVT was diagnosed with ultrasound scanning. The femoral, popliteal, and tibia] veins were scanned before and within 90 minutes after the flights. Of the 205 included subjects, 102 controls and 103 treated subjects completed the study. Drop-outs were due to flight connection problems. Age, gender, and risk distributions were comparable in the two groups. In the treatment group (103 subjects; mean age, 42; SD 9; M:F, 55:48), one limited, distal DVT was observed (0.97%). In the control group (102 subjects; mean age, 42.1; SD 10.3; M:F, 56:46), six subjects (5.8%) had a DVT. There were no superficial thromboses. The difference in DVT incidence is significant (p<0.0025; six times greater in the control group). Intention-to-treat analysis counts 18 failures in the control group (12 lost to follow-up + six thromboses) of 112 subjects (15.8%) versus eight failures (7.3%) in the treatment group (p<0.05). The tolerability of the stockings was very good and there were no complaints or side effects. All events were asymptomatic. Considering these observations, Scholl Flight Socks are effective in reducing the incidence of DVT in high-risk subjects.

Venous thromboembolism in the antiphospholipid syndrome: management guidelines for secondary prophylaxis.

Venous thromboembolism (VTE) in patients suffering from the antiphospholipid syndrome (APS) has been reported in almost any location of the vessel tree and the risk of recurrences has been found in several studies to be more closely associated with the presence of lupus anticoagulant than with the positivity for anti-cardiolipin antibodies. The thrombophilic state of APS raises the problem of the secondary prophylaxis to avoid VTE recurrences. For APS patients with VTE, published data appear to support a longer warfarin treatment if compared with the standard management of antiphospholipid (aPL)-negative patients with VTE. The question of how long oral anticoagulant treatment should be continued for APS patients, however, remains unanswered. Concerning the intensity of anticoagulation, several authors recommend a target international normalized ratio (INR) between 3.0 and 4.0 to efficiently protect from VTE recurrences. A recent decision analysis study does support such a suggestion. On the contrary, in a few prospective studies regimens with lower target INRs appear to be effective, and some authors therefore recommend a target INR of between 2.0 and 3.0. Specific large and prospective trials are needed to address this question. Until such information becomes available, individualized treatment according to the patient's individual risk factors for both bleeding and thrombosis is the general practice.

Incidence of cancer after a first episode of idiopathic venous thromboembolism treated with 3 months or 1 year of oral anticoagulation.

BACKGROUND: A prolonged treatment with oral anticoagulants has been claimed to reduce the incidence of newly diagnosed cancer in the long-term follow-up of patients with venous thromboembolism. OBJECTIVES: In a multicenter prospective study we assessed the incidence of newly diagnosed clinically overt cancer in patients with a first episode of idiopathic venous thromboembolism (VTE) treated with oral anticoagulants for 3 months or 1 year. PATIENTS AND METHODS: Consecutive patients with an idiopathic venous thromboembolism who had completed 3 months of oral anticoagulant therapy without having a recurrence, bleeding or newly diagnosed cancer were randomized to discontinue oral anticoagulant therapy or to continue it for nine additional months. Idiopathic venous thromboembolism was defined as thrombosis occurring in the absence of known cancer, known thrombophilia, or temporary risk factors for venous thromboembolism. All patients were followed up for at least 1 year after randomization. RESULTS: A total of 429 patients, 265 patients with DVT and 164 with PE, were followed up for an average of 43.7 months after randomization. A newly diagnosed cancer occurred in 32 patients (7.5%), 13 (6.2%) of the 210 patients treated for 3 months and 19 (8.7%) of the 219 patients treated for 1 year (RR = 0.71, 95% confidence interval 0.36-1.41). CONCLUSIONS: The incidence of newly diagnosed clinically overt cancer is not reduced in patients with idiopathic venous thromboembolism treated with 1-year anticoagulant treatment compared with patients treated for 3 months.