Stephen E Kimmel

University of Pennsylvania, Filadelfia, Pennsylvania, United States

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Publications (225)1935.41 Total impact

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    Brian S. Finkelman · Benjamin French · Stephen E. Kimmel
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    ABSTRACT: Clinical prediction models often fail to generalize in the context of clustered data, because most models fail to account for heterogeneity in outcome values and covariate effects across clusters. Furthermore, standard approaches for modeling clustered data, including generalized linear mixed-effects models, would not be expected to provide accurate predictions in novel clusters, because such predictions are typically based on the hypothetical mean cluster. We hypothesized that dynamic mixed-effects models, which incorporate data from previous predictions to refine the model for future predictions, would allow for cluster-specific predictions in novel clusters as the model is updated over time, thus improving overall model generalizability. We quantified the potential gains in prediction accuracy from using a dynamic modeling strategy in a simulation study. Furthermore, because clinical prediction models in the context of clustered data often involve outcomes that are dependent on patient volume, we examined whether using dynamic mixed-effects models would be robust to misspecification of the volume-outcome relationship. Our results indicated that dynamic mixed-effects models led to substantial improvements in prediction accuracy in clustered populations over a broad range of conditions, and were uniformly superior to static models. In addition, dynamic mixed-effects models were particularly robust to misspecification of the volume-outcome relationship and to variation in the frequency of model updating. The extent of the improvement in prediction accuracy that was observed with dynamic mixed-effects models depended on the relative impact of fixed and random effects on the outcome as well as the degree of misspecification of model fixed effects. Dynamic mixed-effects models led to substantial improvements in prediction model accuracy across a broad range of simulated conditions. Therefore, dynamic mixed-effects models could be a useful alternative to standard static models for improving the generalizability of clinical prediction models in the setting of clustered data, and, thus, well worth the logistical challenges that may accompany their implementation in practice.
    Preview · Article · Dec 2016 · BioData Mining
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    ABSTRACT: Background: Patients, clinicians, researchers and payers are seeking to understand the value of using genomic information (as reflected by genotyping, sequencing, family history or other data) to inform clinical decision-making. However, challenges exist to widespread clinical implementation of genomic medicine, a prerequisite for developing evidence of its real-world utility. Methods: To address these challenges, the National Institutes of Health-funded IGNITE (Implementing GeNomics In pracTicE; Network, comprised of six projects and a coordinating center, was established in 2013 to support the development, investigation and dissemination of genomic medicine practice models that seamlessly integrate genomic data into the electronic health record and that deploy tools for point of care decision making. IGNITE site projects are aligned in their purpose of testing these models, but individual projects vary in scope and design, including exploring genetic markers for disease risk prediction and prevention, developing tools for using family history data, incorporating pharmacogenomic data into clinical care, refining disease diagnosis using sequence-based mutation discovery, and creating novel educational approaches. Results: This paper describes the IGNITE Network and member projects, including network structure, collaborative initiatives, clinical decision support strategies, methods for return of genomic test results, and educational initiatives for patients and providers. Clinical and outcomes data from individual sites and network-wide projects are anticipated to begin being published over the next few years. Conclusions: The IGNITE Network is an innovative series of projects and pilot demonstrations aiming to enhance translation of validated actionable genomic information into clinical settings and develop and use measures of outcome in response to genome-based clinical interventions using a pragmatic framework to provide early data and proofs of concept on the utility of these interventions. Through these efforts and collaboration with other stakeholders, IGNITE is poised to have a significant impact on the acceleration of genomic information into medical practice.
    Full-text · Article · Dec 2015 · BMC Medical Genomics
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    ABSTRACT: Objectives: Value-based insurance designs are being widely used. We undertook this study to examine whether a financial incentive that lowered co-payments for blood pressure medications below $0 improved blood pressure control among patients with poorly controlled hypertension. Study design: Randomized controlled trial. Methods: Participants from 3 Pennsylvania hospitals (n = 337) were randomly assigned to: a) be paid $8 per medication per month for filling blood pressure prescriptions, b) a computerized behavioral intervention (CBI), c) both payment and CBI, or d) usual care. The primary outcome was change in blood pressure between baseline and 12 months post enrollment. We also measured adherence using the medication possession ratio in a subset of participants. Results: There were no significant interactions between the incentive and the CBI interventions. There were no significant changes in medication possession ratio in the treatment group. Blood pressure decreased among all participants, but to a similar degree between the financial incentive and control groups. Systolic blood pressure (SBP) dropped 13.7 mm Hg for the incentive group versus 10.0 mm Hg for the control group (difference = -3.7; 95% CI, -9.0 to 1.6; P = .17). The proportion of patients with blood pressure under control 12 months post enrollment was 35.6% of the incentive group versus 27.7% of the control group (odds ratio, 1.4; 95% CI, 0.8-2.5; P = .19). Diabetics in the incentive group had an average drop in SBP of 12.7 mm Hg between baseline and 12 months compared with 4.0 mm Hg in the control group (P = .02). Patients in the incentive group without diabetes experienced average SBP reductions of 15.0 mm Hg, compared with 16.3 mm Hg for control group nondiabetics (P = .71). Conclusions: Among patients with poorly controlled blood pressure, financial incentives-as implemented in this trial-did not improve blood pressure control or adherence except among patients with diabetes.
    No preview · Article · Nov 2015 · The American journal of managed care
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    ABSTRACT: Objectives: Efforts to improve adherence by reducing co-payments through value-based insurance design are become more prevalent despite limited evidence of improved health outcomes. The objective of this study was to determine whether eliminating patient co-payments for blood pressure medications improves blood pressure control. Study design: Randomized controlled trial. Methods: The Collaboration to Reduce Disparities in Hypertension (CHORD) was a randomized controlled trial with 12 months' follow-up conducted among patients from the Philadelphia and Pittsburgh Veterans Administration Medical Centers. We enrolled 479 patients with poorly controlled systolic blood pressure. Participants were randomly assigned to: a) receive reductions in co-payments from $8 to $0 per medication per month for each antihypertensive prescription filled, b) a computerized behavioral intervention (CBI), c) both co-pay reduction and CBI, or d) usual care. Our main outcome measure was change in systolic blood pressure from enrollment to 12 months post enrollment. We also measured adherence using the medication possession ratio in a subset of participants. Results: There were no significant interactions between the co-payment interventions and the CBI interventions. There was no relative difference in the change in medication possession ratio between baseline and 12 months (0.05% and -0.90% in control and incentive groups, respectively; P = .74) or in continuous medication gaps of 30, 60, or 90 days. Blood pressure decreased among all participants, but to a similar degree between the financial incentive and control groups. Systolic pressure within the incentive group dropped 13.2 mm Hg versus 15.2 mm Hg for the control group (difference = 2.0; 95% CI, -2.3 to 6.3; P = .36). The proportion of patients with blood pressure under control at 12 months was 29.5% in the incentive group versus 33.9 in the control group (odds ratio, 0.8; 95% CI, 0.5-1.3; P = .36). Conclusions: Among patients with poorly controlled blood pressure, financial incentives-as implemented in this trial-that reduced patient cost sharing for blood pressure medications did not improve medication adherence or blood pressure control.
    No preview · Article · Nov 2015 · The American journal of managed care
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    ABSTRACT: Background: Dosing algorithms for warfarin incorporate clinical and genetic factors but human intervention to overrule algorithm-based dosing may occasionally be required. The frequency and reasons for varying from algorithmic warfarin management have not been well studied. Methods: We analyzed a prospective cohort of 1015 participants from the Clarification of Optimal Anticoagulation through Genetics (COAG) trial who were randomized to either pharmacogenetic- or clinically-guided warfarin dosing algorithms. Clinicians and participants were blinded to dose but not INR during the first 28 days. If an issue arose that raised concern for clinicians but might not be adequately accounted for by the protocol, then clinicians contacted the unblinded medical monitor who could approve exceptions if clinically justified. All granted exceptions were logged and categorized. We analyzed the relationships between dosing exceptions and both baseline characteristics and the outcome of percentage of time in the therapeutic INR range during the first 4 weeks (PTTR). Results: 16% of participants required at least 1 exception to the protocol-defined warfarin dose (15% in the genotype arm and 17% in the clinical arm). 90% of dose exceptions occurred after the first 5 days of dosing. The only baseline characteristic associated with dose exceptions was congestive heart failure (OR 2.12, 95%CI: 1.49-3.02, P<0.001). Neither study arm nor genotype was associated with dose exceptions. Conclusion: Despite rigorous algorithms, human intervention is frequently employed in the early management of warfarin dosing. Congestive heart failure at baseline appears to predict early exceptions to standardized protocol management.
    No preview · Article · Nov 2015 · The American journal of medicine
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    ABSTRACT: Background: Although substantial effort has been devoted to reducing readmissions among heart failure (HF) patients, little is known about factors identified by patients and caregivers that may contribute to readmissions. The goal of this study was to compare the perspectives of HF patients, their caregivers, and their care team on HF management and hospital admissions. Understanding these perspectives may lead to better strategies for improving care during the post-hospital transition and reducing preventable readmissions. Methods and results: We performed freelisting-an anthropological technique in which participants list items in response to a question-with hospitalized HF patients (n=58), their caregivers (n=32), and clinicians (n=67). We asked about home HF management tasks, difficulties in managing HF, and perceived reasons for hospital admission. Results were analyzed in Anthropac(©). Salience indices (measures of the most important words for defining the domain of interest) were calculated. Patients and clinicians described similar home HF management tasks, while caregivers described tasks related to activities of daily living. Clinicians cited socio-economic factors as challenges to HF management, while patients and caregivers cited limited functional status and daily activities. When asked about reasons for hospitalization, patients and caregivers listed distressing symptoms and illness, while clinicians viewed patient behaviors as primarily responsible for admission. Conclusions: These findings highlight that, although some similarities exist, there are important differences among patients, caregivers, and clinicians in how they perceive the challenges of HF management and reasons for readmission. Understanding these differences may be critical to developing strategies to reduce readmissions.
    No preview · Article · Oct 2015 · Journal of cardiac failure
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    ABSTRACT: Variability in vitamin K antagonist (VKA) dosing is partially explained by genetic polymorphisms. We performed a meta-analysis to determine whether genotype-guided VKA dosing algorithms decrease a composite of death, thromboembolic events and major bleeding (primary outcome) and improve time in therapeutic range (TTR). We searched MEDLINE, EMBASE, CENTRAL, trial registries and conference proceedings for randomised trials comparing genotype-guided and standard (non genotype-guided) VKA dosing algorithms in adults initiating anticoagulation. Data were pooled using a random effects model. Of the 12 included studies (3,217 patients), six reported all components of the primary outcome of mortality, thromboembolic events and major bleeding (2,223 patients, 87 events). Our meta-analysis found no significant difference between groups for the primary outcome (relative risk 0.85, 95 % confidence interval [CI] 0.54-1.34; heterogeneity Χ²=4.46, p=0.35, I²=10 %). Based on 10 studies (2,767 patients), TTR was significantly higher in the genotype-guided group (mean difference (MD) 4.31 %; 95 % CI 0.35, 8.26; heterogeneity Χ²=43.31, p< 0.001, I²=79 %). Pre-specified exploratory analyses demonstrated that TTR was significantly higher when genotype-guided dosing was compared with fixed VKA dosing (6 trials, 997 patients: MD 8.41 %; 95 % CI 3.50,13.31; heterogeneity Χ²=15.18, p=0.01, I²=67 %) but not when compared with clinical algorithm-guided dosing (4 trials, 1,770 patients: MD -0.29 %; 95 % CI -2.48,1.90; heterogeneity Χ²=1.53, p=0.68, I²=0 %; p for interaction=0.002). In conclusion, genotype-guided compared with standard VKA dosing algorithms were not found to decrease a composite of death, thromboembolism and major bleeding, but did result in improved TTR. An improvement in TTR was observed in comparison with fixed VKA dosing algorithms, but not with clinical algorithms.
    No preview · Article · Jul 2015 · Thrombosis and Haemostasis
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    ABSTRACT: Dosing algorithms for warfarin incorporate clinical and genetic factors but may not account for the numerous comorbidities affecting patients who start warfarin while hospitalized. We aimed to determine whether these algorithms perform differently when warfarin is initiated for inpatients compared with outpatients. We analyzed a prospective cohort of 1015 participants from the Clarification of Optimal Anticoagulation through Genetics (COAG) trial who were randomized to either pharmacogenetically or clinically guided warfarin dosing algorithms. Clinicians and participants were blinded to dose during the first 28 days. We compared groups, based on location at the time of the first warfarin dose request, in relation to the following outcomes: percentage of time in the therapeutic international normalized ratio (INR) range (PTTR) during the first 4 weeks, time to first therapeutic INR, time to maintenance dose, and the difference between predicted and observed maintenance doses. A total of 527 participants started warfarin as inpatients and 488 as outpatients. There was no difference in PTTR based on location: 43.2 % for inpatient versus 47.4 % for outpatient initiation [mean adjusted difference -2.2 %; 95 % confidence interval (CI) -5.9 to 1.6]. Similarly, there were no differences in time to first therapeutic INR [hazard ratio (HR) 1.06; 95 % CI 0.91-1.24] or to maintenance dose (HR 0.96; 95 % CI 0.81-1.14). There was no evidence of interaction between study intervention (pharmacogenetically vs. clinically guided therapy) and location of initiation for these main outcomes. The difference between predicted and observed maintenance doses was similar for both locations. The warfarin dosing algorithms performed similarly for subjects who initiated warfarin as inpatients and outpatients, regardless of whether dosing was pharmacogenetically or clinically guided.
    No preview · Article · Jun 2015 · American Journal of Cardiovascular Drugs
  • S E Kimmel
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    ABSTRACT: The utility of using genetic information to guide warfarin dosing has remained unclear based on prior observational studies and small clinical trials. Two larger trials of warfarin and one of the acenocoumarol and phenprocoumon have recently been published. The COAG trial addressed the incremental benefit of adding genetic information to clinical information and demonstrated no benefit from the pharmacogenetic-based dosing strategy on the primary outcome. The EU-PACT UK trial compared an algorithm approach using genetic and clinical information to one that used a relatively fixed starting dose. The pharmacogenetic-based algorithms improved the primary outcome. The study of acenocoumarol and phenprocoumon compared a pharmacogenetic with a clinical algorithm and demonstrated no benefit on the primary outcome. The evidence to date does not support an incremental benefit of adding genetic information to clinical information on anticoagulation control. However, compared with fixed dosing, a pharmacogenetic algorithm can improve anticoagulation control. © 2015 International Society on Thrombosis and Haemostasis.
    No preview · Article · Jun 2015 · Journal of Thrombosis and Haemostasis

  • No preview · Article · May 2015 · Thrombosis Research
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    ABSTRACT: We read with interest the recently published systematic review and meta-analysis by Franchini et al.[1] regarding the impact on clinical outcomes of genotype-guided vitamin K antagonist (VKA) dosing. The authors reported that genotype-guided VKA dosing reduces major bleeding events compared with clinically guided approaches (RR = 0.47, 95% CI, 0.23-0.96) and state that "pharmacogenetic analysis halved the risk of major bleeding during the initial phase of anticoagulation." We note four methodological issues that raise concern and warrant further discussion. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Mar 2015 · Journal of Thrombosis and Haemostasis
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    ABSTRACT: There is controversy and little information about whether individual proton pump inhibitors (PPIs) differentially alter the effectiveness of clopidogrel in reducing ischemic stroke risk. We, therefore, aimed to elucidate the risk of ischemic stroke among concomitant users of clopidogrel and individual PPIs. We conducted a propensity score-adjusted cohort study of adult new users of clopidogrel, using 1999 to 2009 Medicaid claims from 5 large states. Exposures were defined by prescriptions for esomeprazole, lansoprazole, omeprazole, rabeprazole, and pantoprazole-with pantoprazole serving as the referent. The end point was hospitalization for acute ischemic stroke, defined by International Classification of Diseases Ninth Revision Clinical Modification codes in the principal position on inpatient claims, within 180 days of concomitant therapy initiation. Among 325 559 concomitant users of clopidogrel and a PPI, we identified 1667 ischemic strokes for an annual incidence of 2.4% (95% confidence interval, 2.3-2.5). Adjusted hazard ratios for ischemic stroke versus pantoprazole were 0.98 (0.82-1.17) for esomeprazole; 1.06 (0.92-1.21) for lansoprazole; 0.98 (0.85-1.15) for omeprazole; and 0.85 (0.63-1.13) for rabeprazole. PPIs of interest did not increase the rate of ischemic stroke among clopidogrel users when compared with pantoprazole, a PPI thought to be devoid of the potential to interact with clopidogrel. © 2015 American Heart Association, Inc.
    No preview · Article · Feb 2015 · Stroke
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    ABSTRACT: PurposePatients starting warfarin often experience lengthy dose-titration periods, when they are at high risk for bleeding and thromboembolism. However, relatively little is known about why some patients take longer than others to reach maintenance dose. Thus, we sought to identify social, clinical, and genetic factors associated with prolonged time to maintenance dose (TTM).Methods We conducted a time-to-event analysis, using a prospective cohort of patients initiating warfarin (N = 390). Additionally, we examined whether changes in post-initiation factors were associated with TTM. Finally, we performed a secondary analysis in a subcohort (N = 156) assessing the effect of adherence on TTM.ResultsNo genetic or post-initiation factors were significantly associated with TTM. However, previous use of warfarin [hazard ratio (HR) = 0.64; 95% confidence interval (CI) 0.46, 0.88], current smoking status (HR = 0.61; 95%CI 0.39, 0.96), fewer than four doctor's visits in the previous year (HR = 0.63 vs 4–12 visits; 95%CI 0.46, 0.88), and worse general health status (HR = 0.63; 95%CI 0.47, 0.84) were significantly associated with longer TTM. Use of illegal injectable drugs (HR = 2.51; 95%CI 1.17, 5.39) was associated with shorter TTM. On secondary analysis, the HR for better adherence and TTM was 1.70 (95%CI 0.88, 3.27).Conclusions Time to maintenance dose was associated with pre-existing behavioral factors, health care utilization, and health quality but not clinical comorbidities or genetic factors in patients initiating warfarin. Future studies are needed to determine whether warfarin patients with prolonged TTM would have better outcomes on alternative agents. Copyright © 2014 John Wiley & Sons, Ltd.
    No preview · Article · Dec 2014 · Pharmacoepidemiology and Drug Safety
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    ABSTRACT: Importance Hypertension is prevalent among patients with psoriasis. The effect of psoriasis and its severity on hypertension control is unknown.Objective To determine the association between uncontrolled blood pressure and psoriasis, both overall and according to objectively measured psoriasis severity, among patients with diagnosed hypertension.Design, Setting, and Participants Population-based cross-sectional study nested in a prospective cohort drawn from The Health Improvement Network (THIN), an electronic medical records database broadly representative of the general population in the United Kingdom. The study population included a random sample of patients with psoriasis (n = 1322) between the ages of 25 and 64 years in THIN who were included in the Incident Health Outcomes and Psoriasis Events prospective cohort and their age- and practice-matched controls without psoriasis (n = 11 977). All included patients had a diagnosis of hypertension; their psoriasis diagnosis was confirmed and disease severity was classified by their general practitioners.Main Outcomes and Measures Uncontrolled hypertension was defined as a systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher based on the blood pressure recorded closest in time to the assessment of psoriasis severity.Results There was a significant positive dose-response relationship between uncontrolled hypertension and psoriasis severity as objectively determined by the affected body surface area in both unadjusted and adjusted analyses that controlled for age, sex, body mass index, smoking and alcohol use status, presence of comorbid conditions, and current use of antihypertensive medications and nonsteroidal anti-inflammatory drugs (adjusted odds ratio [aOR], 0.97; 95% CI, 0.82-1.14 for mild psoriasis; aOR, 1.20; 95% CI, 0.99-1.45 for moderate psoriasis; and aOR, 1.48; 95% CI, 1.08-2.04 for severe psoriasis; P = .01 for trend). The likelihood of uncontrolled hypertension among psoriasis overall was also increased, although not statistically significantly so (aOR, 1.10; 95% CI, 0.98-1.24).Conclusions and Relevance Among patients with hypertension, psoriasis was associated with a greater likelihood of uncontrolled hypertension in a dose-dependent manner, with the greatest likelihood observed among those with moderate to severe psoriasis defined by 3% or more of the body surface area affected. Our data suggest a need for more effective blood pressure management, particularly among patients with more severe psoriasis.
    No preview · Article · Oct 2014 · JAMA Dermatology
  • Stephen E. Kimmel · Benjamin French · Nancy L. Geller

    No preview · Article · May 2014 · New England Journal of Medicine

  • No preview · Conference Paper · Mar 2014
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    ABSTRACT: 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 number, NCT00839657.).
    No preview · Article · Nov 2013 · New England Journal of Medicine
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    ABSTRACT: -The long-term durability and prognostic significance of improvement in renal function following mechanical circulatory support (MCS) has yet to be characterized in a large multicenter population. The primary goals of this analysis were to describe serial post-MCS changes in estimated glomerular filtration rate (eGFR) and determine their association with all-cause mortality. -Adult patients enrolled in INTERMACS with serial creatinine levels available (n=3,363) were studied. Early post-MCS, eGFR improved substantially (median improvement 48.9%, p<0.001) with 22.3% of the population improving their eGFR by ≥100% within the first few weeks. However, in the majority of patients this improvement was transient, and by one year, eGFR was only 6.7% above the pre-MCS value (p<0.001). This pattern of early improvement followed by deterioration in eGFR was observed with both pulsatile and continuous-flow devices. Interestingly, poor survival was associated with both marked improvement (adjusted HR=1.64, 1.19-2.26, p=0.002) and worsening in eGFR (adjusted HR=1.63, 1.15-2.13, p=0.004). -Post-MCS, early improvement in renal function is common but appears to be largely transient and not necessarily indicative of an improved prognosis. This pattern was observed with both pulsatile and continuous-flow devices. Additional research is necessary to better understand the mechanistic basis for these complex post-MCS changes in renal function and their associated survival disadvantage. Clinical Trial Registration-URL: Unique identifier: NCT00119834.
    Preview · Article · Nov 2013 · Circulation Heart Failure
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    ABSTRACT: Antipsychotic drugs have been linked to QT-interval prolongation, a presumed marker of cardiac risk, and torsade de pointes. To examine the associations between antipsychotics and 1) outpatient-originated sudden cardiac death and ventricular arrhythmia (SD/VA) and 2) all-cause death. Two retrospective cohort studies. Medicaid programs of California, Florida, New York, Ohio and Pennsylvania. Incident antipsychotic users aged 30-75 years. 1) Incident, first-listed emergency department or principal inpatient SD/VA diagnoses; and 2) death reported in the Social Security Administration Death Master File. Among 459,614 incident antipsychotic users, the incidences of SD/VA and death were 3.4 and 35.1 per 1,000 person-years, respectively. Compared to olanzapine as the referent, adjusted hazard ratios (HRs) for SD/VA were 2.06 (95% CI, 1.20-3.53) for chlorpromazine, 1.72 (1.28-2.31) for haloperidol, and 0.73 (0.57-0.93) for quetiapine. Adjusted HRs for perphenazine and risperidone were consistent with unity. In a subanalysis limited to first prescription exposures, HRs for chlorpromazine and haloperidol were further elevated (2.54 [1.07-5.99] and 2.68 [1.59-4.53], respectively), with the latter exhibiting a dose-response relationship. Results for death were similar. Haloperidol and chlorpromazine had less favorable cardiac safety profiles than olanzapine. Among atypical agents, risperidone had a similar cardiac safety profile to olanzapine, whereas quetiapine was associated with 30% and 20% lower risks of SD/VA and death, respectively, compared to olanzapine. These measured risks do not correlate well with average QT prolongation, further supporting the notion that average QT prolongation may be a poor surrogate of antipsychotic arrhythmogenicity.
    No preview · Article · Sep 2013 · Journal of Clinical and Experimental Cardiology
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    ABSTRACT: Current dosing practices for warfarin are empiric and result in the need for frequent dose changes as the international normalized ratio gets too high or too low. As a result, patients are put at increased risk for thromboembolism, bleeding, and premature discontinuation of anticoagulation therapy. Prior research has identified clinical and genetic factors that can alter warfarin dose requirements, but few randomized clinical trials have examined the utility of using clinical and genetic information to improve anticoagulation control or clinical outcomes among a large, diverse group of patients initiating warfarin. The COAG trial is a multicenter, double-blind, randomized trial comparing 2 approaches to guiding warfarin therapy initiation: initiation of warfarin therapy based on algorithms using clinical information plus an individual's genotype using genes known to influence warfarin response ("genotype-guided dosing") versus only clinical information ("clinical-guided dosing") ( Identifier: NCT00839657). The COAG trial design is described. The study hypothesis is that, among 1,022 enrolled patients, genotype-guided dosing relative to clinical-guided dosing during the initial dosing period will increase the percentage of time that patients spend in the therapeutic international normalized ratio range in the first 4 weeks of therapy. The COAG will determine if genetic information provides added benefit above and beyond clinical information alone.
    No preview · Article · Sep 2013 · American heart journal

Publication Stats

10k Citations
1,935.41 Total Impact Points


  • 1995-2016
    • University of Pennsylvania
      • • Center for Clinical Epidemiology and Biostatistics
      • • Department of Medicine
      Filadelfia, Pennsylvania, United States
    • Victoria General Hospital
      Winnipeg, Manitoba, Canada
  • 2000-2015
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 2003-2012
    • The Children's Hospital of Philadelphia
      Filadelfia, Pennsylvania, United States
    • Columbia University
      • Division of Pulmonary, Allergy, and Critical Care Medicine
      New York, New York, United States
    • University of Maryland, Baltimore
      • Department of Medicine
      Baltimore, Maryland, United States
  • 2011
    • Washington University in St. Louis
      • Center for Pharmacogenomics
      San Luis, Missouri, United States
  • 2010
    • University of Utah
      • Department of Human Genetics
      Salt Lake City, Utah, United States
  • 2009
    • Carnegie Mellon University
      • Department of Social and Decision Sciences
      Pittsburgh, Pennsylvania, United States
  • 2002
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 2001
    • Cornell University
      Итак, New York, United States
  • 1999-2000
    • Hospital of the University of Pennsylvania
      • Department of Medicine
      Filadelfia, Pennsylvania, United States