The risk of hemorrhage among patients with warfarin-associated coagulopathy.

OBJECTIVES: Among warfarin-treated patients with international normalized ratio (INR) >5, we sought to determine the risk of major bleeding within 30 days. BACKGROUND: For warfarin-treated patients, the risk of bleeding increases as the INR rises, particularly if the INR exceeds 4. The 30-day risk of hemorrhage among outpatients with excessively prolonged INR values is unknown. METHODS: To assess anticoagulation care in the U.S., a cohort of 6,761 patients taking warfarin was prospectively assembled from 101 participating sites (43% were community-based cardiology practices). From this cohort, 1,104 patients were identified with a first episode of INR >5. RESULTS: A total of 979 met eligibility criteria; complete follow-up information was available for 976 (99.7%). Ninety-six percent (n = 937) of patients had an INR value between 5 and 9; 80% of INR values were <7. Thirteen patients (1.3%) experienced major hemorrhage during the 30-day follow-up period; among patients whose INR was >5 and <9, 0.96% experienced major hemorrhage. None of the bleeding events was fatal. Intervention with vitamin K was uncommon (8.7%). Warfarin doses were withheld for the majority of patients. Fifty percent of patients who were managed conservatively and retested on day 4 or 5 had an INR of 2.0 or less. CONCLUSIONS: For warfarin-treated outpatients presenting with an INR >5 and <9, the 30-day risk of major bleeding is low (0.96%). Intervention with vitamin K among asymptomatic patients presenting with an INR <9 is not routine practice in the U.S.     

Short-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of prospective studies investigating symptomatic outcomes

BACKGROUND: The prevalence of asymptomatic deep vein thrombosis diagnosed by venography after hip or knee replacement remains high despite 7 to 10 days of anticoagulant prophylaxis. However, the risk of symptomatic events in such patients is unclear. We performed a meta-analysis to provide reliable estimates of the risk of symptomatic venous thromboembolism occurring within 3 months of hip or knee replacement in patients who received short-duration (7-10 days) anticoagulant prophylaxis. METHODS: The MEDLINE, EMBASE, and Cochrane databases were searched from January 1993 to March 2001, supplemented by a manual search of bibliographies and conference abstracts, to identify prospective studies of patients undergoing hip or knee replacement who received short-duration prophylaxis (ie, 7-10 days of fixed-dose low-molecular-weight heparin or adjusted-dose warfarin, with a target international normalized ratio of 2.0-3.0). Studies were classified as clinical outcome studies if the outcome was symptomatic venous thromboembolism or as venographic outcome studies if the outcome was asymptomatic deep vein thrombosis diagnosed after bilateral venography. RESULTS: There were 4 clinical outcome studies with 6089 patients who had 3 months of follow-up, and 13 venographic outcome studies with 7080 patients who had venography 7 to 10 days after surgery. In clinical outcome studies, the 3-month incidence of nonfatal venous thromboembolism was 3.2% (95% confidence interval [CI], 2.0%-4.4%), and the 3-month incidence of fatal pulmonary embolism was 0.10% (95% CI, 0.02%-0.20%). The postprophylaxis incidence of nonfatal venous thromboembolism was 2.2% (95% CI, 1.4%-3.0%), and the incidence of fatal pulmonary embolism was 0.05% (95% CI, 0%-0.12%). The postprophylaxis incidence of symptomatic venous thromboembolism was higher after hip than after knee replacement (2.5% vs 1.4%; P=.02). In venographic outcome studies, the prevalence of deep vein thrombosis (total and proximal) was higher after knee than after hip replacement (total: 38.8% vs 16.4%; P<.001; proximal: 7.6% vs 3.8%; P<.001). CONCLUSIONS: In patients who undergo hip or knee replacement and receive short-duration anticoagulant prophylaxis, symptomatic nonfatal venous thromboembolism will occur in about 1 of 32 patients and fatal pulmonary embolism will occur in about 1 of 1000 patients within 3 months of the surgery. Although the prevalence of asymptomatic deep vein thrombosis is more than 2-fold higher after knee replacement than after hip replacement 7 to 10 days after surgery, in the subsequent 3 months, symptomatic venous thromboembolism is more likely to occur after hip replacement.     

Weight-related differences in glucose metabolism and free fatty acid production in two South African population groups

OBJECTIVE: The effects of free fatty acids (FFA), leptin, tumour necrosis factor (TNF) alpha and body fat distribution on in vivo oxidation of a glucose load were studied in two South African ethnic groups. DESIGN AND MEASUREMENTS: Anthropometric and various metabolic indices were measured at fasting and during a 7 h oral glucose tolerance test (OGTT). Body composition was measured using bioelectrical impedance analysis and subcutaneous and visceral fat mass was assessed using a five- and two-level CT-scan respectively. Glucose oxidation was evaluated by measuring the ratio of (13)CO(2) to (12)CO(2) in breath following ingestion of 1-(13)C-labelled glucose. SUBJECTS: Ten lean black women (LBW), ten obese black women (OBW), nine lean white women (LWW) and nine obese white women (OWW) were investigated after an overnight fast. RESULTS: Visceral fat levels were significantly higher (P<0.01) in obese white than black women, despite similar body mass indexes (BMIs). There were no ethnic differences in glucose oxidation however; in the lean subjects of both ethnic groups the area under the curve (AUC) was higher than in obese subjects (P<0.05 for both) and was found to correlate negatively with weight (r=-0.69, P<0.01) after correcting for age. Basal TNF alpha concentrations were similar in all groups. Percentage suppression of FFAs at 30 min of the OGTT was 24+/-12% in OWW and -38+/-23% (P<0.05) in OBW, ie the 30 min FFA level was higher than the fasting level in the latter group. AUC for FFAs during the late postprandial period (120--420 min) was significantly higher in OWW than OBW (P<0.01) and LWW (P<0.01) and correlated positively with visceral fat mass independent of age (r=0.78, P<0.05) in the OWW only. Leptin levels were higher (P<0.01) both at fasting and during the course of the OGTT in obese women from both ethnic groups compared to the lean women. CONCLUSIONS: Glucose oxidation is reduced in obese subjects of both ethnic groups; inter- and intra-ethnic differences were observed in visceral fat mass and FFA production and it is possible that such differences may play a role in the differing prevalences of obesity-related disorders that have been reported in these two populations.     

Paper-based dosing algorithms for maintenance of warfarin anticoagulation

We examined the quality of anticoagulation produced by two paper-based warfarin dosing algorithms in a randomized clinical trial of warfarin therapy. Fifty-eight patients were randomized to receive warfarin at a target international normalized ratio (INR) range of 2.1–3.0 and were followed for an average of 2.7 years. As a proportion of total patient-time, the percentage of time spent above, within, and below the therapeutic range was 11%, 71%, and 19% respectively. Fifty-six patients were randomized to receive warfarin at a higher target INR range (3.1–4.0) and had INRs within the therapeutic range for 40% of total patient time. We conclude that the performance, minimal cost, and ease-of-use of these algorithms make them well-suited for patient management within primary-care and research settings. Dr Crowther is a Career Investigator of Heart and Stroke Foundation of Canada This study was supported by the Canadian Institutes for Health Research.     

Thrombolysis for Restoration of Patency to Haemodialysis Central Venous Catheters: A Systematic Review

Urokinase, previously used to restore patency to thrombosed haemodialysis catheters, is now unavailable in North America.We performed systematic reviews of four questions related to the safety and efficacy of alternative agents for catheter thrombolysis, searching Medline and the Cochrane Controlled Clinical Trials Register.In dialysis patients, large case series have documented that urokinase is safe and effective (>70%% efficacy for catheter instillation, and >80%% for systemic lysis). Experience with streptokinase is limited and allergic complications develop with repeated use. Studies of catheter instillation with 1–2[emsp4 ]mg of tPA per lumen reported short-term success in 83–98%% of uses. One non-peer-reviewed study described 44–59%% success using systemic tissue plasminogen activator (tPA), 2.5[emsp4 ]mg through each of 2 lumens, over 1[emsp4 ]h. Meta-analysis of randomized comparisons of urokinase and tPA as full-dose thrombolytic agents suggested that 1[emsp4 ]mg tPA was likely equivalent in thrombolytic potency to 36,000 units urokinase. In nondialysis populations, four case series suggested that catheter instillation with 0.5–2[emsp4 ]mg tPA was effective and safe in reestablishing patency, and a randomized controlled trial found 2–4[emsp4 ]mg tPA more effective than 5,000–10,000 units urokinase. No complications have been reported in any patient treated with systemic or local tPA for catheter thrombolysis. In studies of fistula thrombolysis with 5–50[emsp4 ]mg tPA major complications occurred in one episode in 130 patients treated.This review suggests that 1–2[emsp4 ]mg/lumen tPA is a suitable dose for catheter instillation and likely to be more effective than 5000 units/lumen urokinase. Systemic lysis with 5–10[emsp4 ]mg tPA is likely to be safe and effective in suitably selected patients. Further studies are needed.     

Effect of chronic kidney disease on red blood cell rheology

BACKGROUND: Anemia of renal failure is primarily a problem of decreased RBC production due to erythropoietin deficiency. RBC survival is also reduced, perhaps due to decreased RBC deformability. This study measured blood viscosity over a range of shear rates in erythropoietin-treated patients on hemodialysis (HD), and compared the findings to matched patients with chronic renal insufficiency (CRI) and healthy controls. METHODS: Four groups (control, CRI, non-diabetic HD, and diabetic HD) of 9 matched subjects were recruited. Blood viscosity was measured using a cone-plate viscometer over a variety of shear rates (11 to 225 s(-1)). RESULTS: Control subjects had lower viscosity values throughout all shear rates when compared to the 3 renal disease groups (P value=0.039). A trend was observed to higher levels of renal function being associated with decreased blood viscosity in patients with CRI. CONCLUSIONS: Patients with kidney disease have increased blood viscosity at all shear rates. This may be related to changes in RBC shape and decreased deformability in patients with kidney disease, independent of HD- or DM-status. This may have implications for strategies to treat anemia in these patients.     

Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents

For more than 60 years, heparin and coumarin have been mainstays of anticoagulation therapy. They are widely available, inexpensive, effective, and have specific antidotes but are regarded as problematic because of their need for careful monitoring. In addition, coumarin has a delayed onset of action, interacts with many medications, has a narrow therapeutic window, and is paradoxically prothrombotic in certain settings (ie, can precipitate "coumarin necrosis"). Heparin may require monitoring of its therapeutic effect and can also cause thrombosis (heparin-induced thrombocytopenia/thrombosis syndrome). These limitations have led to the development of new anticoagulants with the potential to replace current agents. These newer agents fall into 2 classes, based on whether they are antithrombin dependent (low-molecular-weight heparin, fondaparinux) or antithrombin independent (direct inhibitors of factor Xa and thrombin [factor IIa]). This paper addresses newer anticoagulants, reviewing their efficacy and limitations, and focuses on the risk of major bleeding that may complicate their use. In contrast to heparin and coumarin, none of these newer agents has a specific antidote that completely reverses its anticoagulant effect. Available data on the efficacy and safety of current and experimental agents for anticoagulant reversal are reviewed, and a plan for management of anticoagulant-induced bleeding is presented.     

A comparison of two methods of assessing orthodontic treatment need in the mixed dentition: DAI and IOTN

This paper assesses the unmet orthodontic treatment need in a random sample of 10-year-old schoolchildren, using two indices: the Dental Aesthetic Index (DAI) and the Index of Orthodontic Treatment Need (IOTN). The DAI scores were adjusted by omitting the missing teeth component of the index because many children were in the mixed dentition with unerupted permanent teeth. Although both indices assessed the same number of children with malocclusions requiring orthodontic treatment, not all were ranked similarly by each index.