BACKGROUND The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. METHODS We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. RESULTS At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], −0.2; 95% confidence interval, −3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. CONCLUSIONS Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.)
HE PREVALENCE OF EXTREMEobesity in the United States is increasing at a rate greater than moderate obesity. 1 , 2 Unfortunately, lifestyle therapy is generally insufficient as a weight management intervention for patients who are extremely obese. To date, effective long-term weight loss through pharmacological therapy has been marginal, leaving bariatric For editorial comment see p 1160.
Patients diagnosed with acute PE in U.S. EDs have high functional status, and their mortality rate is low. These registry data suggest that appropriate initial medical management of ED patients with severe PE with anticoagulation is poorly standardized and indicate a need for research to determine the appropriate threshold for empiric treatment when PE is suspected before diagnostic confirmation.
BACKGROUND: Prospective studies on the incidence of VTE during severe sepsis and septic shock remain absent, hindering effi cacy assessments regarding VTE prevention strategies in sepsis.
Background-Well characterized genes affecting warfarin metabolism (CYP2C9) and sensitivity (VKORC1) explain one-third of the variability in therapeutic dose before the International Normalized Ratio (INR) is measured.
Abstract-Obese subjects have a high prevalence of left ventricular (LV) hypertrophy. It is unclear to what extent LV hypertrophy results directly from obesity or from associated conditions, such as hypertension, impaired glucose homeostasis, or obstructive sleep apnea. We tested the hypothesis that LV hypertrophy in severe obesity is associated with additive effects from each of the major comorbidities. Echocardiography and laboratory testing were performed in 455 severely obese subjects with body mass index 35 to 92 kg/m 2 and 59 nonobese reference subjects. LV hypertrophy, defined by allometrically corrected (LV mass/height 2.7 ), gender-specific criteria, was present in 78% of the obese subjects. Multivariable regression analyses showed that average nocturnal oxygen saturation Ͻ85% was the strongest independent predictor of LV hypertrophy (PϽ0.001), followed by systolic blood pressure (PϽ0.015) and then body mass index (PϽ0.05). With regard to LV mass, there were synergistic effects between hypertension and body mass index (P interaction Ͻ0.001) and between hypertension and reduced nocturnal oxygen saturation. Severely obese subjects had normal LV endocardial fractional shortening (35Ϯ6% versus 35Ϯ6%) but mildly decreased midwall fractional shortening (15Ϯ2% versus 17Ϯ2%; PϽ0.001), indicating subtle myocardial dysfunction. In conclusion, more severe nocturnal hypoxemia, increasing systolic blood pressure, and body mass index are all independently associated with increased LV mass. The effects of increased blood pressure seem to amplify those of sleep apnea and more severe obesity. O besity is associated with an increased risk of developing heart failure, 1 as well as an increased overall risk of death. 2 The association between obesity and heart failure could result from direct adverse effects of obesity on cardiac structure and function or could occur indirectly because obese patients have a high prevalence of coexisting disorders, such as coronary artery disease, diabetes, hypertension (HTN), and sleep-disordered breathing. 3,4 Many studies have shown that obesity is associated with left ventricular (LV) hypertrophy, a potential contributor to heart failure. 5-10 However, because obesity rarely exists in isolation, it has been a challenge to dissect out the relative contributions of various obesity-associated conditions.The majority of published works show a positive, independent relationship between body mass index (BMI) and LV mass. 5,6,9 Several studies also show additive effects of increasing blood pressure and BMI on LV mass. 11,12 The impact of diabetes, glucose intolerance, and insulin resistance on LV hypertrophy has been seen less consistently, [13][14][15][16][17] and this relationship may depend on the population being studied. Obstructive sleep apnea (OSA), a frequent condition in obese patients, is linked with HTN and causes increased sympathetic tone. 18 Sleep apnea has been recognized as a risk factor for and a potential contributor to heart failure 19 and other cardiovascular diseases. 20 Ho...
Introduction In clinical trials, fixed-dose enoxaparin (40 mg once daily) reduces the risk of venous thromboembolism (VTE) in medically-ill patients. However, morbidly obese patients were under-represented in these trials and using fixed-dose enoxaparin in obese patients may be inadequate. We completed a pharmacokinetic study in morbidly obese, medically-ill patients to determine if weight-based dosing of enoxaparin for VTE prophylaxis was feasible, without excessive levels of anticoagulation, as determined by peak anti-Xa levels. Materials and Methods Twenty eight morbidly obese (BMI≥35 kg/m2) patients were enrolled and completed the study protocol. Enoxaparin 0.5 mg/kg was administered once daily subcutaneously and peak anti-Xa levels were measured approximately 4–6 hours after the enoxaparin dose. Results and Conclusions Overall, 46% of patients were female, the average age (±SD) was 54 (±11) years, and the average weight and BMI were 135.6 kg (±25.3) and 48.1 kg/m2 (±11.1), respectively. The average daily dose of enoxaparin was 67 mg (±12). The average peak anti-Xa level was 0.25 (SD±0.11, range 0.08 to 0.59) units/mL. Peak anti-Xa levels did not significantly correlate with weight or BMI. There were no bleeding events, symptomatic VTE, or significant thrombocytopenia. In morbidly obese, medically-ill patients, use of weight-based enoxaparin dosed at 0.5 mg/kg once daily is feasible and results in peak anti-Xa levels within or near recommended range for thromboprophylaxis, without any evidence of excessive anti-Xa activity. These data suggest that this weight-based regimen may be more effective than standard fixed-dose enoxaparin. Clinical outcome studies are warranted to determine the clinical safety and efficacy of this regimen.
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