Social Disparities among Sudden Death victims with HIV.

Although cardiovascular death is a growing source of mortality for people living with human immunodeficiency virus (HIV), the risk factors and circumstances surrounding sudden death in this population are poorly understood. We compared 399 adult sudden death victims reported by Emergency Medical Services in North Carolina to 1,114 controls. Sudden death was more common among HIV-positive than HIV-negative individuals (OR: 2.59, 95% CI: 1.15-5.83). In a multivariable model of sudden death victims including Black race, BMI, and history of divorce, incarceration, substance abuse, and respiratory disease, HIV-positive individuals were more likely to be Black (adjusted OR [aOR]: 6.04, 95% CI: 1.08-33.7) or divorced (aOR: 4.71, 95% CI: 1.04-21.3), adjusted for all other variables in the model. Compared to controls with HIV, sudden death victims with HIV were more likely to have a history of incarceration, divorce, respiratory disease, alcohol abuse, or dyslipidemia. A qualitative assessment of victims suggested that many died in isolation, suffering from past and current substance abuse and depression. HIV infection appears to be an important risk factor for sudden death, and incarceration history, social isolation, and medical comorbidities contribute to sudden death risk for HIV-positive individuals.

Questionnaire-based exposome-wide association studies (ExWAS) reveal expected and novel risk factors associated with cardiovascular outcomes in the Personalized Environment and Genes Study.

While multiple factors are associated with cardiovascular disease (CVD), many environmental exposures that may contribute to CVD have not been examined. To understand environmental effects on cardiovascular health, we performed an exposome-wide association study (ExWAS), a hypothesis-free approach, using survey data on endogenous and exogenous exposures at home and work and data from health and medical histories from the North Carolina-based Personalized Environment and Genes Study (PEGS) (n = 5015). We performed ExWAS analyses separately on six cardiovascular outcomes (cardiac arrhythmia, congestive heart failure, coronary artery disease, heart attack, stroke, and a combined atherogenic-related outcome comprising angina, angioplasty, atherosclerosis, coronary artery disease, heart attack, and stroke) using logistic regression and a false discovery rate of 5%. For each CVD outcome, we tested 502 single exposures and built multi-exposure models using the deletion-substitution-addition (DSA) algorithm. To evaluate complex nonlinear relationships, we employed the knockoff boosted tree (KOBT) algorithm. We adjusted all analyses for age, sex, race, BMI, and annual household income. ExWAS analyses revealed novel associations that include blood type A (Rh-) with heart attack (OR[95%CI] = 8.2[2.2:29.7]); paint exposures with stroke (paint related chemicals: 6.1[2.2:16.0], acrylic paint: 8.1[2.6:22.9], primer: 6.7[2.2:18.6]); biohazardous materials exposure with arrhythmia (1.8[1.5:2.3]); and higher paternal education level with reduced risk of multiple CVD outcomes (stroke, heart attack, coronary artery disease, and combined atherogenic outcome). In multi-exposure models, trouble sleeping and smoking remained important risk factors. KOBT identified significant nonlinear effects of sleep disorder, regular intake of grapefruit, and a family history of blood clotting problems for multiple CVD outcomes (combined atherogenic outcome, congestive heart failure, and coronary artery disease). In conclusion, using statistics and machine learning, these findings identify novel potential risk factors for CVD, enable hypothesis generation, provide insights into the complex relationships between risk factors and CVD, and highlight the importance of considering multiple exposures when examining CVD outcomes.

High Prevalence of Diabetes Mellitus and Mental Illness Among Victims of Sudden Death.

OBJECTIVES: Diabetes mellitus (DM) increases the risk of cardiovascular disease and is associated with sudden death. Mental illness among individuals with DM may confound medical care. This study assessed the association of mental illness with DM and poorly controlled DM in sudden death victims. METHODS: We screened out-of-hospital deaths ages 18 to 64 years in Wake County, North Carolina from 2013 to 2015 to adjudicate sudden deaths. We abstracted demographics and clinical characteristics from health records. Mental illness included anxiety, schizophrenia, bipolar disorder, or depression. Poorly controlled DM was defined as a hemoglobin A1c >8 or taking ≥3 medications for glycemic control. Logistic regression assessed the association between DM and mental illness. RESULTS: Among victims with available records, 109 (29.4%) had DM. Of those, 62 (56.9%) had mental illness. Mental illness was present in 53.42% and 63.89% of victims with mild and poorly controlled DM, respectively. Mental illness was associated with DM (adjusted odds ratio 2.46, 95% confidence interval 1.57-3.91). Victims with poorly controlled DM were more likely to have mental illness (adjusted odds ratio 2.66, 95% confidence interval 1.14-6.18). CONCLUSIONS: DM is a common comorbid condition in sudden death victims. Among victims, mental illness is associated with the control of DM. Early management of comorbid mental illnesses may improve the care of patients with DM and reduce the incidence of sudden death.

Missed Opportunities for Prevention of Sudden Death.

BACKGROUND: We assessed patterns of health care utilization to further characterize chronic comorbidities prior to sudden death. METHOD: From March 1, 2013, through February 28, 2015, all out-of-hospital deaths aged 18-64 reported by emergency medical services in Wake County, North Carolina, were screened to adjudicate 399 sudden death victims. Retrospective analysis of clinical records on victims determined health care utilization. Health care utilization frequency was assessed by latent growth curve analysis. RESULTS: Medical records were available for 264 victims (aged 53.5 ± 9.2) who were predominantly male (65%) and white (64%). Of these, 210 (80%) victims had at least one visit within two years of death and 73 (28%) had a visit within one month of death. Over the two years prior to death, there was an increasing frequency of doctor visits (P < .001). Victims averaged 3.7 ± 4.6 yearly visits and were categorized into low (0.4 visits/year), medium (3.3 visits/year), and high (11.4 visits/year) tiers of visit frequency. The high visit tier had a greater prevalence of coronary artery disease (38%), hypertension (80%), diabetes (58%), depression (74%), anxiety (64%), and substance misuse (46%) (P < .001). LIMITATIONS: Those who were non-free-living, minors, without formal medical records, and adults aged 65 and older were excluded from the analysis. CONCLUSIONS: A majority of sudden death victims utilized health care within two years prior to death and had comorbidities that may have contributed to their unexpected death. The increasing frequency of visits prior to death provided an opportunity for health care providers to address potential victims' chronic medical conditions to potentially prevent death.

Reweighting Oranges to Apples: Transported RE-LY Trial Versus Nonexperimental Effect Estimates of Anticoagulation in Atrial Fibrillation.

BACKGROUND: Results from trials and nonexperimental studies are often directly compared, with little attention paid to differences between study populations. When target and trial population data are available, accounting for these differences through transporting trial results to target populations of interest provides useful perspective. We aimed to compare two-year risk differences (RDs) for ischemic stroke, mortality, and gastrointestinal bleeding in older adults with atrial fibrillation initiating dabigatran and warfarin when using trial transport methods versus nonexperimental methods. METHODS: We identified Medicare beneficiaries who initiated warfarin or dabigatran from a 20% nationwide sample. To transport treatment effects observed in the randomized evaluation of long-term anticoagulation trial, we applied inverse odds weights to standardize estimates to two Medicare target populations of interest, initiators of: (1) dabigatran and (2) warfarin. Separately, we conducted a nonexperimental study in the Medicare populations using standardized morbidity ratio weighting to control measured confounding. RESULTS: Comparing dabigatran to warfarin, estimated two-year RDs for ischemic stroke were similar with trial transport and nonexperimental methods. However, two-year mortality RDs were closer to the null when using trial transport versus nonexperimental methods for the dabigatran target population (transported RD: -0.57%; nonexperimental RD: -1.9%). Estimated gastrointestinal bleeding RDs from trial transport (dabigatran initiator RD: 1.8%; warfarin initiator RD: 1.9%) appeared more harmful than nonexperimental results (dabigatran initiator RD: 0.14%; warfarin initiator RD: 0.57%). CONCLUSIONS: Differences in study populations can and should be considered quantitatively to ensure results are relevant to populations of interest, particularly when comparing trial with nonexperimental findings. See video abstract: http://links.lww.com/EDE/B703.

Incidence of venous thromboembolism following initiation of non-steroidal anti-inflammatory drugs in U.S. women.

OBJECTIVE: To evaluate the risk of venous thromboembolism (VTE, i.e. deep vein thrombosis or pulmonary embolism, or both) following new use of NSAIDs in a long-term cohort of U.S. women. METHODS: We investigated initiation of coxibs and traditional NSAIDs (excluding aspirin) and incident VTE in 39 876 women enrolled in the Women's Health Study from 1993-95 and followed with yearly questionnaires until 2012. We defined initiation as the first reported use of NSAIDs for ≥4 days per month. Incident VTE was confirmed by an end point committee. We estimated hazard ratios (HRs) and risk differences (RDs, expressed as percentages) comparing NSAID initiation with non-initiation and acetaminophen initiation (active comparator) via standardization using a propensity score that incorporated age, BMI, calendar time, and relevant medical, behavioural, and socioeconomic variables updated over time. RESULTS: The HR (95% CI) for risk of VTE in the as treated analyses comparing initiation with non-initiation, was 1.5 (1.2, 1.8) for any NSAID, 1.3 (1.1, 1.7) for traditional NSAIDs, and 2.0 (1.3, 3.1) for coxibs, with 2-year RDs 0.11, 0.08 and 0.32, respectively. When comparing the risk of VTE after initiation of any NSAID with that after acetaminophen initiation, the HRs were 0.9 (0.6, 1.5), 0.9 (0.5, 1.5) and 1.4 (0.6, 3.4), with 2-year RDs 0.03, -0.01, and 0.13, respectively. CONCLUSION: New use of NSAIDs was associated with increased VTE risk compared with non-use, but the association was null or diminished when compared with acetaminophen initiation. Elevated VTE risks associated with NSAID use in observational studies may in part reflect different baseline risks among individuals who need analgesics and may overstate the risk patients incur compared with pharmacologic alternatives.

Coronary Artery Disease and Atherosclerotic Risk Factors in a Population-Based Study of Sudden Death.

BACKGROUND: Sudden death is a public health problem with major impact on society. Coronary artery disease (CAD) is believed to underlie 60-80% of these deaths. While deaths from CAD have decreased in the recent decades, sudden death rates remain unacceptably high. OBJECTIVE: We aimed to assess the prevalence of CAD and its risk factors among 18-64-year-old adults in a population-based case registry of sudden deaths and compare them to a living population from the same geographical area. DESIGN: From 2013 to 2015, all sudden deaths among 18-64-year-old adults in Wake County, NC, were identified (n = 371). A comparison group was formed by randomly selecting individuals from an electronic health record repository of a major healthcare system in the area (N = 4218). MAIN MEASURES: Prevalence of CAD and its risk factors among cases of sudden death and living population across sex and age groups. Odds of sudden death associated with atherosclerotic risk factors and comorbidities. KEY RESULTS: CAD was present in 14.8% of sudden death cases. Among sudden death victims, most risk factors and comorbidities were more common in the older age group, except for obesity which was more common in younger cases, and diabetes which was equally prevalent in younger and older cases. Compared to living population, sudden death cases had higher prevalence of atherosclerotic risk factors across all gender and age groups. Sudden death cases had a numerically higher number of risk factors compared to living population, regardless of age group or presence of CAD. CONCLUSIONS: Coronary artery disease is not common among sudden death cases, but risk factors and comorbidities are prevalent. Our findings support the changing etiology of sudden death. In the absence of clinically diagnosed CAD, use of novel imaging modalities and biomarkers may identify high-risk individuals and lead to prevention of sudden death.

Real-world on-treatment and initial treatment absolute risk differences for dabigatran vs warfarin in older US adults.

PURPOSE: Trials and past observational work compared dabigatran and warfarin in patients with atrial fibrillation, but few reported estimates of absolute harm and benefit under real-world adherence patterns, particularly in older adults that may have differing benefit-harm profiles. We aimed to estimate risk differences for ischemic stroke, death, and gastrointestinal bleeding after initiating dabigatran and warfarin in older adults (a) when patients adhere to treatment and (b) under real-world adherence patterns. METHODS: In a 20% sample of nationwide Medicare claims from 2010 to 2015, we identified beneficiaries aged 66 years and older initiating warfarin and dabigatran. We followed individuals from initiation until death or October 2015 (initial treatment, IT) and separately censored individuals' follow-up after drug switches and gaps in supply (on-treatment, OT). We applied inverse probability of treatment and standardized morbidity ratio weights, as well as inverse probability of censoring weights, to estimate two-year risk differences (RDs) for dabigatran vs warfarin. RESULTS: We identified 10,717 dabigatran and 74,891 warfarin initiators. Weighted OT RDs suggested decreased ischemic stroke risk for dabigatran vs warfarin; IT RDs indicated increased or no change in ischemic stroke risk. Regardless of follow-up approach and weighting strategy, risk of death appeared lower and risk of gastrointestinal bleeding appeared higher when comparing dabigatran vs warfarin. CONCLUSIONS: Dabigatran use was associated with lower risks of mortality and ischemic stroke in routine care when older adults stayed on treatment. IT analyses suggested that these benefits may be diminished under real-world patterns of switching and discontinuation.

Renin-Angiotensin-Aldosterone System-based Antihypertensive Agents and the Risk of Colorectal Cancer Among Medicare Beneficiaries.

BACKGROUND: Biologic evidence suggests that angiotensin II may play a role in tumor progression or growth. We compared the short-term colorectal cancer (CRC) risk among initiators of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) versus guideline-recommended clinical alternatives (beta blockers, calcium channel blockers [CCB], and thiazides). METHODS: We conducted a new-user cohort study on U.S. Medicare beneficiaries aged over 65 years, who initiated antihypertensive monotherapy during 2007-2013 and were free of cancer diagnosis before drug initiation. Follow-up began 6 months postinitiation to allow time for the diagnostic delay. We estimated hazard ratios (HR) with 95% confidence intervals (CI) using propensity score weighted Cox regression, overall and stratified by time since drug initiation, and 5-year cumulative risk differences (RD) using Kaplan-Meier estimator. We assessed the potential for unmeasured confounding using supplemental data from Medicare Current Beneficiary Survey. RESULTS: For analyses without censoring for treatment changes, we observed 532 CRC events among 111,533 ACEI/ARB initiators. After a median follow-up of 2.2 years (interquartile range: 1.0-3.7), CRC risk was similar between ACEI/ARB and active comparators, with adjusted HRs of 1.0 (95% CI = 0.85, 1.1) for ACEI/ARB versus beta blockers, 1.2 (95% CI = 0.97, 1.4) for ACEI/ARB versus CCB and 1.0 (95% CI = 0.80, 1.3) for ACEI/ARB versus thiazide. Five-year RDs and as-treated analyses, which censored follow-up at medication changes, produced similar findings. CONCLUSIONS: Based on real-world antihypertensive utilization patterns in Medicare beneficiaries, our study suggests no association between ACEI/ARB initiation and the short-term CRC risk.

Years of Life and Productivity Loss Because of Adult Sudden Unexpected Death in the United States.

BACKGROUND: Few studies have evaluated the years of life lost (YLL) and productivity loss due to sudden unexpected death (SUD). The burden of SUD on society is undetermined because of lack of population-based studies and comprehensive adjudication methods. OBJECTIVE: We estimated YLL and productivity loss from SUD in working-age adults and compared it with the leading causes of death in the United States. METHODS: We screened all out of hospital deaths among people aged 20-64 in Wake County, NC from 2013 to 2015 to adjudicate SUDs. We extrapolated Wake County incidence to estimate the age-standardized and sex-standardized rate of SUD in the United States. YLL was calculated based on the remaining life expectancy of the victims. Incorporating market and housekeeping value estimated the present value of lifetime productivity loss because of SUD. RESULTS: SUD incidence rates in the US adults aged 20-64 were 49.3 (95% confidence interval, 41.2-58.3) and 21.7 (95% confidence interval, 16.5-27.8) per 100,000 among men and women, respectively. SUD resulted in the loss of 2 million years of life, accounting for 10.0% of YLL from all causes of death. Among natural causes of death, YLL from SUD was only lower than that from all cancers combined and heart disease. Lifetime productivity loss because of SUD was ~$51 billion, exceeding productivity loss from any individual cancer. CONCLUSION: SUD is an important source of YLL and productivity loss among adults aged 20-64. Such a high burden on society justifies prioritizing health policies and interventions toward preventing SUD.

Approaches to Address Premature Death of Patients When Assessing Patterns of Use of Health Care Services After an Index Event.

BACKGROUND: Studies of the use of health care after the onset of disease are important for assessing quality of care, treatment disparities, and guideline compliance. Cohort definition and analysis method are important considerations for the generalizability and validity of study results. We compared different approaches for cohort definition (restriction by survival time vs. comorbidity score) and analysis method [Kaplan-Meier (KM) vs. competing risk] when assessing patterns of guideline adoption in elderly patients. METHODS: Medicare beneficiaries aged 65-95 years old who had an acute myocardial infarction (AMI) in 2008 were eligible for this study. Beneficiaries with substantial frailty or an AMI in the prior year were excluded. We compared KM with competing risk estimates of guideline adoption during the first year post-AMI. RESULTS: At 1-year post-AMI, 14.2% [95% confidence interval (CI), 14.0%-14.5%) of beneficiaries overall initiated cardiac rehabilitation when using competing risk analysis and 15.1% (95% CI, 14.8%-15.3%) from the KM analysis. Guideline medication adoption was estimated as 52.3% (95% CI, 52.0%-52.7%) and 53.4% (95% CI, 53.1%-53.8%) for competing risk and KM methods, respectively. Mortality was 17.0% (95%CI, 16.8%-17.3%) at 1 year post-AMI. The difference in cardiac rehabilitation initiation at 1-year post-AMI from the overall population was 0.1%, 1.7%, and 1.9% compared with 30-day survivor, 1-year survivor, and comorbidity-score restricted populations, respectively. CONCLUSIONS: In this study, the KM method consistently overestimated the competing risk method. Competing risk approaches avoid unrealistic mortality assumptions and lead to interpretations of estimates that are more meaningful.

Medication Use in Women and Men With Sudden Unexpected Death.

BACKGROUND: In Wake County, NC, sudden unexpected death accounts for 10% to 15% of all natural deaths in individuals 18 to 64 years old. Medications such as aspirin, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, and ß-blockers are recommended in guidelines to reduce cardiovascular events and even sudden death (ß-blockers). However, guidelines are often underpracticed, even in high-risk patients, with noted disparities in women. OBJECTIVE: We assessed the relation between prescription of evidence-based medications and sudden unexpected death in Wake County, NC. METHODS: We analyzed 399 cases of sudden unexpected death for the time period March 1, 2013 to February 28, 2015 in Wake County, NC. Medications were assessed from available medical examiner reports and medical records and grouped using the third level of the Anatomical Therapeutic Chemical Classification System (ATC) codes. This study was reviewed and exempt by the University of North Carolina's institutional review board. RESULTS: Among 126 female and 273 male victims, women were prescribed more medications overall than men (6.5 vs 4.3, P = 0.001); however, the use of guideline-directed therapies was not different between genders in the chronic conditions associated with sudden death. Overall, there was remarkably low use of evidence-based medications. CONCLUSIONS: Our findings highlight the need to improve prescribing of evidence-based medications and to further explore the relationship between undertreatment and sudden unexpected death.

Position matters: Validation of medicare hospital claims for myocardial infarction against medical record review in the atherosclerosis risk in communities study.

PURPOSE: The objectives of this study were to investigate sensitivity and specificity of myocardial infarction (MI) case definitions using multiple discharge code positions and multiple diagnosis codes when comparing administrative data to hospital surveillance data. METHODS: Hospital surveillance data for ARIC Study cohort participants with matching participant ID and service dates to Centers for Medicare and Medicaid Services (CMS) hospitalization records for hospitalizations occurring between 2001 and 2013 were included in this study. Classification of Definite or Probable MI from ARIC medical record review defined "gold standard" comparison for validation measures. In primary analyses, an MI was defined with ICD9 code 410 from CMS records. Secondary analyses defined MI using code 410 in combination with additional codes. RESULTS: A total of 25 549 hospitalization records met study criteria. In primary analysis, specificity was at least 0.98 for all CMS definitions by discharge code position. Sensitivity ranged from 0.48 for primary position only to 0.63 when definition included any discharge code position. The sensitivity of definitions including codes 410 and 411.1 were higher than sensitivity observed when using code 410 alone. Specificity of these alternate definitions was higher for women (0.98) than for men (0.96). CONCLUSION: Algorithms that rely exclusively on primary discharge code position will miss approximately 50% of all MI cases due to low sensitivity of this definition. We recommend defining MI by code 410 in any of first 5 discharge code positions overall and by codes 410 and 411.1 in any of first 3 positions for sensitivity analyses of women.

Calendar time as an instrumental variable in assessing the risk of heart failure with antihyperglycemic drugs.

OBJECTIVE: In recent years, second-line diabetes treatment with dipeptidyl peptidase-4 inhibitors (DPP-4i) increased with a corresponding decrease in thiazolidinediones (TZDs). Using hospitalization for heart failure (HF) as a positive control outcome, we explored the use of calendar time as an instrumental variable (IV) and compared this approach to an active comparator new-user study. METHODS: We identified DPP-4i or TZD initiators after a 6-month washout using Medicare claims 2006-2013. The IV was defined as a binary variable comparing initiators during October 2010 to December 2013 (postperiod) versus January 2008 to May 2010 (preperiod). We examined IV strength and estimated risk differences (RDs) for HF using Kaplan-Meier curves, which were compared with propensity score (PS)-weighted RD for DPP-4i versus TZD. RESULTS: The IV compared 22 696 initiators (78% DPP-4i) in the postperiod versus 20 283 initiators (38% DPP-4i) in the preperiod, resulting in 40% compliance. The active-comparator (PS-weighted) approach compared 26 198 DPP-4i and 18 842 TZD initiators. Covariate balance across IV levels was slightly better than across treatments (standardized difference, 3% vs 4.5%). The 1- and 2-year local average treatment effects of RD of HF per 100 patients in the "compliers" (95% confidence intervals) were -0.62 (-0.99 to -0.25) and -0.88 (-1.46 to -0.25). Corresponding PS-weighted results were -0.20 (-0.33 to -0.05) and -0.18 (-0.30 to 0.03). CONCLUSION: Both approaches indicated lesser risk of HF hospitalizations among DPP-4i vs TZD initiators. The magnitude of the estimated effects may differ due to differences in the target populations and assumptions. Calendar time can be leveraged as an IV when market dynamics lead to profound changes in treatments.

Classifying medical histories in US Medicare beneficiaries using fixed vs all-available look-back approaches.

PURPOSE: Evaluate use of fixed and all-available look-backs to identify eligibility criteria and confounders among Medicare beneficiaries. METHODS: We identified outpatient visits (2007-2012) with recently documented (≤180 days) cardiovascular risk and classified patients according to whether the exposure (statin) was initiated within 14 days. We selected each beneficiary's first eligible visit (in each treatment group) that met criteria during the respective look-backs: continuous enrollment (1 or 3 years for fixed look-back; 180 days for all-available), no cancer history, and no statin claims. We estimated crude and standardized mortality ratio weighted hazard ratios (HRs) for the effect of statin initiation on incident 6-month cancer (a known null effect) and 2-year mortality, separately, adjusting for covariates assessed by using each look-back. RESULTS: Analyzing short-term cancer, the estimated HR from the all-available approach (HR = 0.90, 95% CI: 0.83, 0.98) was less biased than the 1-year look-back (HR = 0.79, 95% CI: 0.73, 0.84), which included beneficiaries with prevalent cancer. The 3-year look-back (HR = 1.05, 95% CI: 0.90, 1.21) was somewhat less biased than the all-available estimate but less precise due the exclusion of a large proportion of observations without sufficient continuous enrollment (62.0% and 59.9% of initiators and non-initiators, respectively). All approaches produced similar estimates of the effect on all-cause mortality. Alternative look-backs did not differ in their ability to control confounding. CONCLUSIONS: The all-available look-back performed nearly as well as the 3-year fixed, which produced the least biased point estimate. If 3-year look-backs are infeasible (eg, due to power/sample), all-available look-backs may be preferable to short (1-year) fixed look-backs.

No increased risk of cardiovascular events in older adults initiating dipeptidyl peptidase-4 inhibitors vs therapeutic alternatives.

AIM: To compare the cardiovascular (CV) risk associated with dipeptidyl peptidase-4 (DPP-4) inhibitors relative to sulphonylureas (SUs) and thiazolidinediones (TZDs). METHODS: During 2007 to 2013, using Medicare data for beneficiaries aged >65 years, we identified the following 2 cohorts of new-users, who had not been exposed to the drugs being compared in the 6 months before initiation: (1) DPP-4 inhibitor vs SU initiators and (2) DPP-4 inhibitor vs TZD initiators. Using propensity-score-adjusted Cox models accounting for competing risk by death, we estimated the hazard ratios (HRs), risk differences and 95% confidence intervals (CIs) for myocardial infarction (MI), stroke, hospitalization for heart failure (HF), and a combined outcome (MI, stroke, all-cause mortality). RESULTS: In the DPP-4 inhibitor vs SU comparison, there were 30 130 DPP-4 inhibitor initiators and 68 382 SU initiators. Their mean age was 75 years, 41% were men and 55% had a baseline CV condition. The HR for the composite outcome was 0.75 (95% CI 0.72-0.79) over a median treatment duration of 1 year, but the 1-year risks of MI were 1.00 (95% CI 0.89-1.12) and 1.47 (95% CI 1.38-1.56) per 100 patients for DPP-4 inhibitors and SUs, respectively, and the corresponding stroke risks were 0.98 (95% CI 0.87-1.10) and 1.09 (95% CI 1.01-1.17). For the DPP-4 inhibitor vs TZD comparison, there were 20 596 DPP-4 inhibitor initiators and 13 526 TZD initiators without previous HF. Their mean age was 74 years, 42% were men and 30% had a baseline CV event. The composite outcome HR was 0.94 (95% CI 0.86-1.02) over a median treatment duration of 1 year. The 1-year risk for MI was ~0.90 and for stroke it was ~0.80 per 100 patients in both DPP-4 inhibitor and TZD initiators. CONCLUSION: Although limited by the short treatment period, the present study suggests there is no increased short-term risk of MI, stroke or HF with DPP-4 inhibitors vs SUs/TZDs.

Validation of Medicaid Claims-based Diagnosis of Myocardial Infarction Using an HIV Clinical Cohort.

BACKGROUND: In nonexperimental comparative effectiveness research using health care databases, outcome measurements must be validated to evaluate and potentially adjust for misclassification bias. We aimed to validate claims-based myocardial infarction (MI) algorithms in a Medicaid population using an HIV clinical cohort as the gold standard. METHODS: Medicaid administrative data were obtained for the years 2002-2008 and linked to the UNC CFAR HIV Clinical Cohort based on social security number, first name, and last name and MI were adjudicated. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated. RESULTS: There were 1063 individuals included in the study. Over a median observed time of 2.5 years, 17 had an MI. Specificity ranged from 0.979 to 0.993 with the highest specificity obtained using the ICD-9 code 410.xx in the primary or secondary position and a length of stay >3 days. Sensitivity of MI ascertainment varied from 0.588 to 0.824 depending on algorithm. CONCLUSIONS: Specificities of varying claims-based MI ascertainment criteria are high but small changes impact positive predictive value in a cohort with low incidence. Sensitivities vary based on ascertainment criteria. Type of algorithm used should be prioritized based on study question and maximization of specific validation parameters that will minimize bias while also considering precision.

Matching on the disease risk score in comparative effectiveness research of new treatments.

PURPOSE: We use simulations and an empirical example to evaluate the performance of disease risk score (DRS) matching compared with propensity score (PS) matching when controlling large numbers of covariates in settings involving newly introduced treatments. METHODS: We simulated a dichotomous treatment, a dichotomous outcome, and 100 baseline covariates that included both continuous and dichotomous random variables. For the empirical example, we evaluated the comparative effectiveness of dabigatran versus warfarin in preventing combined ischemic stroke and all-cause mortality. We matched treatment groups on a historically estimated DRS and again on the PS. We controlled for a high-dimensional set of covariates using 20% and 1% samples of Medicare claims data from October 2010 through December 2012. RESULTS: In simulations, matching on the DRS versus the PS generally yielded matches for more treated individuals and improved precision of the effect estimate. For the empirical example, PS and DRS matching in the 20% sample resulted in similar hazard ratios (0.88 and 0.87) and standard errors (0.04 for both methods). In the 1% sample, PS matching resulted in matches for only 92.0% of the treated population and a hazard ratio and standard error of 0.89 and 0.19, respectively, while DRS matching resulted in matches for 98.5% and a hazard ratio and standard error of 0.85 and 0.16, respectively. CONCLUSIONS: When PS distributions are separated, DRS matching can improve the precision of effect estimates and allow researchers to evaluate the treatment effect in a larger proportion of the treated population. However, accurately modeling the DRS can be challenging compared with the PS.

Patient and physician factors influence decision-making in hypercholesterolemia: a questionnaire-based survey.

BACKGROUND: Goal attainment of guideline-recommended low-density lipoprotein cholesterol (LDL-C) is suboptimal. Little is known about how patient factors influence physicians' treatment decision-making in hypercholesterolemia. We examined physicians' treatment recommendations in high-risk patients whose LDL-C remained uncontrolled despite statin monotherapy. METHODS: Physicians completed a questionnaire prior to randomization into period I of a two-period randomized controlled trial evaluating LDL-C goal attainment in patients whose LDL-C remained ≥100 mg/dL after 5 weeks' treatment with atorvastatin 10 mg/day (NCT01154036). Physicians' treatment recommendations were surveyed for two hypothetical and one real scenario: (1) LDL-C presumed near goal (between 100-105 mg/dL), (2) LDL-C presumed far from goal (~120 mg/dL), and (3) observed baseline LDL-C of enrolled patients. Prognostic factors considered during decision-making were identified by regression analysis. Observed lipid outcomes at the end of period I (following 6 weeks' treatment with ezetimibe 10 mg plus atorvastatin 10 mg, atorvastatin 20 mg, or rosuvastatin 10 mg) were compared with estimated LDL-C outcomes for physicians' treatment recommendations after 6 weeks (based on individual patients' pre-randomization LDL-C and expected incremental change). RESULTS: Questionnaires were completed for 1,534 patients. No change in therapy, or double atorvastatin dose, were frequently recommended, even when LDL-C was far from goal (6.5% and 52.2% of patients, respectively). Double atorvastatin dose was commonly recommended in all scenarios (43-52% of patients). More intensive LDL-C-lowering regimens were recommended infrequently e.g. double atorvastatin dose and add ezetimibe only <12% in all scenarios. Overall, cardiovascular risk factors and desire to achieve a more aggressive LDL-C goal were prominent factors in decision-making for treatment. Comparison of observed and estimated LDL-C levels showed that physicians tended to overestimate the effectiveness of their recommendations. CONCLUSIONS: This study provides insight into physicians' perspectives on clinical management of hypercholesterolemia and highlights a gap in knowledge translation from guidelines to clinical practice. The need for lower LDL-C and cardiovascular risk were key drivers in clinical decision-making, but physicians' treatment choices were more conservative than guideline recommendations, potentially resulting in poorer LDL-C reduction. When compared with actual outcomes, projected LDL-C control was better if physicians used more comprehensive strategies rather than simply doubling the statin dose. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01154036.