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.
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.
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.
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.).
BACKGROUND Prospective studies on the incidence of VTE during severe sepsis and septic shock remain absent, hindering efficacy assessments regarding VTE prevention strategies in sepsis. METHODS We ...prospectively studied 113 consecutively enrolled patients in the ICU with severe sepsis and septic shock at three hospitals. All patients provided informed consent. VTE thromboprophylaxis was recorded for all patients. Patients underwent ultrasonography and were followed for VTE prior to ICU discharge. All-cause 28-day mortality was recorded. Variables from univariate analyses that were associated with VTE (including central venous catheter CVC insertion, age, length of stay, and mechanical ventilation) were included in a multivariable logistic regression analysis using backward stepwise elimination to determine VTE predictors. RESULTS Mean APACHE (Acute Physiology and Chronic Health Evaluation) II score was 18.2 ± 7.0, and age was 50 ± 18 years. Despite all patients receiving guideline-recommended thromboprophylaxis, the incidence of VTE was 37.2% (95% CI, 28.3-46.8). Most VTE events were clinically significant (defined as pulmonary embolism, proximal DVT, and/or symptomatic distal DVT) and associated with an increased length of stay (18.2 ± 9.9 days vs 13.4 ± 11.5 days, P < .05). Mortality was higher in patients with acute VTE but did not reach statistical significance. Insertion of a CVC and longer mechanical ventilation duration were significant VTE risk factors. VTE incidence did not differ by thromboprophylaxis type. CONCLUSIONS To our knowledge this is the first multicenter prospective study to identify a high incidence of VTE in patients with severe sepsis and septic shock, despite the use of universal, guideline-recommended thromboprophylaxis. Our findings suggest that the systemic inflammatory milieu of sepsis may uniquely predispose patients with sepsis to VTE. More effective VTE prevention strategies are necessary in patients with sepsis. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT02353910; URL: www.clinicaltrials.gov
Transformation of US health care from volume to value requires meaningful quantification of costs and outcomes at the level of individual patients.
To measure the association of a value-driven ...outcomes tool that allocates costs of care and quality measures to individual patient encounters with cost reduction and health outcome optimization.
Uncontrolled, pre-post, longitudinal, observational study measuring quality and outcomes relative to cost from 2012 to 2016 at University of Utah Health Care. Clinical improvement projects included total hip and knee joint replacement, hospitalist laboratory utilization, and management of sepsis.
Physicians were given access to a tool with information about outcomes, costs (not charges), and variation and partnered with process improvement experts.
Total and component inpatient and outpatient direct costs across departments; cost variability for Medicare severity diagnosis related groups measured as coefficient of variation (CV); and care costs and composite quality indexes.
From July 1, 2014, to June 30, 2015, there were 1.7 million total patient visits, including 34 000 inpatient discharges. Professional costs accounted for 24.3% of total costs for inpatient episodes ($114.4 million of $470.4 million) and 41.9% of total costs for outpatient visits ($231.7 million of $553.1 million). For Medicare severity diagnosis related groups with the highest total direct costs, cost variability was highest for postoperative infection (CV = 1.71) and sepsis (CV = 1.37) and among the lowest for organ transplantation (CV ≤ 0.43). For total joint replacement, a composite quality index was 54% at baseline (n = 233 encounters) and 80% 1 year into the implementation (n = 188 encounters) (absolute change, 26%; 95% CI, 18%-35%; P < .001). Compared with the baseline year, mean direct costs were 7% lower in the implementation year (95% CI, 3%-11%; P < .001) and 11% lower in the postimplementation year (95% CI, 7%-14%; P < .001). The hospitalist laboratory testing mean cost per day was $138 (median IQR, $113 $79-160; n = 2034 encounters) at baseline and $123 (median IQR, $99 $66-147; n = 4276 encounters) in the evaluation period (mean difference, -$15; 95% CI, -$19 to -$11; P < .001), with no significant change in mean length of stay. For a pilot sepsis intervention, the mean time to anti-infective administration following fulfillment of systemic inflammatory response syndrome criteria in patients with infection was 7.8 hours (median IQR, 3.4 0.8-7.8 hours; n = 29 encounters) at baseline and 3.6 hours (median IQR, 2.2 1.0-4.5 hours; n = 76 encounters) in the evaluation period (mean difference, -4.1 hours; 95% CI, -9.9 to -1.0 hours; P = .02).
Implementation of a multifaceted value-driven outcomes tool to identify high variability in costs and outcomes in a large single health care system was associated with reduced costs and improved quality for 3 selected clinical projects. There may be benefit for individual physicians to understand actual care costs (not charges) and outcomes achieved for individual patients with defined clinical conditions.
Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is ...unknown.
To determine whether genotype-guided dosing improves the safety of warfarin initiation.
The randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016.
Patients were genotyped for the following polymorphisms: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. In a 2 × 2 factorial design, patients were randomized to genotype-guided (n = 831) or clinically guided (n = 819) warfarin dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. The recommended doses of warfarin were open label, but the patients and clinicians were blinded to study group assignment.
The primary end point was the composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Patients underwent a screening lower-extremity duplex ultrasound approximately 1 month after arthroplasty.
Among 1650 randomized patients (mean age, 72.1 years SD, 5.4 years; 63.6% women; 91.0% white), 1597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% 95% CI, 0.7%-7.2%, P = .02; relative rate RR, 0.73 95% CI, 0.56-0.95). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0.05-1.15), 56 vs 77 for INR of 4 or greater (RR, 0.71; 95% CI, 0.51-0.99), 33 vs 38 for venous thromboembolism (RR, 0.85; 95% CI, 0.54-1.34), and there were no deaths.
Among patients undergoing elective hip or knee arthroplasty and treated with perioperative warfarin, genotype-guided warfarin dosing, compared with clinically guided dosing, reduced the combined risk of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Further research is needed to determine the cost-effectiveness of personalized warfarin dosing.
clinicaltrials.gov Identifier: NCT01006733.
Extreme obesity is associated with health and cardiovascular disease risks. Although gastric bypass surgery induces rapid weight loss and ameliorates many of these risks in the short term, long-term ...outcomes are uncertain.
To examine the association of Roux-en-Y gastric bypass (RYGB) surgery with weight loss, diabetes mellitus, and other health risks 6 years after surgery.
A prospective Utah-based study conducted between July 2000 and June 2011 of 1156 severely obese (body mass index BMI ≥ 35) participants aged 18 to 72 years (82% women; mean BMI, 45.9; 95% CI, 31.2-60.6) who sought and received RYGB surgery (n = 418), sought but did not have surgery (n = 417; control group 1), or who were randomly selected from a population-based sample not seeking weight loss surgery (n = 321; control group 2).
Weight loss, diabetes, hypertension, dyslipidemia, and health-related quality of life were compared between participants having RYGB surgery and control participants using propensity score adjustment.
Six years after surgery, patients who received RYGB surgery (with 92.6% follow-up) lost 27.7% (95% CI, 26.6%-28.9%) of their initial body weight compared with 0.2% (95% CI, -1.1% to 1.4%) gain in control group 1 and 0% (95% CI, -1.2% to 1.2%) in control group 2. Weight loss maintenance was superior in patients who received RYGB surgery, with 94% (95% CI, 92%-96%) and 76% (95% CI, 72%-81%) of patients receiving RYGB surgery maintaining at least 20% weight loss 2 and 6 years after surgery, respectively. Diabetes remission rates 6 years after surgery were 62% (95% CI, 49%-75%) in the RYGB surgery group, 8% (95% CI, 0%-16%) in control group 1, and 6% (95% CI, 0%-13%) in control group 2, with remission odds ratios (ORs) of 16.5 (95% CI, 4.7-57.6; P < .001) vs control group 1 and 21.5 (95% CI, 5.4-85.6; P < .001) vs control group 2. The incidence of diabetes throughout the course of the study was reduced after RYGB surgery (2%; 95% CI, 0%-4%; vs 17%; 95% CI, 10%-24%; OR, 0.11; 95% CI, 0.04-0.34 compared with control group 1 and 15%; 95% CI, 9%-21%; OR, 0.21; 95% CI, 0.06-0.67 compared with control group 2; both P < .001). The numbers of participants with bariatric surgery-related hospitalizations were 33 (7.9%), 13 (3.9%), and 6 (2.0%) for the RYGB surgery group and 2 control groups, respectively.
Among severely obese patients, compared with nonsurgical control patients, the use of RYGB surgery was associated with higher rates of diabetes remission and lower risk of cardiovascular and other health outcomes over 6 years.
Medicine is the only business transaction in which consumers make important purchase decisions without knowing how much they have to pay. Lack of price transparency in health care imposes financial ...burden and anxiety among patients as the cost of health care has been shifting from employers to patients through high-deductible health plans (HDHPs). Health economists and policymakers anticipated that HDHPs with price transparency would be a catalyst for patients to “shop” for low-price providers, thus reducing overall health care spending. For patients to shop health care services, price transparency is a requisite. The Department of Health and Human Services mandate of publicly disclosing the hospital chargemaster and state legislatures demanding greater health care price transparency are just two examples of external forces challenging the long history of price opacity in health care. Imaging, pharmacy, laboratory tests, and ambulatory surgeries are considered potentially shoppable health care services. This article examines the intended motivation of price transparency, the limitations of current price transparency tools, and what impact price transparency may have on radiology. We share our experience in developing and implementing University of Utah’s online interactive price transparency tool to estimate patients’ out-of-pocket expenses.
In a large U.S. sample, this study measured the presentation features, testing, treatment strategies, and outcomes of patients diagnosed with pulmonary embolism (PE) in the emergency department (ED).
...No data have quantified the demographics, clinical features, management, and outcomes of outpatients diagnosed with PE in the ED in a large, multicenter U.S. study.
Patients of any hemodynamic status were enrolled from the ED after confirmed acute PE or with a high clinical suspicion prompting anticoagulation before imaging for PE. Exclusions were inability to provide informed consent (where required) or unavailability for follow-up.
A total of 1,880 patients with confirmed acute PE were enrolled from 22 U.S. EDs. Diagnosis of PE was based upon positive results of computerized tomographic pulmonary angiogram in most cases (n = 1,654 88%). Patients represented both sexes equally, and racial and ethnic composition paralleled the overall U.S. ED population. Most (79%) patients with PE were employed, and one-third were older than age 65 years. The mortality rate directly attributed to PE was 20 in 1,880 (1%; 95% confidence interval CI: 0% to 1.6%). Mortality from hemorrhage was 0.2%, and the all-cause 30-day mortality rate was 5.4% (95% CI: 4.4% to 6.6%). Only 3 of 20 patients with major PE that ultimately proved fatal had systemic anticoagulation initiated before diagnostic confirmation, and another 3 of these 20 received a fibrinolytic agent.
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.
Enoxaparin is commonly used to prevent venous thromboembolism(VTE) 1,2 but has not been well-studied in patients with extreme obesity,a population at high risk for VTE. We prospectively compared ...three enoxaparin dosing regimens for the achievement of goal peak anti-Factor Xa levels in medically ill patients (n 5 31) with extreme obesity (body mass index (BMI) ‡ 40 kg/m2). Patients were assigned to receive fixed-dose (FD) enoxaparin 40 mg daily (QDay, n 5 11), weight based,lower-dose (LD) enoxaparin 0.4 mg/kg QDay (n 5 9), or weight based,higher-dose (HD) enoxaparin 0.5 mg/kg QDay (n 5 11). The average BMI and weight of the entire cohort was 62.1 kg/m2 (range40.5–82.4) and 176 kg (range 115–256 kg) and did not differ between groups. Peak anti-Factor Xa levels were significantly higher in the HD group compared to either LD or FD groups. Patients in the HD group achieved target anti-Factor Xa levels more frequently than the LD and FD groups (P < 0.05). Peak anti-Factor Xa levels did not correlate with age, weight, BMI, or creatinine clearance, demonstrating the predictability of weight-based enoxaparin dosing. There were no adverse events (e.g., bleeding, thrombosis, thrombocytopenia). To our knowledge this is the first prospective comparative study demonstrating that in extremely obese, medically ill patients enoxaparin 0.5 mg/kg QDay is superior to FD and LD enoxaparin for the achievement of target anti-Factor Xa levels.
By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the ...contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6-11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6-11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that "effective" dose constituted a treatment response index . Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R(2) was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R(2)= 69.1% (p<0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.
The objective of this study was to test the hypothesis that gastric bypass surgery (GBS) would favorably impact cardiac remodeling and function.
GBS is increasingly used to treat severe obesity, but ...there are limited outcome data.
We prospectively studied 423 severely obese patients undergoing GBS and a reference group of severely obese subjects that did not have surgery (n = 733).
At a 2-year follow up, GBS subjects had a large reduction in body mass index compared with the reference group (-15.4 ± 7.2 kg/m(2) vs. -0.03 ± 4.0 kg/m(2); p < 0.0001), as well as significant reductions in waist circumference, systolic blood pressure, heart rate, triglycerides, low-density lipoprotein cholesterol, and insulin resistance. High-density lipoprotein cholesterol increased. The GBS group had reductions in left ventricular (LV) mass index and right ventricular (RV) cavity area. Left atrial volume did not change in GBS but increased in reference subjects. In conjunction with reduced chamber sizes, GBS subjects also had increased LV midwall fractional shortening and RV fractional area change. In multivariable analysis, age, change in body mass index, severity of nocturnal hypoxemia, E/E', and sex were independently associated with LV mass index, whereas surgical status, change in waist circumference, and change in insulin resistance were not.
Marked weight loss in patients undergoing GBS was associated with reverse cardiac remodeling and improved LV and RV function. These data support the use of bariatric surgery to prevent cardiovascular complications in severe obesity.
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