Jonas H. Ellenberg

A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing

BACKGROUNDnThe clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results.nnnMETHODSnWe 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.nnnRESULTSnAt 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.nnnCONCLUSIONSnGenotype-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.).

Use of the Noninvasive Components of the Mayo Score to Assess Clinical Response in Ulcerative Colitis

Background: The Mayo score and a noninvasive 9‐point partial Mayo score are used as outcome measures for clinical trials assessing therapy for ulcerative colitis (UC). There are limited data assessing what defines a clinically relevant change in these indices. We sought to assess what constitutes a clinically meaningful change in these indices using data from a recently completed placebo‐controlled clinical trial. Methods: In all, 105 patients were enrolled in a 12‐week randomized, placebo‐controlled trial assessing rosiglitazone for treatment of mild to moderate UC. We compared the change in the Mayo score, the partial Mayo score, and a 6‐point score composed just of the stool frequency and bleeding components of the Mayo score to the patients perception of disease activity at week 0 and week 12. Optimal cutpoints were calculated as the maximal product of sensitivity and specificity. Results: Each index was strongly correlated with the patients rating of disease activity at week 12 (Spearman correlations 0.61–0.71, P < 0.0001 for all correlations). The maximal product of sensitivity and specificity to identify patient reported improvement of disease activity was achieved using cutpoints for change of 2.5 for the Mayo score (sensitivity 88%, specificity 80%), 2.5 for the partial Mayo score (sensitivity 88%, specificity 87%), and 1.5 for the 6‐point score (sensitivity 88%, specificity 80%). Conclusions: The partial Mayo score and the 6‐point score composed solely of the stool frequency and bleeding components performed as well as the full Mayo score to identify patient perceived clinical response.

Rosiglitazone for Active Ulcerative Colitis: A Randomized Placebo-Controlled Trial

BACKGROUND & AIMSnThiazolidinedione ligands for the gamma subtype of peroxisome proliferator-activated receptors (PPARgamma), widely used to treat type 2 diabetes mellitus, have been proposed as novel therapies for ulcerative colitis (UC).nnnMETHODSnThis multicenter, randomized, double-blind, placebo-controlled clinical trial compared the efficacy of rosiglitazone (Avandia; GlaxoSmithKline, Philadelphia, PA) 4 mg orally twice daily vs placebo twice daily for 12 weeks in 105 patients with mild to moderately active UC. Disease activity was measured with the Mayo score. The primary end point was clinical response (>/=2-point reduction) at week 12. Clinical remission (Mayo score </=2), endoscopic remission, and quality of life were secondary outcomes.nnnRESULTSnAfter 12 weeks of therapy, 23 patients (44%) treated with rosiglitazone and 12 patients (23%) treated with placebo achieved clinical response (P = .04). Remission was achieved in 9 patients (17%) treated with rosiglitazone and 1 patient (2%) treated with placebo (P = .01). Endoscopic remission was uncommon in either treatment arm (8% rosiglitazone vs 2% placebo; P = .34). Clinical improvement was evident as early as 4 weeks after beginning treatment (P = .049). Quality of life was improved significantly at week 8 (P = .01), but not at week 4 (P = .48) or week 12 (P = .14). Serious adverse events were rare.nnnCONCLUSIONSnRosiglitazone was efficacious in the treatment of mild to moderately active UC.

Statistical design of personalized medicine interventions: The Clarification of Optimal Anticoagulation through Genetics (COAG) trial

BackgroundThere is currently much interest in pharmacogenetics: determining variation in genes that regulate drug effects, with a particular emphasis on improving drug safety and efficacy. The ability to determine such variation motivates the application of personalized drug therapies that utilize a patients genetic makeup to determine a safe and effective drug at the correct dose. To ascertain whether a genotype-guided drug therapy improves patient care, a personalized medicine intervention may be evaluated within the framework of a randomized controlled trial. The statistical design of this type of personalized medicine intervention requires special considerations: the distribution of relevant allelic variants in the study population; and whether the pharmacogenetic intervention is equally effective across subpopulations defined by allelic variants.MethodsThe statistical design of the Clarification of Optimal Anticoagulation through Genetics (COAG) trial serves as an illustrative example of a personalized medicine intervention that uses each subjects genotype information. The COAG trial is a multicenter, double blind, randomized clinical trial that will compare two approaches to initiation of warfarin therapy: genotype-guided dosing, the initiation of warfarin therapy based on algorithms using clinical information and genotypes for polymorphisms in CYP2C9 and VKORC1; and clinical-guided dosing, the initiation of warfarin therapy based on algorithms using only clinical information.ResultsWe determine an absolute minimum detectable difference of 5.49% based on an assumed 60% population prevalence of zero or multiple genetic variants in either CYP2C9 or VKORC1 and an assumed 15% relative effectiveness of genotype-guided warfarin initiation for those with zero or multiple genetic variants. Thus we calculate a sample size of 1238 to achieve a power level of 80% for the primary outcome. We show that reasonable departures from these assumptions may decrease statistical power to 65%.ConclusionsIn a personalized medicine intervention, the minimum detectable difference used in sample size calculations is not a known quantity, but rather an unknown quantity that depends on the genetic makeup of the subjects enrolled. Given the possible sensitivity of sample size and power calculations to these key assumptions, we recommend that they be monitored during the conduct of a personalized medicine intervention.Trial Registrationclinicaltrials.gov: NCT00839657

Respiratory consequences of prematurity: Evolution of a diagnosis and development of a comprehensive approach

Bronchopulmonary dysplasia (BPD) is the most common respiratory consequence of premature birth and contributes to significant short- and long-term morbidity, mortality and resource utilization. Initially defined as a radiographic, clinical and histopathological entity, the chronic lung disease known as BPD has evolved as obstetrical and neonatal care have improved the survival of lower gestational age infants. Now, definitions based on the need for supplementary oxygen at 28 days and/or 36 weeks provide a useful reference point in the neonatal intensive-care unit (NICU), but are no longer based on histopathological findings, and are neither designed to predict longer term respiratory consequences nor to study the evolution of a multifactorial disease. The aims of this review are to critically examine the evolution of the diagnosis of BPD and the challenges inherent to current classifications. We found that the increasing use of respiratory support strategies that administer ambient air without supplementary oxygen confounds oxygen-based definitions of BPD. Furthermore, lack of reproducible, genetic, biochemical and physiological biomarkers limits the ability to identify an impending BPD for early intervention, quantify disease severity for standardized classification and approaches and reliably predict the long-term outcomes. More comprehensive, multidisciplinary approaches to overcome these challenges involve longitudinal observation of extremely preterm infants, not only those with BPD, using genetic, environmental, physiological and clinical data as well as large databases of patient samples. The Prematurity and Respiratory Outcomes Program (PROP) will provide such a framework to address these challenges through high-resolution characterization of both NICU and post-NICU discharge outcomes.

The association of cerebral palsy with birth asphyxia: a definitional quagmire.

Aimu2002 The aim of this study was to investigate whether current literature provides a useful body of evidence reflecting the proportion of cerebral palsy (CP) that is attributable to birth asphyxia.

Prematurity and respiratory outcomes program (PROP): study protocol of a prospective multicenter study of respiratory outcomes of preterm infants in the United States

BackgroundWith improved survival rates, short- and long-term respiratory complications of premature birth are increasing, adding significantly to financial and health burdens in the United States. In response, in May 2010, the National Institutes of Health (NIH) and the National Heart, Lung, and Blood Institute (NHLBI) funded a 5-year

Association Between Efavirenz-Based Compared With Nevirapine-Based Antiretroviral Regimens and Virological Failure in HIV-Infected Children

18.5 million research initiative to ultimately improve strategies for managing the respiratory complications of preterm and low birth weight infants. Using a collaborative, multi-disciplinary structure, the resulting Prematurity and Respiratory Outcomes Program (PROP) seeks to understand factors that correlate with future risk for respiratory morbidity.Methods/DesignThe PROP is an observational prospective cohort study performed by a consortium of six clinical centers (incorporating tertiary neonatal intensive care units [NICU] at 13 sites) and a data-coordinating center working in collaboration with the NHLBI. Each clinical center contributes subjects to the study, enrolling infants with gestational ages 23 0/7 to 28 6/7xa0weeks with an anticipated target of 750 survivors at 36xa0weeks post-menstrual age. In addition, each center brings specific areas of scientific focus to the Program. The primary study hypothesis is that in survivors of extreme prematurity specific biologic, physiologic and clinical data predicts respiratory morbidity between discharge and 1xa0year corrected age. Analytic statistical methodology includes model-based and non-model-based analyses, descriptive analyses and generalized linear mixed models.DiscussionPROP incorporates aspects of NICU care to develop objective biomarkers and outcome measures of respiratory morbidity in the <29xa0week gestation population beyond just the NICU hospitalization, thereby leading to novel understanding of the nature and natural history of neonatal lung disease and of potential mechanistic and therapeutic targets in at-risk subjects.Trial registrationClinical Trials.gov NCT01435187.

Microscopic colitis and Medication Use.

IMPORTANCEnWorldwide, the nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine are commonly used in first-line antiretroviral regimens in both adults and children with human immunodeficiency virus (HIV) infection. Data on the comparative effectiveness of these medications in children are limited.nnnOBJECTIVEnTo investigate whether virological failure is more likely among children who initiated 1 or the other NNRTI-based HIV treatment.nnnDESIGN, SETTING, AND PARTICIPANTSnRetrospective cohort study of children (aged 3-16 years) who initiated efavirenz-based (n = 421) or nevirapine-based (n = 383) treatment between April 2002 and January 2011 at a large pediatric HIV care setting in Botswana.nnnMAIN OUTCOMES AND MEASURESnThe primary outcome was time from initiation of therapy to virological failure. Virological failure was defined as lack of plasma HIV RNA suppression to less than 400 copies/mL by 6 months or confirmed HIV RNA of 400 copies/mL or greater after suppression. Cox proportional hazards regression analysis compared time to virological failure by regimen. Multivariable Cox regression controlled for age, sex, baseline immunologic category, baseline clinical category, baseline viral load, nutritional status, NRTIs used, receipt of single-dose nevirapine, and treatment for tuberculosis.nnnRESULTSnWith a median follow-up time of 69 months (range, 6-112 months; interquartile range, 23-87 months), 57 children (13.5%; 95% CI, 10.4%-17.2%) initiating treatment with efavirenz and 101 children (26.4%; 95% CI, 22.0%-31.1%) initiating treatment with nevirapine had virological failure. There were 11 children (2.6%; 95% CI, 1.3%-4.6%) receiving efavirenz and 20 children (5.2%; 95% CI, 3.2%-7.9%) receiving nevirapine who never achieved virological suppression. The Cox proportional hazard ratio for the combined virological failure end point was 2.0 (95% CI, 1.4-2.7; log rank P < .001, favoring efavirenz). None of the measured covariates affected the estimated hazard ratio in the multivariable analyses.nnnCONCLUSIONS AND RELEVANCEnAmong children aged 3 to 16 years infected with HIV and treated at a clinic in Botswana, the use of efavirenz compared with nevirapine as initial antiretroviral treatment was associated with less virological failure. These findings may warrant additional research evaluating the use of efavirenz and nevirapine for pediatric patients.

Shorter time to target temperature is associated with poor neurologic outcome in post-arrest patients treated with targeted temperature management.

Background The incidence of microscopic colitis (MC) is increasing, but its etiology remains unknown. Case reports and limited controlled data suggest that commonly prescribed drugs may be triggers. The aim of this study was to evaluate the prevalence of selected medication use [Proton pump inhibitors (PPIs), HMG-CoA reductase inhibitors (statins), and Selective serotonin reuptake inhibitors (SSRIs)] in patients with MC compared to ‘random controls’ and ‘diarrhea controls. Methods All patients were selected from primary care practices of a university health system during 2002 to 2007. Patients with biopsy proven lymphocytic or collagenous colitis were identified as cases. Diarrhea controls consisted of a 10:1 random sample of patients with chronic diarrhea and normal colon biopsies. Ten random controls were matched to each case on sex and index date (date of biopsy proven diagnosis). Drugs prescribed within the year prior to the index date were collected from the electronic medical record system. Results 26 cases (median age 68.9 yrs), 259 random, and 259 diarrhea controls were identified. The adjusted ORs for PPI, SSRI, and statin prescription within 12 months of diagnosis of MC between cases and diarrhea controls were 0.28 (0.07-1.07), 0.87 (0.28-2.64), 1.12 (0.34-3.71) respectively. Use of PPI and statins was less common in MC patients than in random controls (P < 0.05 for both comparisons). Conclusions While prior data suggest that PPIs, statins, and SSRIs may be etiologically related to MC, our study found no increased association with these drugs.