Stephen E Kimmel

Philadelphia University, Filadelfia, Pennsylvania, United States

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Publications (194)1568.06 Total impact

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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.
    Journal of Thrombosis and Haemostasis 03/2015; DOI:10.1111/jth.12903 · 5.55 Impact Factor
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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.
    Stroke 02/2015; 46(3). DOI:10.1161/STROKEAHA.114.006866 · 6.02 Impact Factor
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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.
    Pharmacoepidemiology and Drug Safety 12/2014; 24(3). DOI:10.1002/pds.3735 · 3.17 Impact Factor
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    ABSTRACT: Hypertension is prevalent among patients with psoriasis. The effect of psoriasis and its severity on hypertension control is unknown.
    JAMA Dermatology 10/2014; DOI:10.1001/jamadermatol.2014.2094 · 4.30 Impact Factor
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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 ClinicalTrials.gov number, NCT00839657 .).
    New England Journal of Medicine 11/2013; DOI:10.1056/NEJMoa1310669 · 54.42 Impact Factor
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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: http://www.clinicaltrials.gov. Unique identifier: NCT00119834.
    Circulation Heart Failure 11/2013; 7(1). DOI:10.1161/CIRCHEARTFAILURE.113.000507 · 5.95 Impact Factor
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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") (www.clinicaltrials.gov 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.
    American heart journal 09/2013; 166(3):435-441.e2. DOI:10.1016/j.ahj.2013.04.009 · 4.56 Impact Factor
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    ABSTRACT: IMPORTANCE Despite the growing literature on comorbidity risks in psoriasis, there remains a critical knowledge gap on the degree to which objectively measured psoriasis severity may affect the prevalence of major medical comorbidity. OBJECTIVE To examine the prevalence of major medical comorbidity in patients with mild, moderate, or severe psoriasis, classified objectively based on body surface area involvement, compared with that in patients without psoriasis. DESIGN, SETTING, AND PARTICIPANTS Population-based cross-sectional study of patient data fromUnited Kingdom-based electronic medical records; analysis included9035 patients aged 25 to 64 years with psoriasis and 90 350 age- and practice-matched patients without psoriasis. MAIN OUTCOMES AND MEASURES Prevalence of major medical comorbidity included in the Charlson comorbidity index. RESULTS Among patients with psoriasis, 51.8%, 35.8%, and 12.4%, respectively, had mild, moderate, or severe disease based on body surface area criteria. The mean Charlson comorbidity index was increasingly higher in patients with mild (0.375 vs 0.347), moderate (0.398 vs 0.342), or severe psoriasis (0.450 vs 0.348) (each P < .05). Psoriasis overall was associated with higher prevalence of chronic pulmonary disease (adjusted odds ratio, 1.08; 95% CI, 1.02-1.15), diabetes mellitus (1.22; 1.11-1.35), diabetes with systemic complications (1.34; 1.11-1.62), mild liver disease (1.41; 1.12-1.76), myocardial infarction (1.34; 1.07-1.69), peptic ulcer disease (1.27; 1.03-1.58), peripheral vascular disease (1.38; 1.07-1.77), renal disease (1.28; 1.11-1.48), and rheumatologic disease (2.04; 1.71-2.42). Trend analysis revealed significant associations between psoriasis severity and each of the above comorbid diseases (each P < .05). CONCLUSIONS AND RELEVANCE The burdens of overall medical comorbidity and of specific comorbid diseases increase with increasing disease severity among patients with psoriasis. Physicians should be aware of these associations in providing comprehensive care to patients with psoriasis, especially those presenting with more severe disease.
    08/2013; 149(10). DOI:10.1001/jamadermatol.2013.5015
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    ABSTRACT: Digitalis glycosides are known to improve the hemodynamic and neurohormonal perturbations that contribute to heart failure (HF)-induced renal dysfunction (RD). The objective of this study was to determine if randomization to digoxin is associated with improvement in renal function (IRF) and to evaluate if patients with digoxin-induced IRF have improved clinical outcomes. Patients in the Digitalis Investigation Group (DIG) dataset with protocol-driven 1-year serum creatinine levels (performed in a central laboratory; n = 980) were studied. IRF was defined as a postrandomization ≥20% increase in estimated glomerular filtration rate (eGFR). IRF occurred in 15.5% of the population (mean improvement in eGFR 34.5 ± 15.4%) and was more common in patients randomized to digoxin (adjusted odds ratio 1.6; P = .02). In patients without IRF, digoxin was not associated with reduced death or hospitalization (adjusted hazard ratio [HR] 0.96, 95% CI 0.8-1.2; P = .67). However, in the group with IRF, digoxin was associated with substantially improved hospitalization-free survival (adjusted HR 0.49, 95% CI 0.3-0.8; P = .006; P interaction = .026). In this subset of the DIG trial, digoxin was associated with long-term improvement in kidney function and, in patients demonstrating this favorable renal response, reduction in death or hospitalization. Additional research is necessary to confirm these hypothesis-generating findings.
    Journal of cardiac failure 05/2013; 19(5):295-302. DOI:10.1016/j.cardfail.2013.03.002 · 3.07 Impact Factor
  • Thrombosis and Haemostasis 03/2013; 109(6). DOI:10.1160/TH13-02-0111 · 5.76 Impact Factor
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    Journal of the American College of Cardiology 03/2013; 61(10). DOI:10.1016/S0735-1097(13)60760-3 · 15.34 Impact Factor
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    ABSTRACT: To compare the incidence rates of serious cardiovascular events in adult initiators of amphetamines or atomoxetine to rates in non-users. This was a retrospective cohort study of new amphetamines (n = 38,586) or atomoxetine (n = 20,995) users. Each medication user was matched to up to four non-users on age, gender, data source, and state (n = 238,183). The following events were primary outcomes of interest 1) sudden death or ventricular arrhythmia, 2) stroke, 3) myocardial infarction, 4) a composite endpoint of stroke or myocardial infarction. Cox proportional hazard regression was used to calculate propensity-adjusted hazard ratios for amphetamines versus matched non-users and atomoxetine versus matched non-users, with intracluster dependence within matched sets accounted for using a robust sandwich estimator. The propensity-score adjusted hazard ratio for amphetamines use versus non-use was 1.18 (95% CI: 0.55-2.54) for sudden death/ventricular arrhythmia, 0.80 (95% CI: 0.44-1.47) for stroke, 0.75 (95% CI: 0.42-1.35) for myocardial infarction, and 0.78 (95% CI: 0.51-1.19) for stroke/myocardial infarction. The propensity-score adjusted hazard ratio for atomoxetine use versus non-use was 0.41 (95% CI: 0.10-1.75) for sudden death/ventricular arrhythmia, 1.30 (95% CI: 0.52-3.29) for stroke, 0.56 (95% CI: 0.16-2.00) for myocardial infarction, and 0.92 (95% CI: 0.44-1.92) for stroke/myocardial infarction. Initiation of amphetamines or atomoxetine was not associated with an elevated risk of serious cardiovascular events. However, some of the confidence intervals do not exclude modest elevated risks, e.g. for sudden death/ventricular arrhythmia.
    PLoS ONE 01/2013; 8(1):e52991. DOI:10.1371/journal.pone.0052991 · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: -Identifying reversible renal dysfunction (RD) in the setting of heart failure (HF) is challenging. The goal of this study was to evaluate if an elevated admission blood urea nitrogen to creatinine ratio (BUN/Cr) could identify decompensated HF patients likely to experience improvement in renal function (IRF) with treatment. METHODS AND RESULTS: -Consecutive hospitalizations with a discharge diagnosis of HF were reviewed. IRF was defined as ≥20% increase and worsening renal function (WRF) ≥20% decrease in estimated glomerular filtration rate (eGFR). IRF occurred in 31% of the 896 patients meeting eligibility criteria. Higher admission BUN/Cr was associated with in-hospital IRF (OR=1.5 per 10 increase, 95% CI: 1.3-1.8, p<0.001), an association persisting after adjustment for baseline characteristics (OR=1.4, 95% CI: 1.1-1.8, p=0.004). However, higher admission BUN/Cr was also associated with post-discharge WRF (OR= 1.4, 95% CI: 1.1-1.8, p=0.011). Notably, in patients with an elevated admission BUN/Cr, the risk of death associated with RD (eGFR<45) was substantial (HR=2.2, 95% CI: 1.6-3.1, p<0.001). However, in patients with a normal admission BUN/Cr, RD was not associated with increased mortality (HR=1.2, 95% CI: 0.67-2.0, p=0.59, p interaction= 0.03). CONCLUSIONS: -An elevated admission BUN/Cr identifies decompensated HF patients likely to experience IRF with treatment, providing proof of concept that reversible RD may be a discernible entity. However, this improvement appears to be largely transient and RD in the setting of an elevated BUN/Cr remains strongly associated with death. Further research is warranted to develop strategies for the optimal detection and treatment of these high-risk patients.
    Circulation Heart Failure 01/2013; 6(2). DOI:10.1161/CIRCHEARTFAILURE.112.968230 · 5.95 Impact Factor
  • CIRCULATION; 01/2013
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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.
    01/2013; Suppl 10(6):1-9. DOI:10.4172/2155-9880.S10-006
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    ABSTRACT: PURPOSE: To describe the design and rationale of a series of postmarketing studies to examine the safety of saxagliptin, an oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus, in real-world settings. METHODS: We are conducting a series of retrospective cohort studies using two UK (General Practice Research Database, and The Health Improvement Network) and two US (Medicare, HealthCore Integrated Research Database(SM) ) data sources. The primary outcomes of interest will include (i) hospitalization with acute liver failure, (ii) hospitalization for acute kidney injury, (iii) hospitalization for severe hypersensitivity reactions, (iv) hospitalization for severe infections, (v) hospitalization with infections associated with T-lymphocyte dysfunction (i.e., herpes zoster, tuberculosis, or nontuberculous mycobacteria), and (vi) major cardiovascular events. Diagnosis codes for the outcomes of interest will be validated by medical record review within each data source. Projected use and estimated incidence rates of outcomes of interest suggest there will be at least 80% statistical power to detect a minimum hazard ratio of 1.5 for major cardiovascular events, 2.0 for acute kidney injury and severe infections, 2.4 for acute liver failure, and 4.0 for severe hypersensitivity reactions. RESULTS: Forthcoming. CONCLUSIONS: This postmarketing safety assessment will provide important information regarding the safety of saxagliptin and could potentially identify important dipeptidyl peptidase-4 inhibitor class effects. The methods described may be useful to others planning similar evaluations. Copyright © 2012 John Wiley & Sons, Ltd.
    Pharmacoepidemiology and Drug Safety 11/2012; 21(11). DOI:10.1002/pds.3318 · 3.17 Impact Factor
  • Journal of Cardiac Failure 08/2012; 18(8):S38-S39. DOI:10.1016/j.cardfail.2012.06.132 · 3.07 Impact Factor
  • Journal of Cardiac Failure 08/2012; 18(8):S15. DOI:10.1016/j.cardfail.2012.06.050 · 3.07 Impact Factor
  • Journal of Cardiac Failure 08/2012; 18(8):S72. DOI:10.1016/j.cardfail.2012.06.468 · 3.07 Impact Factor
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    ABSTRACT: Poor adherence to medications is a major cause of morbidity and inadequate drug effectiveness. Efforts to improve adherence have typically been either ineffective or too complex to implement in clinical practice. Lottery-based incentive interventions could be a scalable approach to improving adherence. This was a randomized, controlled clinical trial of a daily lottery-based incentive in patients on warfarin stratified by baseline international normalized ratio (INR). The trial randomized 100 patients to either a lottery-based incentive or no lottery intervention. Main outcome was out-of-range INRs. Over 6 months, the overall percentage of out-of-range INRs did not differ between the 2 arms (mean 23.0% in lottery arm and 25.9% in control arm, adjusted odds ratio [OR] 0.93, 95% CI 0.62-1.41). However, among the a priori subgroup with a baseline INR below therapeutic range, there was a significant reduction in out-of-range INR in the lottery arm versus the control arm (adjusted OR 0.39, 95% CI 0.25-0.62), whereas there was no such effect among those with therapeutic INRs at baseline (adjusted OR 1.26, 95% CI, 0.76-2.09, P value for interaction = .0016). Among those with low INR at baseline, there was a nonsignificant 49% reduction in the odds of nonadherence with the intervention (OR 0.51, 95% CI 0.23-1.14). Although a lottery-based intervention was not associated with a significant improvement in anticoagulation control among all study participants, it improved control among an a priori group of patients at higher risk for poor adherence.
    American heart journal 08/2012; 164(2):268-74. DOI:10.1016/j.ahj.2012.05.005 · 4.56 Impact Factor

Publication Stats

7k Citations
1,568.06 Total Impact Points

Institutions

  • 2015
    • Philadelphia University
      Filadelfia, Pennsylvania, United States
  • 1995–2014
    • University of Pennsylvania
      • • Center for Clinical Epidemiology and Biostatistics
      • • Department of Medicine
      Filadelfia, Pennsylvania, United States
    • Victoria General Hospital
      Winnipeg, Manitoba, Canada
  • 1997–2013
    • William Penn University
      Filadelfia, Pennsylvania, United States
    • Hospital of the University of Pennsylvania
      • Department of Medicine
      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
    • Weill Cornell Medical College
      • Division of General Internal Medicine (WCIMA)
      New York City, New York, United States