Anne R. Bass

Integration of genetic, clinical, and INR data to refine warfarin dosing

Well‐characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one‐third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R2 of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R2 of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R2 was 26–43% with the clinical algorithm and 42–58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.

Anakinra's Efficacy is Variable in Refractory Gout: Report of Ten Cases

OBJECTIVES To evaluate the efficacy of anakinra for patients with acute gout. METHODS We reviewed the charts of 10 patients who received anakinra for urate crystal-induced arthritis at the Hospital for Special Surgery since 2007. Demographic information, comorbidities, short-term treatment outcomes, and subsequent flares were reviewed. RESULTS Patients in our study had a high prevalence of comorbidities. All patients received corticosteroids before anakinra treatment. The mean number of anakinra injections was 3.2 per patient (100 mg subcutaneously per day). Six patients had a good response. Three patients had a partial response and 1 patient had no response. Nine patients had documented recurrent flares after discontinuing anakinra (ranging from 3 to 45 days after). CONCLUSION Anakinra is a therapeutic option for patients with acute urate crystal-induced arthritis who do not respond to or have a contraindication to traditional treatments. Although a short course of anakinra resulted in favorable outcomes for some of our patients, response rates were poorer in our study than in previously published reports, and relapses were common.

Genetics informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT): rationale and study design.

The risk of venous thromboembolism (VTE) is higher after the total hip or knee replacement surgery than after almost any other surgical procedure; warfarin sodium is commonly prescribed to reduce this peri-operative risk. Warfarin has a narrow therapeutic window with high inter-individual dose variability and can cause hemorrhage. The genetics-informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT) is a 2 × 2 factorial-design, randomized controlled trial designed to compare the safety and effectiveness of warfarin-dosing strategies. GIFT will answer two questions: (1) does pharmacogenetic (PGx) dosing reduce the rate of adverse events in orthopedic patients; and (2) is a lower target international normalized ratio (INR) non-inferior to a higher target INR in orthopedic participants? The composite primary endpoint of the trial is symptomatic and asymptomatic VTE (identified on screening ultrasonography), major hemorrhage, INR⩾4, and death.

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

Overlap between systemic lupus erythematosus and Kikuchi Fujimoto disease: a clinical pathology conference held by the Department of Rheumatology at Hospital for Special Surgery.

Each author certifies that he or she has no commercial associations (e.g., consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. Each author certifies that his or her institution has approved the reporting of this case, that all investigations were conducted in conformity with ethical principles of research.

Disparities in TKA Outcomes: Census Tract Data Show Interactions Between Race and Poverty

BackgroundRace is an important predictor of TKA outcomes in the United States; however, analyses of race can be confounded by socioeconomic factors, which can result in difficulty determining the root cause of disparate outcomes after TKA.Questions/purposesWe asked: (1) Are race and socioeconomic factors at the individual level associated with patient-reported pain and function 2 years after TKA? (2) What is the interaction between race and community poverty and patient-reported pain and function 2 years after TKA?MethodsWe identified all patients undergoing TKA enrolled in a hospital-based registry between 2007 and 2011 who provided 2-year outcomes and lived in New York, Connecticut, or New Jersey. Of patients approached to participate in the registry, more than 82% consented and provided baseline data, and of these patients, 72% provided 2-year data. Proportions of patients with complete followup at 2 years were lower among blacks (57%) than whites (74%), among patients with Medicaid insurance (51%) compared with patients without Medicaid insurance (72%), and among patients without a college education (67%) compared with those with a college education (71%). Our final study cohort consisted of 4035 patients, 3841 (95%) of whom were white and 194 (5%) of whom were black. Using geocoding, we linked individual-level registry data to US census tracts data through patient addresses. We constructed a multivariate linear mixed-effect model in multilevel frameworks to assess the interaction between race and census tract poverty on WOMAC pain and function scores 2 years after TKA. We defined a clinically important effect as 10 points on the WOMAC (which is scaled from 1 to 100 points, with higher scores being better).ResultsRace, education, patient expectations, and baseline WOMAC scores are all associated with 2-year WOMAC pain and function; however, the effect sizes were small, and below the threshold of clinical importance. Whites and blacks from census tracts with less than 10% poverty have similar levels of pain and function 2 years after TKA (WOMAC pain, 1.01 ± 1.59 points lower for blacks than for whites, p = 0.53; WOMAC function, 2.32 ± 1.56 lower for blacks than for whites, p = 0.14). WOMAC pain and function scores 2 years after TKA worsen with increasing levels of community poverty, but do so to a greater extent among blacks than whites. Disparities in pain and function between blacks and whites are evident only in the poorest communities; decreasing in a linear fashion as poverty increases. In census tracts with greater than 40% poverty, blacks score 6 ± 3 points lower (worse) than whites for WOMAC pain (p = 0.03) and 7 ± 3 points lower than whites for WOMAC function (p = 0.01).ConclusionsBlacks and whites living in communities with little poverty have similar patient-reported TKA outcomes, whereas in communities with high levels of poverty, there are important racial disparities. Efforts to improve TKA outcomes among blacks will need to address individual- and community-level socioeconomic factors.Level of EvidenceLevel III, therapeutic study.

Disparities in Outcomes for African Americans and Whites Undergoing Total Knee Arthroplasty: A Systematic Literature Review

Objective. African Americans in the United States undergo total knee arthroplasty (TKA) less often than whites, in part because of lower expectations among African Americans for successful surgery. Whether this lower expectation is justified is unknown. Our objective is to compare health-related quality of life (HRQOL) and satisfaction after TKA between African Americans and whites. Methods. A systematic review of English language articles using Medline, the Cochrane register, Embase (April 21, 2015), and a hand search of unlisted disparities journals was performed. Search terms included total knee replacement, quality of life, outcomes, and satisfaction. High-quality cohort studies that examined HRQOL in African Americans and white adults 6 months or more after TKA were included. Results. Of the 4781 studies screened by title, and 346 by abstract, 7 studies included race in their analysis. Results included 5570 TKA patients, 4077 whites (89%), and 482 (11%) blacks. Because studies used different outcome measures and were inconsistent in their adjustment for confounders, we could not perform a quantitative synthesis of results. In 5 studies, US blacks had worse pain, in 5 worse function, and in 1 less satisfaction 6 months to 2 years after TKA. Conclusion. US blacks may derive less benefit from TKA than whites as measured by HRQOL, pain, function, and satisfaction. Many studies assessing predictors of patient-related TKA outcomes fail to analyze race as a variable, which limited our study. More studies assessing the effect of race and socioeconomic factors on TKA outcome are needed.

Catastrophic Antiphospholipid Syndrome Triggered by Sepsis

A Clinical Pathology Conference held by the Department of Rheumatology at Hospital for Special Surgery

The Use of Spiral Computed Tomography Scans for the Detection of Pulmonary Embolism

Total joint arthroplasty carries a risk of symptomatic pulmonary embolism (PE). This study examined symptoms and risk factors of patients who underwent postoperative spiral computed tomography (CT) scans. The presenting symptoms and risk factors of total hip arthroplasty and total knee arthroplasty patients who had a postoperative CT scan were reviewed and the location of PE/deep vein thrombosis (DVT) was noted for positive scans. Of the 10209 patients who had total hip or total knee arthroplasty, 478 (4.7%) underwent a spiral CT scan to rule out PE and 136 (1.3%) had scans positive for PE. Twenty-two and four tenths percent of scans were positive for PE only, 2.1% for proximal DVT only, and 6.1% for PE and proximal DVT. Patients taking estrogen and patients presenting with low oxygen saturation postoperatively were significantly (P = .010, P < .001) more likely to have a positive scan. Spiral CT is the gold standard for detection of PE. Thirty-one and one half percent of scans were positive for PE and/or DVT, yet only 19.2% of patients had a predisposing risk factor for PE. Total knee arthroplasty carried a greater risk for PE than THA.

Detection of Pulmonary Embolism in the Postoperative Orthopedic Patient Using Spiral CT Scans

Orthopedic surgery is associated with a significant risk of postoperative pulmonary embolism (PE) and/or deep vein thrombosis (DVT). This study was performed to compare the clinical presentations of a suspected versus a documented PE/DVT and to determine the actual incidence of PE/DVT in the post-operative orthopedic patient in whom CT was ordered. All 695 patients at our institution who had a postoperative spiral CT to rule out PE/DVT from March 2004 to February 2006 were evaluated and information regarding their surgical procedure, risk factors, presenting symptoms, location of PE/DVT, and anticoagulation were assessed. Statistical analysis was performed using an independent samples t test with a two-tailed p value to examine significant associations between the patient variables and CT scans positive for PE. Logistic regression models were used to determine which variables appeared to be significant predictors of a positive chest CT. Of 32,854 patients admitted for same day surgery across all services, 695 (2.1%) had a postoperative spiral CT based on specific clinical guidelines. The incidence of a positive scan was 27.8% (193/695). Of these, 155 (22.3%) scans were positive for PE only, 24 (3.5%) for PE and DVT, and 14 (2.0%) for DVT only. The most common presenting symptoms were tachycardia (56%, 393/695), low oxygen saturation (48%, 336/695), and shortness of breath (19.6%, 136/695). Symptoms significantly associated with DVT were syncope and chest pain. A past medical history of PE/DVT was the only significant predictor of a positive scan. Patients who have a history of thromboembolic disease should be carefully monitored in the postoperative setting.