Publications by authors named "Stephen E Kimmel"

159 Publications

Risk factors for 30-day readmission in adults hospitalized for pulmonary hypertension.

Pulm Circ 2020 Oct-Dec;10(4):2045894020966889. Epub 2020 Nov 23.

Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Readmissions for pulmonary hypertension are poorly understood and understudied. We sought to determine national estimates and risk factors for 30-day readmission after pulmonary hypertension-related hospitalizations. We utilized the Healthcare Cost and Utilization Project Nationwide Readmission Database, which has weighted estimates of roughly 35 million discharges in the US. Adult patients with primary International Classification of Disease, Ninth Revision, Clinical Modification diagnosis codes of 416.0 and 416.8 for primary and secondary pulmonary hypertension with an index admission between 2012 and 2014 and any readmission within 30 days of the index event were identified. Predictors of 30-day readmission were identified using multivariable logistic regression with adjustment for covariates. Results showed that the national estimate for Primary Pulmonary Hypertension vs Secondary Pulmonary Hypertension-related index events between 2012 and 2014 with 30-day readmission was 247 vs 2550 corresponding to a national readmission risk estimate of 17% vs 18.3%, respectively. The presence of fluid and electrolyte disorders, renal failure, and alcohol abuse were associated with increased risk of readmission in Primary Pulmonary Hypertension, while factors associated with Secondary Pulmonary Hypertension readmissions included anemia, congestive heart failure, lung disease, fluid and electrolyte disorders, renal failure, diabetes, and liver disease. The median cost of Primary Pulmonary Hypertension admissions and readmissions were $46,132 (IQR: $25,384-$85,647) and $41,604.50 (IQR: $22,481.50-$84,420.50), respectively. The median costs of Secondary Pulmonary Hypertension admissions and readmissions were $34,893 (IQR: $19,670-$66,143) and $36,279 (IQR: $19,059-$74,679), respectively. In conclusion, approximately 19% of Primary Pulmonary Hypertension and Secondary Pulmonary Hypertension hospitalizations result in 30-day readmission, with significant costs accrued during the index hospitalization and readmission. With evolving clinical terminology and diagnostic codes, future study will need to better clarify underlying factors associated with readmissions amongst pulmonary hypertension sub-types, and identify methods and procedures to minimize readmission risk.
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http://dx.doi.org/10.1177/2045894020966889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686634PMC
November 2020

Evaluation of COVID-19 Testing Strategies for Repopulating College and University Campuses: A Decision Tree Analysis.

J Adolesc Health 2021 01 3;68(1):28-34. Epub 2020 Nov 3.

Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Purpose: The optimal approach to identify SARS-CoV-2 infection among college students returning to campus is unknown. Recommendations vary from no testing to two tests per student. This research determined the strategy that optimizes the number of true positives and negatives detected and reverse transcription polymerase chain reaction (RT-PCR) tests needed.

Methods: A decision tree analysis evaluated five strategies: (1) classifying students with symptoms as having COVID-19, (2) RT-PCR testing for symptomatic students, (3) RT-PCR testing for all students, (4) RT-PCR testing for all students and retesting symptomatic students with a negative first test, and (5) RT-PCR testing for all students and retesting all students with a negative first test. The number of true positives, true negatives, RT-PCR tests, and RT-PCR tests per true positive (TTP) was calculated.

Results: Strategy 5 detected the most true positives but also required the most tests. The percentage of correctly identified infections was 40.6%, 29.0%, 53.7%, 72.5%, and 86.9% for Strategies 1-5, respectively. All RT-PCR strategies detected more true negatives than the symptom-only strategy. Analysis of TTP demonstrated that the repeat RT-PCR strategies weakly dominated the single RT-PCR strategy and that the thresholds for more intensive RT-PCR testing decreased as the prevalence of infection increased.

Conclusion: Based on TTP, the single RT-PCR strategy is never preferred. If the cost of RT-PCR testing is of concern, a staged approach involving initial testing of all returning students followed by a repeat testing decision based on the measured prevalence of infection might be considered.
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http://dx.doi.org/10.1016/j.jadohealth.2020.09.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606071PMC
January 2021

Development and Validation of a Seizure Prediction Model in Neonates Following Cardiac Surgery.

Ann Thorac Surg 2020 Jul 29. Epub 2020 Jul 29.

Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine.

Background: Electroencephalographic seizures (ES) following neonatal cardiac surgery are often subclinical and have been associated with poor outcomes. An accurate ES prediction model could allow targeted continuous electroencephalographic monitoring (CEEG) for high-risk neonates.

Methods: Development and validation of ES prediction models in a multi-center prospective cohort where all postoperative neonates with cardiopulmonary bypass (CPB) underwent CEEG.

Results: ES occurred in 7.4% of neonates (78 of 1053). Model predictors included gestational age, head circumference, single ventricle defect, DHCA duration, cardiac arrest, nitric oxide, ECMO, and delayed sternal closure. The model performed well in the derivation cohort (c-statistic 0.77, Hosmer-Lemeshow p=0.56), with a net benefit (NB) over monitoring all and none over a threshold probability of 2% in decision curve analysis (DCA). The model had good calibration in the validation cohort (Hosmer-Lemeshow, p=0.60); however, discrimination was poor (c-statistic 0.61) and in DCA there was no NB of the prediction model between the threshold probabilities of 8% and 18%. Using a cut-point that emphasized negative predictive value (NPV) in the derivation cohort, 32% (236 of 737) of neonates would not undergo CEEG, including 3.5% (2 of 58) with ES (NPV 99%, sensitivity 97%).

Conclusions: In this large prospective cohort, a prediction model of ES in neonates following CPB had good performance in the derivation cohort with a NB in DCA. However, performance in the validation cohort was weak with poor discrimination, calibration, and no NB in DCA. These findings support CEEG monitoring of all neonates following CPB.
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http://dx.doi.org/10.1016/j.athoracsur.2020.05.157DOI Listing
July 2020

Testing small study effects in multivariate meta-analysis.

Biometrics 2020 12 29;76(4):1240-1250. Epub 2020 Aug 29.

Department of Biostatistics, Epidemiology & Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Small study effects occur when smaller studies show different, often larger, treatment effects than large ones, which may threaten the validity of systematic reviews and meta-analyses. The most well-known reasons for small study effects include publication bias, outcome reporting bias, and clinical heterogeneity. Methods to account for small study effects in univariate meta-analysis have been extensively studied. However, detecting small study effects in a multivariate meta-analysis setting remains an untouched research area. One of the complications is that different types of selection processes can be involved in the reporting of multivariate outcomes. For example, some studies may be completely unpublished while others may selectively report multiple outcomes. In this paper, we propose a score test as an overall test of small study effects in multivariate meta-analysis. Two detailed case studies are given to demonstrate the advantage of the proposed test over various naive applications of univariate tests in practice. Through simulation studies, the proposed test is found to retain nominal Type I error rates with considerable power in moderate sample size settings. Finally, we also evaluate the concordance between the proposed tests with the naive application of univariate tests by evaluating 44 systematic reviews with multiple outcomes from the Cochrane Database.
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http://dx.doi.org/10.1111/biom.13342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736122PMC
December 2020

COVID-19 Clinical Trials: A Teachable Moment for Improving Our Research Infrastructure and Relevance.

Ann Intern Med 2020 10 16;173(8):652-653. Epub 2020 Jun 16.

Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (E.L.O.).

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http://dx.doi.org/10.7326/M20-2959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322771PMC
October 2020

A population-based study of risk factors for heart failure in pediatric and adult-onset systemic lupus erythematosus.

Semin Arthritis Rheum 2020 08 3;50(4):527-533. Epub 2020 May 3.

Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Center for Pediatric Clinical Effectiveness, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Objectives: The increased relative risk of heart failure (HF) from systemic lupus erythematosus (SLE) is greatest at younger ages, but the etiology remains unclear. We identified risk factors for HF in children and adults with SLE and evaluated associations between SLE manifestations and HF.

Methods: Incident SLE cases without preceding HF were identified using Clinformatics DataMart® (OptumInsight, Eden Prairie, MN) US claims data (2000-2015), and categorized by age of SLE onset (children 5-17, young adults 18-24, adults 25-44 years old). The primary outcome was the first HF ICD-9-CM diagnosis code (428.x), categorized as early-onset (< 6 months) or delayed-onset. Multivariable logistic regression was used to identify factors associated with early or delayed-onset HF. Cox proportional hazards regression was used to identify time-dependent associations between the onset of SLE manifestations and incident HF.

Results: There were 523 (2.3%) HF cases among 1,466 children, 2,163 young adults and 19,349 adults age 25-44 with SLE. HF in children and young adults was early-onset in 50% and 60% of cases, respectively, compared to 35% of cases in adults 25-44 years old. There was a temporal association between incident myopericarditis and valvular disease diagnoses and early-onset HF, whereas nephritis and hypertension were more strongly associated with delayed-onset HF. Black race remained independently associated with a 1.5-fold increased HF risk at any time.

Conclusion: Hypertension remains an important traditional CV risk factor across all ages and should be managed aggressively even in younger patients with SLE. Cardiac dysfunction due to acute cardiac manifestations of SLE may contribute to the very high relative incidence of early HF diagnoses among younger SLE patients. Therefore, future prospective studies will need to address heterogeneity in the types and severity of heart failure in order to determine etiology and which patients should be monitored.
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http://dx.doi.org/10.1016/j.semarthrit.2020.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492402PMC
August 2020

Update to an early investigation of outcomes with the new 2018 donor heart allocation system in the United States.

J Heart Lung Transplant 2020 07 5;39(7):725-726. Epub 2020 Mar 5.

Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1016/j.healun.2020.02.018DOI Listing
July 2020

Trends in Mechanical Support Use as a Bridge to Adult Heart Transplant Under New Allocation Rules.

JAMA Cardiol 2020 06;5(6):728-729

Perelman School of Medicine, Division of Cardiology, University of Pennsylvania, Philadelphia.

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http://dx.doi.org/10.1001/jamacardio.2020.0667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160744PMC
June 2020

Pharmacoepidemiologic Screening of Potential Oral Anticoagulant Drug Interactions Leading to Thromboembolic Events.

Clin Pharmacol Ther 2020 Aug 16;108(2):377-386. Epub 2020 May 16.

Department of Biostatistics, Epidemiology, and Informatics, Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

Drug-drug interactions (DDIs) with oral anticoagulants may lead to under-anticoagulation and increased risk of thromboembolism. Although warfarin is susceptible to numerous DDIs, few studies have examined DDIs resulting in thromboembolism or those involving direct-acting oral anticoagulants (DOACs). We aimed to identify medications that increase the rate of hospitalization for thromboembolic events when taken concomitantly with oral anticoagulants. We conducted a high-throughput pharmacoepidemiologic screening study using Optum Clinformatics Data Mart, 2000-2016. We performed self-controlled case series studies among adult users of oral anticoagulants (warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban) with at least one hospitalization for a thromboembolic event. Among eligible patients, we identified all oral medications frequently co-prescribed with oral anticoagulants as potential interacting precipitants. Conditional Poisson regression was used to estimate rate ratios comparing precipitant exposed vs. unexposed time for each anticoagulant-precipitant pair. To minimize within-person confounding by indication for the precipitant, we used pravastatin as a negative control object drug. Multiple estimation was adjusted using semi-Bayes shrinkage. We screened 1,622 oral anticoagulant-precipitant drug pairs and identified 226 (14%) drug pairs associated with statistically significantly elevated risk of thromboembolism. Using pravastatin as the negative control object drug, this list was reduced to 69 potential DDI signals for thromboembolism, 33 (48%) of which were not documented in the DDI knowledge databases Lexicomp and/or Micromedex. There were more DDI signals associated with warfarin than DOACs. This study reproduced several previously documented oral anticoagulant DDIs and identified potential DDI signals that deserve to be examined in future etiologic studies.
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http://dx.doi.org/10.1002/cpt.1845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765337PMC
August 2020

A behavioral economics-based telehealth intervention to improve aspirin adherence following hospitalization for acute coronary syndrome.

Pharmacoepidemiol Drug Saf 2020 05 31;29(5):513-517. Epub 2020 Mar 31.

Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Purpose: A significant number of patients with acute coronary syndrome (ACS) are nonadherent to aspirin after hospital discharge, with an associated increased risk of subsequent cardiovascular events. The purpose of this pilot study was to test the efficacy of a telehealth intervention based on behavioral economics to improve aspirin adherence following hospitalization for ACS.

Methods: We enrolled 130 participants (c¯X = 58 ± 10.7 years of age, 38% female, 45% black) from two hospitals. Patients were eligible if they owned a smartphone and were admitted to the hospital for ACS, prescribed aspirin at discharge, and responsible for administering their own medications. Consenting participants were randomized to the intervention or usual care group. The intervention group was eligible to receive up to $50 per month if they took their medicine daily, with $2 per day deducted if a dose was missed. All participants received an electronic monitoring (EM) pill bottle containing a 90-day supply of aspirin, which was used to measure adherence calculated as the proportion of prescribed drug taken using the EM device. Based on the skewness in the adherence distribution, quantile regression was used to evaluate the effect of the intervention on median adherence over time.

Results: After 90 days, adherence fell in the control group but remained high in the intervention group (median adherence 81% vs 90%, P = .18). Rehospitalization was higher in the control group (24% vs 13%, P = .17).

Conclusion: A loss aversion behavioral economics-based telehealth intervention is a promising approach to improving aspirin adherence following hospitalization for ACS.
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http://dx.doi.org/10.1002/pds.4988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217735PMC
May 2020

The risk of sudden cardiac arrest and ventricular arrhythmia with rosiglitazone versus pioglitazone: real-world evidence on thiazolidinedione safety.

Cardiovasc Diabetol 2020 02 25;19(1):25. Epub 2020 Feb 25.

Center for Pharmacoepidemiology Research and Training, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, 423 Guardian Drive, Philadelphia, PA, 19104, USA.

Background: The low cost of thiazolidinediones makes them a potentially valuable therapeutic option for the > 300 million economically disadvantaged persons worldwide with type 2 diabetes mellitus. Differential selectivity of thiazolidinediones for peroxisome proliferator-activated receptors in the myocardium may lead to disparate arrhythmogenic effects. We examined real-world effects of thiazolidinediones on outpatient-originating sudden cardiac arrest (SCA) and ventricular arrhythmia (VA).

Methods: We conducted population-based high-dimensional propensity score-matched cohort studies in five Medicaid programs (California, Florida, New York, Ohio, Pennsylvania | 1999-2012) and a commercial health insurance plan (Optum Clinformatics | 2000-2016). We defined exposure based on incident rosiglitazone or pioglitazone dispensings; the latter served as an active comparator. We controlled for confounding by matching exposure groups on propensity score, informed by baseline covariates identified via a data adaptive approach. We ascertained SCA/VA outcomes precipitating hospital presentation using a validated, diagnosis-based algorithm. We generated marginal hazard ratios (HRs) via Cox proportional hazards regression that accounted for clustering within matched pairs. We prespecified Medicaid and Optum findings as primary and secondary, respectively; the latter served as a conceptual replication dataset.

Results: The adjusted HR for SCA/VA among rosiglitazone (vs. pioglitazone) users was 0.91 (0.75-1.10) in Medicaid and 0.88 (0.61-1.28) in Optum. Among Medicaid but not Optum enrollees, we found treatment effect heterogeneity by sex (adjusted HRs = 0.71 [0.54-0.93] and 1.16 [0.89-1.52] in men and women respectively, interaction term p-value = 0.01).

Conclusions: Rosiglitazone and pioglitazone appear to be associated with similar risks of SCA/VA.
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http://dx.doi.org/10.1186/s12933-020-00999-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041286PMC
February 2020

The Galaxy Plot: A New Visualization Tool for Bivariate Meta-Analysis Studies.

Am J Epidemiol 2020 08;189(8):861-869

Funnel plots have been widely used to detect small-study effects in the results of univariate meta-analyses. However, there is no existing visualization tool that is the counterpart of the funnel plot in the multivariate setting. We propose a new visualization method, the galaxy plot, which can simultaneously present the effect sizes of bivariate outcomes and their standard errors in a 2-dimensional space. We illustrate the use of the galaxy plot with 2 case studies, including a meta-analysis of hypertension trials with studies from 1979-1991 (Hypertension. 2005;45(5):907-913) and a meta-analysis of structured telephone support or noninvasive telemonitoring with studies from 1966-2015 (Heart. 2017;103(4):255-257). The galaxy plot is an intuitive visualization tool that can aid in interpreting results of multivariate meta-analysis. It preserves all of the information presented by separate funnel plots for each outcome while elucidating more complex features that may only be revealed by examining the joint distribution of the bivariate outcomes.
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http://dx.doi.org/10.1093/aje/kwz286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438574PMC
August 2020

Genetic Factors Influencing Warfarin Dose in Black-African Patients: A Systematic Review and Meta-Analysis.

Clin Pharmacol Ther 2020 06 28;107(6):1420-1433. Epub 2020 Jan 28.

Department of Molecular and Clinical Pharmacology, The Wolfson Centre for Personalized Medicine, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.

Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high interindividual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in black-Africans, we performed a meta-analysis of 48 studies (2,336 patients). Significant predictors for CYP2C9 and stable dose included rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), rs28371686 (CYP2C9*5), rs9332131 (CYP2C9*6), and rs28371685 (CYP2C9*11) reducing dose by 6.8, 12.5, 13.4, 8.1, and 5.3 mg/week, respectively. VKORC1 variants rs9923231 (-1639G>A), rs9934438 (1173C>T), rs2359612 (2255C>T), rs8050894 (1542G>C), and rs2884737 (497T>G) decreased dose by 18.1, 21.6, 17.3, 11.7, and 19.6 mg/week, respectively, whereas rs7294 (3730G>A) increased dose by 6.9 mg/week. Finally, rs12777823 (CYP2C gene cluster) was associated with a dose reduction of 12.7 mg/week. Few studies were conducted in Africa, and patient numbers were small, highlighting the need for further work in black-Africans to evaluate genetic factors determining warfarin response.
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http://dx.doi.org/10.1002/cpt.1755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217737PMC
June 2020

Predictive risk stratification using HEART (history, electrocardiogram, age, risk factors, and initial troponin) and TIMI (thrombolysis in myocardial infarction) scores in non-high risk chest pain patients: An African American urban community based hospital study.

Medicine (Baltimore) 2019 Aug;98(32):e16370

Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania.

Validated risk scoring systems in African American (AA) population are under studied. We utilized history, electrocardiogram, age, risk factors, and initial troponin (HEART) and thrombolysis in myocardial infarction (TIMI) scores to predict major adverse cardiovascular events (MACE) in non-high cardiovascular (CV) risk predominantly AA patient population.A retrospective emergency department (ED) charts review of 1266 chest pain patients where HEART and TIMI scores were calculated for each patient. Logistic regression model was computed to predict 6-week and 1-year MACE and 90-day cardiac readmission. Decision curve analysis (DCA) was constructed to differentiate between clinical strategies in non-high CV risk patients.Of the 817 patients included, 500 patients had low HEART score vs. 317 patients who had moderate HEART score. Six hundred sixty-three patients had low TIMI score vs. 154 patients had high TIMI score. The univariate logistic regression model shows odds ratio of predicting 6-week MACE using HEART score was 3.11 (95% confidence interval [CI] 1.43-6.76, P = .004) with increase in risk category from low to moderate vs. 2.07 (95% CI 1.18-3.63, P = .011) using TIMI score with increase in risk category from low to high and c-statistic of 0.86 vs. 0.79, respectively. DCA showed net benefit of using HEART score is equally predictive of 6-week MACE when compared to TIMI.In non-high CV risk AA patients, HEART score is better predictive tool for 6-week MACE when compared to TIMI score. Furthermore, patients presenting to ED with chest pain, the optimal strategy for a 2% to 4% miss rate threshold probability should be to discharge these patients from the ED.
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http://dx.doi.org/10.1097/MD.0000000000016370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708799PMC
August 2019

Development and Initial Validation of the PROMIS®-Plus-HF Profile Measure.

Circ Heart Fail 2019 06 5;12(6):e005751. Epub 2019 Jun 5.

Department of Medical Social Sciences (M.A.K., S.E.Y., D.C.), Northwestern University Feinberg School of Medicine, Chicago, IL.

Background Bringing together generic and heart failure (HF)-specific items in a publicly available, patient-reported outcome measure may facilitate routine health status assessment for improving clinical care and shared decision-making, assessing quality of care, evaluating new interventions, and comparing groups with different conditions. Methods and Results We performed a mixed-methods study to develop and validate the PROMIS®-Plus-HF (Patient-Reported Outcomes Measurement Information System®-Plus-Heart Failure) profile measure-a HF-specific instrument based on the generic PROMIS. We conducted 8 focus groups with 61 patients with HF and phone interviews with 10 HF clinicians. The measure was developed via an iterative process of reviewing existing PROMIS items and developing and testing new HF items. In a 600-patient sample, we estimated reliability (internal consistency; test-retest, with n=100 participants). We conducted validity analyses using Pearson r and Spearman ρ correlations with Kansas City Cardiomyopathy Questionnaire subscores. In a longitudinal sample, we performed responsiveness testing (paired t tests) with 75 patients with HF receiving interventions with expected health status improvement. The PROMIS-Plus-HF measure comprises 86 items (64 existing; 22 new) across 18 domains. Internal consistency reliability (Cronbach α) coefficients ranged from 0.52 to 0.96, with α≥0.70 in 12 of 17 domains. Test-retest intraclass correlation coefficients were ≥0.90. Correlations with Kansas City Cardiomyopathy Questionnaire subscores supported expected convergent ( r/ρ>0.60) and divergent validity ( r/ρ<0.30). In the longitudinal sample, 10 of 18 domains had improved ( P<0.05) scores from baseline to follow-up. Conclusions The PROMIS-Plus-HF profile measure-a complete assessment of physical, mental, and social health-exhibited good psychometric characteristics and may facilitate patient-centered care and research. Subsets of domains and items can be used depending on the clinical or research purpose.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.118.005751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711378PMC
June 2019

Qualitative study of system-level factors related to genomic implementation.

Genet Med 2019 07 23;21(7):1534-1540. Epub 2018 Nov 23.

Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, USA.

Purpose: Research on genomic medicine integration has focused on applications at the individual level, with less attention paid to implementation within clinical settings. Therefore, we conducted a qualitative study using the Consolidated Framework for Implementation Research (CFIR) to identify system-level factors that played a role in implementation of genomic medicine within Implementing GeNomics In PracTicE (IGNITE) Network projects.

Methods: Up to four study personnel, including principal investigators and study coordinators from each of six IGNITE projects, were interviewed using a semistructured interview guide that asked interviewees to describe study site(s), progress at each site, and factors facilitating or impeding project implementation. Interviews were coded following CFIR inner-setting constructs.

Results: Key barriers included (1) limitations in integrating genomic data and clinical decision support tools into electronic health records, (2) physician reluctance toward genomic research participation and clinical implementation due to a limited evidence base, (3) inadequate reimbursement for genomic medicine, (4) communication among and between investigators and clinicians, and (5) lack of clinical and leadership engagement.

Conclusion: Implementation of genomic medicine is hindered by several system-level barriers to both research and practice. Addressing these barriers may serve as important facilitators for studying and implementing genomics in practice.
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http://dx.doi.org/10.1038/s41436-018-0378-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533158PMC
July 2019

Heart Failure Home Management Challenges and Reasons for Readmission: a Qualitative Study to Understand the Patient's Perspective.

J Gen Intern Med 2018 10 10;33(10):1700-1707. Epub 2018 Jul 10.

Perelman School of Medicine, University of Pennsylvania, 923 Blockley Hall, 423 Guardian Drive, Philadelphia, PA, 19104, USA.

Background: Heart failure patients have high 30-day hospital readmission rates. Interventions designed to prevent readmissions have had mixed success. Understanding heart failure home management through the patient's experience may reframe the readmission "problem" and, ultimately, inform alternative strategies.

Objective: To understand patient and caregiver challenges to heart failure home management and perceived reasons for readmission.

Design: Observational qualitative study.

Participants: Heart failure patients were recruited from two hospitals and included those who were hospitalized for heart failure at least twice within 30 days and those who had been recently discharged after their first heart failure admission.

Approach: Open-ended, semi-structured interviews. Conclusions vetted using focus groups.

Key Results: Semi-structured interviews with 31 patients revealed a combination of physical and socio-emotional influences on patients' home heart failure management. Major themes identified were home management as a struggle between adherence and adaptation, and hospital readmission as a rational choice in response to distressing symptoms. Patients identified uncertainty regarding recommendations, caused by unclear instructions and temporal incongruence between behavior and symptom onset. This uncertainty impaired their competence in making routine management decisions, resulting in a cycle of limit testing and decreasing adherence. Patients reported experiencing hopelessness and frustration in response to perceiving a deteriorating functional status. This led some to a cycle of despair characterized by worsening adherence and negative emotions. As these cycles progressed and distressing symptoms worsened, patients viewed the hospital as the safest place for recovery and not a "negative" outcome.

Conclusion: Cycles of limit testing and despair represent important patient-centered struggles in managing heart failure. The resulting distress and fear make readmission a rational choice for patients rather than a negative outcome. Interventions (e.g., palliative care) that focus on methods to address these patient-centered factors should be further studied rather than methods to reduce hospital readmissions.
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http://dx.doi.org/10.1007/s11606-018-4542-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153210PMC
October 2018

Incorporating patient-centered factors into heart failure readmission risk prediction: A mixed-methods study.

Am Heart J 2018 06 9;200:75-82. Epub 2018 Mar 9.

University of Pennsylvania, Philadelphia, PA. Electronic address:

Background: Capturing and incorporating patient-centered factors into 30-day readmission risk prediction after hospitalized heart failure (HF) could improve the modest performance of current models.

Methods: Using a mixed-methods approach, we developed a patient-centered survey and evaluated the additional predictive utility of the survey compared to a traditional readmission risk model (the Krumholz et al. model). Area under the receiver operating characteristic curve (AUC) and the Hosmer-Lemeshow goodness-of-fit statistic quantified the performance of both models. We measured the amount of model improvement with the addition of patient-centered factors to the Krumholz et al. model with the integrated discrimination improvement (IDI). In an exploratory analysis, we used hierarchical clustering algorithms to identify groups with similar survey responses and tested for differences between clusters using standard descriptive statistics.

Results: From 3/24/2014 to 3/12/2015, 183 patients hospitalized with HF were enrolled from an urban, academic health system and followed for 30days after discharge. The Krumholz et al. plus patient-centered factors model had similar-to-slightly lower performance (AUC [95%CI]:0.62 [0.52, 0.71]; goodness-of-fit P=.10) than the Krumholz et al. model (AUC [95%CI]:0.66 [0.57, 0.76]; goodness-of-fit P=.19). The IDI (95%CI) was 0.003 (-0.014,0.020). We identified three patient clusters based on patient-centered survey responses. The clusters differed with respect to gender, self-rated health, employment status, and prior hospitalization frequency (all P<.05).

Conclusions: The addition of patient-centered factors did not improve 30-day readmission model performance. Rather than designing interventions based on predicted readmission risk, tailoring interventions to all patients, based on their characteristics, could inform the design of targeted, readmission reduction strategies.
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http://dx.doi.org/10.1016/j.ahj.2018.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004826PMC
June 2018

Palliative care: Is now the time?

Eur J Cardiovasc Nurs 2018 08 2;17(6):474-476. Epub 2018 Jan 2.

2 Perelman School of Medicine, University of Pennsylvania, USA.

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http://dx.doi.org/10.1177/1474515117751905DOI Listing
August 2018

Thromboembolic and neurologic sequelae of discontinuation of an antihyperlipidemic drug during ongoing warfarin therapy.

Sci Rep 2017 12 21;7(1):18037. Epub 2017 Dec 21.

Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Warfarin and antihyperlipidemics are commonly co-prescribed. Some antihyperlipidemics may inhibit warfarin deactivation via the hepatic cytochrome P450 system. Therefore, antihyperlipidemic discontinuation has been hypothesized to result in underanticoagulation, as warfarin metabolism is no longer inhibited. We quantified the risk of venous thromboembolism (VTE) and ischemic stroke (IS) due to statin and fibrate discontinuation in warfarin users, in which warfarin was initially dose-titrated during ongoing antihyperlipidemic therapy. Using 1999-2011 United States Medicaid claims among 69 million beneficiaries, we conducted a set of bidirectional self-controlled case series studies-one for each antihyperlipidemic. Outcomes were hospital admissions for VTE/IS. The risk segment was a maximum of 90 days immediately following antihyperlipidemic discontinuation, the exposure of interest. Time-varying confounders were included in conditional Poisson models. We identified 629 study eligible-persons with at least one outcome. Adjusted incidence rate ratios (IRRs) for all antihyperlipidemics studied were consistent with the null, and ranged from 0.21 (0.02, 2.82) for rosuvastatin to 2.16 (0.06, 75.0) for gemfibrozil. Despite using an underlying dataset of millions of persons, we had little precision in estimating IRRs for VTE/IS among warfarin-treated persons discontinuing individual antihyperlipidemics. Further research should investigate whether discontinuation of gemfibrozil in warfarin users results in serious underanticoagulation.
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http://dx.doi.org/10.1038/s41598-017-18318-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740131PMC
December 2017

Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

JACC Cardiovasc Interv 2018 01 1;11(2):181-191. Epub 2017 Nov 1.

Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, Florida; Department of Medicine, Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida.

Objectives: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI).

Background: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI.

Methods: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights.

Results: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60).

Conclusions: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.
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http://dx.doi.org/10.1016/j.jcin.2017.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775044PMC
January 2018

Palliative Care in Heart Failure: Rationale, Evidence, and Future Priorities.

J Am Coll Cardiol 2017 Oct;70(15):1919-1930

Department of Medicine, Division of General Internal Medicine, Section of Palliative Care and Medical Ethics, University of Pittsburgh, Pittsburgh, Pennsylvania.

Patients with heart failure (HF) and their families experience stress and suffering from a variety of sources over the course of the HF experience. Palliative care is an interdisciplinary service and an overall approach to care that improves quality of life and alleviates suffering for those living with serious illness, regardless of prognosis. In this review, we synthesize the evidence from randomized clinical trials of palliative care interventions in HF. While the evidence base for palliative care in HF is promising, it is still in its infancy and requires additional high-quality, methodologically sound studies to clearly elucidate the role of palliative care for patients and families living with the burdens of HF. Yet, an increase in attention to primary palliative care (e.g., basic physical and emotional symptom management, advance care planning), provided by primary care and cardiology clinicians, may be a vehicle to address unmet palliative needs earlier and throughout the illness course.
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http://dx.doi.org/10.1016/j.jacc.2017.08.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731659PMC
October 2017

Developing a common framework for evaluating the implementation of genomic medicine interventions in clinical care: the IGNITE Network's Common Measures Working Group.

Genet Med 2018 06 14;20(6):655-663. Epub 2017 Sep 14.

Implementation Pathways, LLC, Ann Arbor, Michigan, USA.

PurposeImplementation research provides a structure for evaluating the clinical integration of genomic medicine interventions. This paper describes the Implementing Genomics in Practice (IGNITE) Network's efforts to promote (i) a broader understanding of genomic medicine implementation research and (ii) the sharing of knowledge generated in the network.MethodsTo facilitate this goal, the IGNITE Network Common Measures Working Group (CMG) members adopted the Consolidated Framework for Implementation Research (CFIR) to guide its approach to identifying constructs and measures relevant to evaluating genomic medicine as a whole, standardizing data collection across projects, and combining data in a centralized resource for cross-network analyses.ResultsCMG identified 10 high-priority CFIR constructs as important for genomic medicine. Of those, eight did not have standardized measurement instruments. Therefore, we developed four survey tools to address this gap. In addition, we identified seven high-priority constructs related to patients, families, and communities that did not map to CFIR constructs. Both sets of constructs were combined to create a draft genomic medicine implementation model.ConclusionWe developed processes to identify constructs deemed valuable for genomic medicine implementation and codified them in a model. These resources are freely available to facilitate knowledge generation and sharing across the field.
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http://dx.doi.org/10.1038/gim.2017.144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851794PMC
June 2018

Postauthorization safety study of the DPP-4 inhibitor saxagliptin: a large-scale multinational family of cohort studies of five outcomes.

BMJ Open Diabetes Res Care 2017 31;5(1):e000400. Epub 2017 Jul 31.

Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Objective: To evaluate the risk of serious adverse events among patients with type 2 diabetes mellitus initiating saxagliptin compared with oral antidiabetic drugs (OADs) in classes other than dipeptidyl peptidase-4 (DPP-4) inhibitors.

Research Design And Methods: Cohort studies using 2009-2014 data from two UK medical record data sources (Clinical Practice Research Datalink, The Health Improvement Network) and two USA claims-based data sources (HealthCore Integrated Research Database, Medicare). All eligible adult patients newly prescribed saxagliptin (n=110 740) and random samples of up to 10 matched initiators of non-DPP-4 inhibitor OADs within each data source were selected (n=913 384). Outcomes were hospitalized major adverse cardiovascular events (MACE), acute kidney injury (AKI), acute liver failure (ALF), infections, and severe hypersensitivity events, evaluated using diagnostic coding algorithms and medical records. Cox regression was used to determine HRs with 95% CIs for each outcome. Meta-analyses across data sources were performed for each outcome as feasible.

Results: There were no increased incidence rates or risk of MACE, AKI, ALF, infection, or severe hypersensitivity reactions among saxagliptin initiators compared with other OAD initiators within any data source. Meta-analyses demonstrated a reduced risk of hospitalization/death from MACE (HR 0.91, 95% CI 0.85 to 0.97) and no increased risk of hospitalization for infection (HR 0.97, 95% CI 0.93 to 1.02) or AKI (HR 0.99, 95% CI 0.88 to 1.11) associated with saxagliptin initiation. ALF and hypersensitivity events were too rare to permit meta-analysis.

Conclusions: Saxagliptin initiation was not associated with increased risk of MACE, infection, AKI, ALF, or severe hypersensitivity reactions in clinical practice settings.

Trial Registration Number: NCT01086280, NCT01086293, NCT01086319, NCT01086306, and NCT01377935; Results.
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http://dx.doi.org/10.1136/bmjdrc-2017-000400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574452PMC
July 2017

Influence of common and rare genetic variation on warfarin dose among African-Americans and European-Americans using the exome array.

Pharmacogenomics 2017 Jul 7;18(11):1059-1073. Epub 2017 Jul 7.

Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Aim: We conducted a genome-wide association study using the Illumina Exome Array to identify coding SNPs that may explain additional warfarin dose variability.

Patients & Methods: Analysis was performed after adjustment for clinical variables and genetic factors known to influence warfarin dose among 1680 warfarin users (838 European-Americans and 842 African-Americans). Replication was performed in an independent sample.

Results: We confirmed the influence of known genetic variants on warfarin dose variability. Our study is the first to show the association between rs12772169 and warfarin dose in African-Americans. In addition, genes COX15 and FGF5 showed significant association in European-Americans.

Conclusion: We identified some novel genes/SNPs that underpin warfarin dose response. Further replication is needed to confirm our findings.
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http://dx.doi.org/10.2217/pgs-2017-0046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619051PMC
July 2017

Association Between Patient-Reported Medication Adherence and Anticoagulation Control.

Am J Med 2017 09 26;130(9):1092-1098.e2. Epub 2017 Apr 26.

Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Center for Clinical Epidemiology and Biostatistics, Philadelphia, Penn; Center for Therapeutic Effectiveness Research, Philadelphia, Penn. Electronic address:

Background: The prevention of thromboembolism events remains challenging in cases of poor medication adherence. Unfortunately, clinical prediction of future adherence has been suboptimal. The objective of this study was to examine the correlation between 2 measures of real-time, self-reported adherence and anticoagulation control.

Methods: The IN-RANGE2 cohort recruited patients initiating warfarin therapy in 3 urban anticoagulation clinics. At each study visit, participants reported adherence using a 100-point visual analogue scale (VAS, marking percentage of pills taken since prior visit on a linear scale) and 7-day recall of pill-taking behavior. Anticoagulation control was measured by between-visit percent time in international normalized ratio range (BVTR), dichotomized at the cohort median. The longitudinal association between adherence and anticoagulation control was estimated using generalized estimating equations, controlling for clinical and demographic characteristics, prior BVTR, and warfarin dose changes.

Results: Among 598 participants with 3204 (median 4) visits, the median BVTR was 36.8% (interquartile range 0%-73.9%). Participants reported ≤80% adherence in 182 visits (5.7%) and missed pills in the past 7 days in 377 visits (11.8%). Multivariable regression analysis found poorer anticoagulation control (BVTR <36.8%) in those with a VAS ≤80% (odds ratio 1.89; 95% confidence interval, 1.12-3.18; P = .02) and self-reported change in adherence since last visit (odds ratio 1.55; 95% confidence interval, 1.20-2.01; P = .001).

Conclusion: Self-reported VAS medication adherence at a clinic visit and changes in reported adherence since the last visit are independently associated with BVTR. Clinicians may gain additional insight into patients' medication adherence by incorporating this information into patient management.
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http://dx.doi.org/10.1016/j.amjmed.2017.03.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572106PMC
September 2017

Gastrointestinal bleeding and intracranial hemorrhage in concomitant users of warfarin and antihyperlipidemics.

Int J Cardiol 2017 Feb 12;228:761-770. Epub 2016 Nov 12.

Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Center for Pharmacoepidemiology Research and Training, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Background: Drug interactions, particularly those involving warfarin, are a major clinical and public health problem. Minimizing serious bleeding caused by anticoagulants is a recent major focus of the United States (US) Department of Health and Human Services. This study quantified the risk of gastrointestinal bleeding (GIB) and intracranial hemorrhage (ICH) among concomitant users of warfarin and individual antihyperlipidemics.

Methods: The authors conducted a high-dimensional propensity score-adjusted cohort study of new concomitant users of warfarin and an antihyperlipidemic, among US Medicaid beneficiaries from five states during 1999-2011. Exposure was defined by concomitant use of warfarin plus one of eight antihyperlipidemics. The primary outcome measure was a composite of GIB/ICH within the first 30days of concomitant use. As a secondary outcome measure, GIB/ICH was examined within the first 180days of concomitant use.

Results: Among 236,691 persons newly-exposed to warfarin and an antihyperlipidemic, the crude incidence of GIB/ICH was 13.2 (95% confidence interval 12.7 to 13.8) per 100person-years. Users were predominantly older, female, and Caucasian. Adjusted hazard ratios (aHRs) for warfarin and individual statins were consistent with no association. Warfarin+gemfibrozil was associated with an 80% increased risk of GIB/ICH within the first month of concomitant use (aHR=1.8, 1.4 to 2.4). Warfarin+fenofibrate was associated with a similar increased risk (aHR=1.8, 1.2 to 2.7), yet with an onset during the second month of concomitant use.

Conclusions: Among warfarin-treated persons, the use of fibrates-but not statins-increases the risk of hospital presentation for GIB/ICH.
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http://dx.doi.org/10.1016/j.ijcard.2016.11.245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203951PMC
February 2017

A randomized trial of lottery-based incentives and reminders to improve warfarin adherence: the Warfarin Incentives (WIN2) Trial.

Pharmacoepidemiol Drug Saf 2016 11 4;25(11):1219-1227. Epub 2016 Sep 4.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: Previous research has suggested that daily lottery incentives could improve medication adherence. Such daily incentives include implicit reminders. However, the comparative effectiveness of reminders alone versus daily incentives has not been tested.

Methods: A total of 270 patients on warfarin were enrolled in a four-arm, multi-center, randomized controlled trial comparing a daily lottery-based incentive, a daily reminder, and a combination of the two against a control group (usual care).

Results: Participants in the reminder group had the lowest percentage of time out of target international normalized ratio (INR) range, the primary outcome, with an adjusted odds of an out-of-range INR 36% lower than among those in the control group, 95%CI [7%, 55%]. No other group had a statistically significant improvement in anticoagulation control relative to the control group or to each other. The only group that had significant improvement in incorrect adherence was the lottery group (incorrect adherence: 12.1% compared with 23.7% in the control group, difference of -7.4% 95%CI [-14%, -0.3%]). However, there was no relationship between changes in adherence and anticoagulation control in the lottery group.

Conclusions: Automated reminders led to the largest improvements in anticoagulation control, although without impacting measured adherence. Lottery-based reminders improved measured adherence but did not lead to improved anticoagulation control. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/pds.4094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093038PMC
November 2016

Predicting prolonged dose titration in patients starting warfarin.

Pharmacoepidemiol Drug Saf 2016 11 26;25(11):1228-1235. Epub 2016 Jul 26.

Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Purpose: Patients initiating warfarin therapy generally experience a dose-titration period of weeks to months, during which time they are at higher risk of both thromboembolic and bleeding events. Accurate prediction of prolonged dose titration could help clinicians determine which patients might be better treated by alternative anticoagulants that, while more costly, do not require dose titration.

Methods: A prediction model was derived in a prospective cohort of patients starting warfarin (n = 390), using Cox regression, and validated in an external cohort (n = 663) from a later time period. Prolonged dose titration was defined as a dose-titration period >12 weeks. Predictor variables were selected using a modified best subsets algorithm, using leave-one-out cross-validation to reduce overfitting.

Results: The final model had five variables: warfarin indication, insurance status, number of doctor's visits in the previous year, smoking status, and heart failure. The area under the ROC curve (AUC) in the derivation cohort was 0.66 (95%CI 0.60, 0.74) using leave-one-out cross-validation, but only 0.59 (95%CI 0.54, 0.64) in the external validation cohort, and varied across clinics. Including genetic factors in the model did not improve the area under the ROC curve (0.59; 95%CI 0.54, 0.65). Relative utility curves indicated that the model was unlikely to provide a clinically meaningful benefit compared with no prediction.

Conclusions: Our results suggest that prolonged dose titration cannot be accurately predicted in warfarin patients using traditional clinical, social, and genetic predictors, and that accurate prediction will need to accommodate heterogeneities across clinical sites and over time. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/pds.4069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093054PMC
November 2016