In intermediate- or high-risk PE, catheter-directed thrombolysis is linked to reduced mortality vs. systemic thrombolysis or anticoagulation.

SOURCE CITATION: Planer D, Yanko S, Matok I, et al. Catheter-directed thrombolysis compared with systemic thrombolysis and anticoagulation in patients with intermediate- or high-risk pulmonary embolism: systematic review and network meta-analysis. CMAJ. 2023;195:E833-E843. 37336568.

NSAIDs and hormonal contraceptives are linked to VTE in women with no previous thrombotic disease.

SOURCE CITATION: Meaidi A, Mascolo A, Sessa M, et al. Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study. BMJ. 2023;382:e074450. 37673431.

Individually experienced heat index in a coastal Southeastern US city among an occupationally exposed population.

Recent studies have characterized individually experienced temperatures or individually experienced heat indices, including new exposure metrics that capture dimensions of exposure intensity, frequency, and duration. Yet, few studies have examined the personal thermal exposure in underrepresented groups, like outdoor workers, and even fewer have assessed corresponding changes in physiologic heat strain. The objective of this paper is to examine a cohort of occupationally exposed grounds and public safety workers (n = 25) to characterize their heat exposure and resulting heat strain. In addition, a secondary aim of this work is to compare individually heat index exposure (IHIE) across exposure metrics, fixed-site in situ weather stations, and raster-derived urban heat island (UHI) measurements in Charleston, SC, a humid coastal climate in the Southeastern USA. A Bland-Altman (BA) analysis was used to assess the level of agreement between the personal IHIE measurements and weather-station heat index (HI) and Urban Heat Island (UHI) measurements. Linear mixed-effect models were used to determine the association between individual risk factors and in situ weather station measurements significantly associated with IHIE measurements. Multivariable stepwise Cox proportional hazard modeling was used to identify the individual and workplace factors associated with time to heat strain in workers. We also examined the non-linear association between heat strain and exposure metrics using generalized additive models. We found significant heterogeneity in IHIE measurements across participants. We observed that time to heat strain was positively associated with a higher IHIE, older age, being male, and among Caucasian workers. Important nonlinear associations between heat strain occurrence and the intensity, frequency, and duration of personal heat metrics were observed. Lastly, our analysis found that IHIE measures were significantly similar for weather station HI, although differences were more pronounced for temperature and relative humidity measurements. Conversely, our IHIE findings were much lower than raster-derived UHI measurements. Real-time monitoring can offer important insights about unfolding temperature-health trends and emerging behaviors during thermal extreme events, which have significant potential to provide situational awareness.

Cost-effectiveness of managing low-risk pulmonary embolism patients without hospitalization. The low-risk pulmonary embolism prospective management study.

OBJECTIVE: Evaluate the cost-effectiveness and difference in length-of-stay when patients in the ED diagnosed with low-risk pulmonary embolism (PE) are managed with early discharge or observation. METHODS: Single cohort prospective management study from January 2013 to October 2016 of patients with PE diagnosed in the ED and evaluated for a primary composite endpoint of mortality, recurrent venous thromboembolism, and/or major bleeding event at 90 days. Low-risk patients had a PE Severity Index score < 86, no evidence of proximal deep vein thrombosis on venous compression ultrasonography of both lower extremities, and no evidence of right heart strain on echocardiography. Patients were managed either in the ED or in the hospital on observation status. Primary outcomes were total length of stay, total encounter costs, and 30-day costs. RESULTS: 213 patients were enrolled. 13 were excluded per the study protocol. Of the remaining 200, 122 were managed with emergency department observation (EDO) and 78 with hospital observation (HO). One patient managed with EDO met the composite outcome due to a major bleeding event on day 61. The mean length of stay for EDO was 793.4 min (SD -169.7, 95% CI:762-823) and for HO was 1170 (SD -211.4, 95% CI:1122-1218) with a difference of 376.8 (95% CI: 430-323, p < 0.0001). Total encounter mean costs for EDO were $1982.95 and $2759.59 for HO, with a difference of $776.64 (95% CI: 972-480, p > 0.0001). 30-day total mean costs for EDO were $2864.14 and $3441.52 for HO, with a difference of $577.38 (95% CI: -1372-217, p = 0.15). CONCLUSIONS: Patients with low-risk PE managed with ED-based observation have a shorter length of stay and lower total encounter costs than patients managed with Hospital-based observation.

Antiphospholipid antibodies and recurrent thrombosis after a first unprovoked venous thromboembolism.

It is uncertain whether antiphospholipid antibodies (APAs) increase the risk of recurrence after a first unprovoked venous thromboembolism (VTE). We tested for anticardiolipin antibodies, anti-ß2 glycoprotein 1 antibodies, and lupus anticoagulant on 2 occasions ∼6 months apart in 307 patients with a first unprovoked VTE who were part of a prospective cohort study. We then determined if APAs were associated with recurrent thrombosis in the 290 patients who stopped anticoagulant therapy in response to negative D-dimer results. Compared with those without an APA, the hazard ratios for recurrent VTE were 1.8 (95% confidence interval [CI], 0.9-3.7; P = .09) in the 25.9% of patients with an APA on ≥1 occasions, 2.7 (95% CI, 1.1-.7; P = .03) in the 9.0% of patients with the same APA on 2 occasions, and 4.5 (95% CI, 1.5-13.0; P = .006) in the 3.8% of patients with 2 or 3 different APA types on either the same or different occasions. There was no association between having an APA and D-dimer levels. We conclude that having the same type of APA on 2 occasions or having >1 type of APA on the same or different occasions is associated with recurrent thrombosis in patients with a first unprovoked VTE who stop anticoagulant therapy in response to negative D-dimer tests. APA and D-dimer levels seem to be independent predictors of recurrence in patients with an unprovoked VTE. This trial was registered at www.clinicaltrials.gov as #NCT00720915.

Wearable sensors for personal temperature exposure assessments: A comparative study.

The impacts of heat on human health has sparked research on different approaches to measure, map, and predict heat exposure at more accurate and precise spatiotemporal scales. Personal heat sensor studies rely on small sensors that can continuously measure ambient temperatures as individuals move through time and space. The comparison between different types of sensors and sensor placements have yet to be fully researched. The objective of this study is to assess the validity of personal ambient temperature sensors. To accomplish this objective, we evaluated the performance of multiple low-cost wearable sensors (HOBOs, iButton Thermochrons, iButton Hygrochrons, and Kestrel DROP D3FW Fire) for measuring ambient temperature in a (1) field exposure study by varying the placement on human subjects and in a (2) field calibration study by co-locating sensors with fixed site weather station monitors. A secondary aim involved investigating consensus between validation metrics that can be used in future sensor comparison studies. Bland-Altman analysis, correlation coefficients, and index of agreement statistics were used to quantify the difference between sensor and weather station ambient temperature measurements. Results demonstrated significant differences in measured temperatures for sensors based on sensor type and placement on participants. Future research should account for the differences in personal ambient temperature readings based on sensor type and placement.

Intractable Generalized Epilepsy: Therapeutic Approaches.

PURPOSE OF REVIEW: To summarize recent developments in therapeutic options, both medical and surgical, for patients with drug-resistant generalized epilepsy syndromes, which continue to be a multifaceted challenge for patients and physicians. RECENT FINDINGS: Newer generation pharmaceutical options are now available, such as brivaracetam, rufinamide, lacosamide, perampanel, and cannabidiol. Less restrictive dietary options appear to be nearly as effective as classic ketogenic diet for amelioration of seizures. The latest implantable devices include responsive neurostimulation and deep brain stimulation. Corpus callosotomy is an effective treatment for some seizure types, and newer and less invasive approaches are being explored. Resective surgical options have demonstrated success in carefully selected patients despite generalized electrographic findings on electroencephalogram. The current literature reflects a widening range of clinical experience with newer anticonvulsant medications including cannabinoids, dietary therapies, surgical approaches, and neurostimulation devices for patients with intractable generalized epilepsy.

Estimating personal ambient temperature in moderately cold environments for occupationally exposed populations.

Despite high mortality and morbidity rates in the winter season, few studies have investigated the health effects from working in moderately cold environments, especially among vulnerable outdoor worker populations in the southeastern US. Yet recent research has shown that the mortality risk from cold events is greatest in southern cities compared to other US locations. We performed repeated personal cold exposure measurements in outdoor grounds management workers in the southeastern US using consumer-based sensors. We recruited outdoor workers from two locations (Raleigh, NC and Boone, NC) each characterized by climatological differences in cold temperature to participate in a 3-week data collection period at the peak of the winter (Jan/Feb 2018). Lower personal ambient temperatures were observed among participants who worked in a warmer climate (Raleigh, NC). The relative risk for cold symptomatology was higher in moderately cold personal ambient temperatures (0 °C to 20 °C) than extremely cold personal ambient temperatures (less than 0 °C). A weak significant relationship was observed between personal ambient temperatures and weather station measurements highlighting that epidemiological researchers should be cautious when investigating the health effects of ambient temperatures based on fixed site measurements. As mobile technology progresses, real-time temperature health monitoring and analysis of environmental conditions at the individual level across multiple occupational-settings will become more feasible and ultimately, we believe, a digitally enhanced workforce will become standard practice in the field.

The Efficacy of Systemic Doxycycline Administration as an Inhibitor of Intimal Hyperplasia after Balloon Angioplasty Arterial Injury.

BACKGROUND: Intimal hyperplasia (IH) is the most common indicator for secondary intervention in peripheral vascular disease. Matrix metalloproteinases (MMPs) play a role in IH development due to their degradation of the extracellular matrix. Doxycycline (Doxy), a member of the tetracycline family of antibiotics, is a potent MMP inhibitor. We have previously shown that Doxy inhibits MMP activity and vascular smooth muscle cell migration in vitro. We hypothesized that Doxy would decrease MMP activity in vivo and inhibit the development of IH in a rodent model of vascular injury. METHODS AND RESULTS: Doxy (400 mg/pellet) was delivered by a slow-release pellet implanted 3 days prior to or at the time of balloon angioplasty (BA) of the common carotid artery in female rats. At 14 days post-BA, intima-to-media (I:M) ratios were 0.77 ± 0.21 and 1.04 ± 0.32 in the Doxy treated groups, respectively, compared to 1.25 ± 0.26 in the control group (P = not significant; n = 3). Additionally, the tested dose of Doxy in either group had no inhibitory effect on membrane type 1-MMP or MMP-2 tissue levels, as measured by immunohistochemistry, or on systemic levels of MMP, as measured by total MMP serum levels using enzyme-linked immunosorbent assay. At 14 days post-BA, VSMC proliferation in the injured artery was increased to Doxy treatment prior to and at the time of surgery (23.5 ± 3.4 and 27.2 ± 3.9%, respectively), compared to control (11.4 ± 0.4%; n = 3), as measured by proliferating cellular nuclear antigen immunostaining. CONCLUSIONS: In our in vivo model of vascular injury, systemic Doxy administration prior to or at the time of vascular injury does not significantly hinder the progression of IH development. Additional doses and routes of administration could be examined in order to correlate therapeutic serum levels of Doxy with effective MMP inhibition in serum and arterial tissue. However, alternative drug delivery systems are needed in order to optimize therapeutic administration of targeted MMP inhibitors for the prevention of IH development.

Painful Seizures: a Review of Epileptic Ictal Pain.

PURPOSE OF REVIEW: To summarize the literature regarding the prevalence, pathophysiology, and anatomic networks involved with painful seizures, which are a rare but striking clinical presentation of epilepsy. RECENT FINDINGS: Several recent large case series have explored the prevalence of the main cephalgic, somatosensory, and abdominal variants of this rare disorder. Research studies including the use of electrical stimulation and functional neuroimaging have demonstrated the networks underlying painful somatosensory or visceral seizures. Improved understanding of some of the overlapping mechanisms between migraines and seizures has elucidated their common pathophysiology. The current literature reflects a widening range of awareness and understanding of painful seizures, despite their rarity.

Effects of seasonality and daylight savings time on emergency department visits for mental health disorders.

OBJECTIVES: Emergency Department (ED) utilization accounts for a large portion of healthcare services in the US. Disturbance of circadian rhythms may affect mental and behavioral health (MBH) conditions, which could result in increased ED visits and subsequent hospitalizations, thus potentially inducing staffing shortages and increasing ED wait time. Predicting the burden of ED admissions helps to better plan care at the EDs and provides significant benefits. This study investigates if increased ED visits for MBH conditions are associated with seasonality and changes in daylight savings time. METHODS: Using ED encounter data from a large academic medical center, we have examined univariate and multivariate associations between ED visits for MBH conditions and the annual time periods during which MBH conditions are more elevated due to changes in the seasons. We hypothesize that ED visits for MBH conditions increase within the 2-week period following the daylight savings time changes. RESULTS: Increased MBH ED visits were observed in certain seasons. This was especially true for non-bipolar depressive illness. We saw no significant changes in MBH visits as associated with changes in the daylight savings time. CONCLUSIONS: Data do not provide conclusive evidence of a uniform seasonal increase in ED visits for MBH conditions. Variation in ED MBH visits may be due to secular trends, such as socioeconomic factors. Future research should explore contemporaneous associations between time-driven events and MBH ED visits. It will allow for greater understanding of challenges regarding psychiatric patients and opportunities for improvement.

Spliceosomal intronogenesis.

The presence of intervening sequences, termed introns, is a defining characteristic of eukaryotic nuclear genomes. Once transcribed into pre-mRNA, these introns must be removed within the spliceosome before export of the processed mRNA to the cytoplasm, where it is translated into protein. Although intron loss has been demonstrated experimentally, several mysteries remain regarding the origin and propagation of introns. Indeed, documented evidence of gain of an intron has only been suggested by phylogenetic analyses. We report the use of a strategy that detects selected intron gain and loss events. We have experimentally verified, to our knowledge, the first demonstrations of intron transposition in any organism. From our screen, we detected two separate intron gain events characterized by the perfect transposition of a reporter intron into the yeast genes RPL8B and ADH2, respectively. We show that the newly acquired introns are able to be removed from their respective pre-mRNAs by the spliceosome. Additionally, the novel allele, RPL8Bint, is functional when overexpressed within the genome in a strain lacking the Rpl8 paralogue RPL8A, demonstrating that the gene targeted for intronogenesis is functional.

Metal dependence and branched RNA cocrystal structures of the RNA lariat debranching enzyme Dbr1.

Intron lariats are circular, branched RNAs (bRNAs) produced during pre-mRNA splicing. Their unusual chemical and topological properties arise from branch-point nucleotides harboring vicinal 2',5'- and 3',5'-phosphodiester linkages. The 2',5'-bonds must be hydrolyzed by the RNA debranching enzyme Dbr1 before spliced introns can be degraded or processed into small nucleolar RNA and microRNA derived from intronic RNA. Here, we measure the activity of Dbr1 from Entamoeba histolytica by using a synthetic, dark-quenched bRNA substrate that fluoresces upon hydrolysis. Purified enzyme contains nearly stoichiometric equivalents of Fe and Zn per polypeptide and demonstrates turnover rates of ∼3 s-1 Similar rates are observed when apo-Dbr1 is reconstituted with Fe(II)+Zn(II) under aerobic conditions. Under anaerobic conditions, a rate of ∼4.0 s-1 is observed when apoenzyme is reconstituted with Fe(II). In contrast, apo-Dbr1 reconstituted with Mn(II) or Fe(II) under aerobic conditions is inactive. Diffraction data from crystals of purified enzyme using X-rays tuned to the Fe absorption edge show Fe partitions primarily to the ß-pocket and Zn to the α-pocket. Structures of the catalytic mutant H91A in complex with 7-mer and 16-mer synthetic bRNAs reveal bona fide RNA branchpoints in the Dbr1 active site. A bridging hydroxide is in optimal position for nucleophilic attack of the scissile phosphate. The results clarify uncertainties regarding structure/function relationships in Dbr1 enzymes, and the fluorogenic probe permits high-throughput screening for inhibitors that may hold promise as treatments for retroviral infections and neurodegenerative disease.

Effect of Low-Intensity vs Standard-Intensity Warfarin Prophylaxis on Venous Thromboembolism or Death Among Patients Undergoing Hip or Knee Arthroplasty: A Randomized Clinical Trial.

Importance: The optimal international normalized ratio (INR) to prevent venous thromboembolism (VTE) in warfarin-treated patients with recent arthroplasty is unknown. Objective: To determine the safety and efficacy of a target INR of 1.8 vs 2.5 for VTE prophylaxis after orthopedic surgery. Design, Setting, and Participants: The randomized Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis enrolled 1650 patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016. Interventions: In a 2 × 2 factorial design, participants were randomized to a target INR of 1.8 (n = 823) or 2.5 (n = 827) and to either genotype-guided or clinically guided warfarin dosing. For the first 11 days of therapy, open-label warfarin dosing was guided by a web application. Main Outcomes and Measures: The primary outcome was the composite of VTE (within 60 days) or death (within 30 days). Participants underwent screening duplex ultrasound postoperatively. The hypothesis was that an INR target of 1.8 would be noninferior to an INR target of 2.5, using a noninferiority margin of 3% for the absolute risk of VTE. Secondary end points were bleeding and INR values of 4 or more. Results: Among 1650 patients who were randomized (mean age, 72.1 years; 1049 women [63.6%]; 1502 white [91.0%]), 1597 (96.8%) received at least 1 dose of warfarin and were included in the primary analysis. The rate of the primary composite outcome of VTE or death was 5.1% (41 of 804) in the low-intensity-warfarin group (INR target, 1.8) vs 3.8% (30 of 793) in the standard-treatment-warfarin group (INR target, 2.5), for a difference of 1.3% (1-sided 95% CI, -∞ to 3.05%, P = .06 for noninferiority). Major bleeding occurred in 0.4% of patients in the low-intensity group and 0.9% of patients in the standard-intensity group, for a difference of -0.5% (95% CI, -1.6% to 0.4%). The INR values of 4 or more occurred in 4.5% of patients in the low-intensity group and 12.2% of the standard-intensity group, for a difference of -7.8% (95% CI, -10.5% to -5.1%). Conclusions and Relevance: Among older patients undergoing hip or knee arthroplasty and receiving warfarin prophylaxis, an international normalized ratio goal of 1.8 compared with 2.5 did not meet the criterion for noninferiority for risk of the composite outcome of VTE or death. However, the trial may have been underpowered to meet this criterion and further research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01006733.

Atrial fibrillation incrementally increases dementia risk across all CHADS2 and CHA2DS2VASc strata in patients receiving long-term warfarin.

BACKGROUND: Patients with atrial fibrillation (AF) are at higher risk for developing dementia. Warfarin is a common therapy for the prevention of thromboembolism in AF, valve replacement, and thrombosis patients. The extent to which AF itself increases dementia risk remains unknown. METHODS: A total 6030 patients with no history of dementia and chronically anticoagulated with warfarin were studied. Warfarin management was provided through a Clinical Pharmacy Anticoagulation Service. Patients were stratified by warfarin indication of AF (n=3015) and non-AF (n=3015) and matched by propensity score (±0.01). Patients were stratified by the congestive heart failure, hypertension, age >75 years, diabetes, stroke (CHADS2) score calculated at the time of warfarin initiation and followed for incident dementia. RESULTS: The average age of the AF cohort was 69.3±11.2 years, and 52.7% were male; average age of non-AF cohort was 69.3±10.9 years, and 51.5% were male. Increasing CHADS2 score was associated with increased dementia incidence, P trend=.004. When stratified by warfarin indication, AF patients had an increased risk of dementia incidence. After multivariable adjustment, AF patients continued to display a significantly increased risk of dementia when compared with non-AF patients across all CHADS2 scores strata. CONCLUSIONS: In patients receiving long-term warfarin therapy, dementia risk increased with increasing CHADS2 scores. However, the presence of AF was associated with higher rates of dementia across all CHADS2 score strata. These data suggest that AF contributes to the risk of dementia and that this risk is not solely attributable to anticoagulant use. Dementia may be an end manifestation of a systemic disease state, and AF likely contributes to its progression.

Thrombophilic Evaluation in Patients with Acute Pulmonary Embolism.

Patients with acute pulmonary embolism (PE) are often tested for thrombophilias, which are hereditary and acquired conditions that predispose to thrombosis. If a hereditary condition is identified, then testing is often performed on members of the patient's family. Testing for these conditions can be complex, as the presence of acute thrombosis and antithrombotic therapies can make the results of many tests unreliable. Many risk factors for thrombosis exist that are not routinely assessed by laboratory testing, and it is likely that many hereditary thrombophilia conditions remain to be discovered. Also, various risk factors for thrombosis interact with one another. Therefore, the results of a laboratory thrombophilia evaluation provide a limited ability to assess a patient or family members' risk for future thrombosis, and such testing usually does not provide information that improves a management decision. Thrombophilia testing is expensive and carries potential risks. This article reviews common thrombophilias, their epidemiology and classification, and timing and technical aspects of accurate testing and provides rational suggestions for the use of thrombophilia testing in five clinical situations: (1) following provoked PE (or other venous thromboembolism), (2) following unprovoked venous thromboembolism, (3) in relatives of patients with thrombosis, (4) in female relatives of patients with thrombosis considering estrogen use, and (5) in female relatives of patients with thrombosis who are considering pregnancy. Published guidelines and guidance statements from professional societies and other groups are also reviewed. Clinicians should carefully consider the relevant risks and benefits before testing patients for thrombophilia. When performed, testing should be timed correctly and care should be taken to properly interpret results. New models that incorporate multiple genetic and clinical markers may improve the utility of testing, but these await further research.

Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial.

Importance: 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. Objective: To determine whether genotype-guided dosing improves the safety of warfarin initiation. Design, Setting, and Patients: 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. Interventions: 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. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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. Trial Registration: clinicaltrials.gov Identifier: NCT01006733.

A pharmacogenetic versus a clinical algorithm for warfarin dosing.

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.).