Fang Niu

Association of Testosterone Replacement With Cardiovascular Outcomes Among Men With Androgen Deficiency

Importance Controversy exists regarding the safety of testosterone replacement therapy (TRT) following recent reports of an increased risk of adverse cardiovascular events. Objective To investigate the association between TRT and cardiovascular outcomes in men with androgen deficiency. Design, Setting, and Participants A retrospective cohort study was conducted within an integrated health care delivery system. Men at least 40 years old with evidence of androgen deficiency either by a coded diagnosis and/or a morning serum total testosterone level of less than 300 ng/dL were included. The eligibility window was January 1, 1999, to December 31, 2010, with follow-up through December 31, 2012. Exposures Any prescribed TRT given by injection, orally, or topically. Main Outcomes and Measures The primary outcome was a composite of cardiovascular end points that included acute myocardial infarction (AMI), coronary revascularization, unstable angina, stroke, transient ischemic attack (TIA), and sudden cardiac death (SCD). Multivariable Cox proportional hazards models were used to investigate the association between TRT and cardiovascular outcomes. An inverse probability of treatment weight, propensity score methodology, was used to balance baseline characteristics. Results The cohorts consisted of 8808 men (19.8%) ever dispensed testosterone (ever-TRT) (mean age, 58.4 years; 1.4% with prior cardiovascular events) and 35u2009527 men (80.2%) never dispensed testosterone (never-TRT) (mean age, 59.8 years; 2.0% with prior cardiovascular events). Median follow was 3.2 years (interquartile range [IQR], 1.7-6.6 years) in the never-TRT group vs 4.2 (IQR, 2.1-7.8) years in the ever-TRT group. The rates of the composite cardiovascular end point were 23.9 vs 16.9 per 1000 person-years in the never-TRT and ever-TRT groups, respectively. The adjusted hazard ratio (HR) for the composite cardiovascular end point in the ever-TRT group was 0.67 (95% CI, 0.62-0.73. Similar results were seen when the outcome was restricted to combined stroke events (stroke and TIA) (HR, 0.72; 95% CI, 0.62-0.84) and combined cardiac events (AMI, SCD, unstable angina, revascularization procedures) (HR, 0.66; 95% CI, 0.60-0.72). Conclusions and Relevance Among men with androgen deficiency, dispensed testosterone prescriptions were associated with a lower risk of cardiovascular outcomes over a median follow-up of 3.4 years.

Stroke and Bleeding Risk Associated With Antithrombotic Therapy for Patients With Nonvalvular Atrial Fibrillation in Clinical Practice

Background The quality of antithrombotic therapy for patients with nonvalvular atrial fibrillation during routine medical care is often suboptimal. Evidence linking stroke and bleeding risk with antithrombotic treatment is limited. The purpose of this study was to evaluate the associations between antithrombotic treatment episodes and outcomes. Methods and Results A retrospective longitudinal observational cohort study was conducted using patients newly diagnosed with nonvalvular atrial fibrillation with 1 or more stroke risk factors (CHADS2 ≥1) in Kaiser Permanente Southern California between January 1, 2006 and December 31, 2011. A total of 1782 stroke and systemic embolism (SE) and 3528 major bleed events were identified from 23 297 patients during the 60 021 person-years of follow-up. The lowest stroke/SE rates and major bleed rates were observed in warfarin time in therapeutic range (TTR) ≥55% episodes (stroke/SE: 0.87 [0.71 to 1.04]; major bleed: 4.91 [4.53 to 5.28] per 100 person-years), which was similar to the bleed rate in aspirin episodes (4.95 [4.58 to 5.32] per 100 person-years). The warfarin TTR ≥55% episodes were associated with a 77% lower risk of stroke/SE (relative risk=0.23 [0.18 to 0.28]) compared to never on therapy; and the warfarin TTR <55% and on-aspirin episodes were associated with a 20% lower and with a 26% lower risk of stroke/SE compared to never on therapy, respectively. The warfarin TTR <55% episodes were associated with nearly double the risk of a major bleed compared to never on therapy (relative risk=1.93 [1.74 to 2.14]). Conclusions Continuation of antithrombotic therapy as well as maintaining an adequate level of TTR is beneficial to prevent strokes while minimizing bleeding events.

Warfarin Management and Outcomes in Patients with Nonvalvular Atrial Fibrillation Within an Integrated Health Care System

BACKGROUNDnWarfarin is a common treatment option to manage patients with nonvalvular atrial fibrillation (NVAF) in clinical practice. Understanding current pharmacist-led anticoagulation clinic management patterns and associated outcomes is important for quality improvement; however, currently little evidence associating outcomes with management patterns exists.nnnOBJECTIVESnTo (a) describe warfarin management patterns and (b) evaluate associations between warfarin treatment and clinical outcomes for patients with NVAF in an integrated health care system.nnnMETHODSnA retrospective cohort study was conducted among NVAF patients with warfarin therapy between January 1, 2006, and December 31, 2011, using Kaiser Permanente Southern California data, and followed until December 31, 2013. Management patterns related to international normalized ratio (INR) monitoring, anticoagulation clinic pharmacist intervention (consultation), and warfarin dose adjustments were investigated along with yearly attrition rates, time-in-therapeutic ranges (TTRs), and clinical outcomes (stroke or systemic embolism and major bleeding). Descriptive statistics and multivariable Cox proportional hazard models were used to determine associations between TTR and clinical outcomes.nnnRESULTSnA total of 32,074 NVAF patients on warfarin treatment were identified and followed for a median of 3.8 years. About half (49%) of the patients were newly initiating warfarin therapy. INR monitoring and pharmacist interventions were conducted roughly every 3 weeks after 6 months of warfarin treatment. Sixty-three percent of the study population had ≥ 1 warfarin dose adjustments with a mean (SD) of 6.7 (6.3) annual dose adjustments. Warfarin dose adjustments occurred at a median of 1 day (interquartile ranges [IQR] 1-3) after the INR measurement. Yearly attrition rate was from 3.3% to 6.3% during the follow-up, and median (IQR) TTR was 61% (46%-73%). Patients who received frequent INR monitoring (≥ 27 times per year), pharmacist interventions (≥ 24 times per year), or frequently adjusted warfarin dose (≥ 11 times per year) consistently showed poor TTRs (mean TTR for the highest quartiles was 45.3%-48.3%). A higher TTR was associated with a lower risk of clinical outcomes regardless of frequency of INR monitoring, pharmacist interventions, or number of dose adjustments. Patients whose TTRs were < 65%, even with frequent pharmacist interventions, had similar stroke or systemic embolism event rates, as compared with patients with TTRs < 65% and less frequent interventions (1.88 vs. 1.54 stroke or systemic embolism rates per 100 person-years, respectively, P = 0.78). The lowest TTR quartile (< 46%) was associated with a 3 times higher risk of stroke or systemic embolism (hazard ratio [HR] = 3.19, 95% CI = 2.71-3.77) and a 2 times higher risk of major bleeding (HR = 2.10, 95% CI = 1.96-2.24) compared with the highest TTR quartile (≥ 73%).nnnCONCLUSIONSnDespite close monitoring with timely warfarin dose adjustments, there were still a substantial number of challenging patients whose TTRs were suboptimal despite a higher number of pharmacist interventions. These patients eventually experienced more stroke or systemic embolism and bleeding events among NVAF patients managed by anticoagulation clinics. New individualized treatment or management strategies for patients who are not able to reach optimal therapeutic ranges are necessary to improve outcomes.nnnDISCLOSURESnThis research and manuscript were funded by Bristol-Myers Squibb Company and Pfizer. Authors from Bristol-Myers Squibb Company and Pfizer participated in the design of the study, interpretation of the data, review/revision of the manuscript, and approval of the final version of the manuscript. An received a grant for research support from Bristol-Myers Squibb/Pfizer. Niu, Rashid, and Zheng received a grant from Bristol-Myers Squibb/Pfizer to their institutions for salary reimbursement. Vo, Singh, and Aranda are employed by Bristol-Myers Squibb; Bruno was employed by Bristol-Myers Squibb at the time of this study. Mendes and Dills are employed by Pfizer, and Mendes was a member of the Pfizer Cardiovascular and Metabolic Field Medical Team during the time of this study. Lang, Jazdzewski, and Le have no known conflicts of interest to report. Study concept and design were contributed primarily by An and Rashid, along with the other authors. Niu took the lead in data collection, along with Zheng, and data interpretation was performed by An, along with Mendes and Dills, with assistance from the other authors. The manuscript was written by An and revised by Mendes, Dills, Vo, Singh, Bruno, and Aranda, along with Lang, Le, and Jazdezewski. Part of this studys findings was presented at the CHEST 2015 Annual Meeting in Montreal, Canada, on October 28, 2015.

PS2-42: Assessment of Drug Induced Liver Injury Using an Automated Causality Assessment Tool

Background/Aims Drugs are a common cause of acute liver failure. However, confirming the diagnosis of drug-induced liver injury (DILI) is challenging due to its low incidence, lack of diagnostic markers and idiosyncratic nature. Our aim was to develop an automated scoring algorithm to identify potential DILI cases based on the Roussel Uclaf Causality Assessment Method (RUCAM) and test it in healthcare data. Methods RUCAM includes seven criteria of causality assessment. Operational scoring definitions were developed for each of the criteria in collaboration with DILI experts and programmed into an automated algorithm. The automated algorithm was then tested on a retrospective cohort of patients at Kaiser Permanente Southern California. Study participants were 18 years old with twelve months of continuous membership plus drug benefit prior to exposure to one of 14 drugs commonly associated with DILI. Eligible patients filled at least one of the study drugs between January 1, 2003 and August 31, 2011. Patients were scored and cases were categorized into one of five categories ranging from ‘Highly Probable’ to ‘Excluded’. Rates of DILI events per 10,000 exposures were calculated and frequency counts of possible scores for each of the seven criteria were analyzed. Results We identified 14,925 potential DILI events following 3,321,835 study drug exposures. Four antibiotics accounted for 89.4% of events. The average (SD) patient age was 60 (16) years and 54.5% of potential DILI events occurred in females. Cholestatic injury (65.0%) was the most common type followed by hepatocellular 29.4%, and mixed 5.6%. DILI events were categorized as probable or highly probable in 15.5% of cases, 59.6% were identified as possible, and 24.9% were unlikely or excluded. The overall rate of probable or highly probable DILI events was 6.9 per 10,000 exposures. The scores for most criteria spanned the entire range of possible scores and there were no obvious floor or ceiling effects. However, Criteria 5 (other non-drug causes of liver injury) showed poor discrimination of possible scores. Conclusions An electronic causality assessment algorithm was developed and successfully tested on healthcare data. Further validation is needed comparing these results with the ‘gold standard’ medical record review by DILI experts.

Adherence to the American Diabetes Association retinal screening guidelines for population with diabetes in the United States

ABSTRACT Purpose: (1) To assess long-term adherence to American Diabetes Association guideline-recommended retinal screening among population with diabetes in the United States. (2) To determine factors associated with long-term adherence to routine eye screening exams. Methods: A retrospective cohort study was conducted in adult patients with diabetes identified from January 2009 to December 2010. Patients were followed until disenrollment, death, or study end date (December 2013). A patient was defined as adherent when having at least one exam in each 12-month period if there was evidence of retinopathy, or at least one exam in each 24-month period if there was no evidence of retinopathy. Multivariate logistic regressions were used to investigate patient demographics and other baseline characteristics associated with adherence to guidelines. Results: A total of 204,073 patients were identified; the mean age (SD) was 61 (13) years and 48% were female. Overall, 71.1% were adherent to the retinal screening guidelines during a median of 4.8 years of follow-up including 27.7% who received an eye exam every year. Patient socioeconomic status (younger age, black race, lower income/education), less comorbidity, insulin use, higher specialist copayment plans, and proxies for poor patient behavior (lower adherence to the oral hypoglycemic agents, less diabetes education, hemoglobin A1C >9%) were associated with nonadherence to routine eye screening exams. Conclusion: During nearly 5 years of follow-up, 28.9% of patients with diabetes were nonadherent to the retinal screening guidelines. Future research should focus on the development of interventions to address modifiable factors associated with nonadherence.

PS3-7: Improving the Detection of Drug-Induced Liver Injury with an Electronic Causality Assessment Tool

Background/Aims The Roussel Uclaf Causality Assessment Method (RUCAM) is the most commonly used algorithm to evaluate drug-induced liver injury (DILI). It uses 7 criteria to assess causality and provides a total score ranging from −9 to 15, which is stratified into 5 categories describing the likelihood of DILI ranging from ‘Highly Probable’ to ‘Excluded’. An electronic RUCAM (eRUCAM) was previously developed at Kaiser Permanente Southern California (KPSC) with the Observational Medical Outcomes Partnership and GlaxoSmithKline to detect DILI in an electronic medical record. The study aim was to identify areas of improvement for future iterations of the eRUCAM based on results from chart review. Methods The eRUCAM was used to score potential cases of DILI identified in patients taking at least one of 14 drugs commonly associated with DILI. Patients were required to be at least 18 years of age and have 12 months of continuous membership plus drug benefit prior to drug initiation. A random sample of 20 patients without pre-existing liver disease was selected for chart review to perform quality assurance on the programming specifications and identify areas for improvement in the algorithm. A hepatologist manually scored each patient using the paper-based RUCAM. Scores from the hepatologist were compared to those from the eRUCAM using the Wilcoxon signed rank test. Qualitative findings from chart review regarding future improvements to the algorithm were summarized. Results The total score from eRUCAM was identical to those of the hepatologist for 6 cases (30%). The absolute difference between the hepatologist and eRUCAM scores was greatest for Criteria 5, which assesses non-drug causes of liver injury (P =0.001). Differences in scores were not statistically significant for other remaining criteria. Issues that were identified with Criteria 5 included: inadequate time windows for identifying non-drug causes, failure to consider laboratory results (e.g., hepatitis serology), incomplete lists of ICD-9 codes for non-drug causes, and inability to extract information from physician progress notes. Conclusions Future work related to the development of an electronic causality assessment tool based on the RUCAM should focus on improving Criteria 5 by using wider time windows to identify non-drug cases, laboratory results, and natural language processing.

PS3-31: Patients with Hyperuricemia and the Effect of Urate-Lowering Therapies on Renal Function in a Managed Care Organization

Background/Aims Preliminary data suggests that elevated serum uric acid levels (sUA) play a significant role in the development of renal disease. Few studies have evaluated urate-lowering therapies (ULT) in a population with hyperuracemia and the impact on development of renal disease. Our aim was to investigate whether initiation and maintenance of ULT, in patients with sUA ≥7.0 mg/dL, has a beneficial impact on renal function as measured by glomerular filter rate (GFR) reductions and adverse renal outcomes. Methods Patients 18 years and older, with sUA ≥7mg/dL and kidney disease stage 1, 2 or 3 from 01/01/2002 to 12/31/2010 were identified within Kaiser Permanente Southern California. Serum UA levels and GFR were collected at baseline and throughout follow-up for all patients. Patients on ULT were categorized into no-treatment, ≤70% time on treatment, and >70% time on treatment during follow-up. Patients were followed until they had one of the following primary outcomes: new onset dialysis, a 30% reduction in their GFR level from baseline, receipt of a kidney transplant, or a GFR level <15 mL/min/1.72m2. Baseline characteristics between the treatment groups were compared using descriptive statistics. A Cox proportional hazards model was used to estimate the hazard ratio (HR) and 95% confidence intervals (95% CI) associated with ULT treatment controlling for patient characteristics. Results A total of 33,745 patients were identified (n = 21,481 no-treatment, n = 9,136 ≤70% time on treatment, n = 3,128 >70% time on treatment). Overall, 3,592 patients reached a study endpoint; 2,114 patients in the no-treatment, 1,109 in the ≤70% treatment and 369 in the >70% treatment group. Controlling for demographics and co-morbid conditions, treatment for >70% of the time was associated with a 20% reduction in events (HR = 0.8; 95% CI 0.71–0.90). Factors associated with high risk of events included age, female gender, renal disease, congestive heart failure, and diabetes. Conclusions Our findings suggest that ULT may preserve renal function, and prevent or delay renal outcomes such as reductions in GFR and time to dialysis.