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Congress mandated the creation of a postmarket Active Risk Identification and Analysis (ARIA) system containing data on 100 million individuals for monitoring risks associated with drug and biologic products using data from disparate sources to complement the US Food and Drug Administration's (FDA's) existing postmarket capabilities. We report on the first 6 years of ARIA utilization in the Sentinel System (2016–2021). The FDA has used the ARIA system to evaluate 133 safety concerns; 54 of these evaluations have closed with regulatory determinations, whereas the rest remain in progress. If the ARIA system and the FDA's Adverse Event Reporting System are deemed insufficient to address a safety concern, then the FDA may issue a postmarket requirement to a product's manufacturer. One hundred ninety‐seven ARIA insufficiency determinations have been made. The most common situation for which ARIA was found to be insufficient is the evaluation of adverse pregnancy and fetal outcomes following in utero drug exposure, followed by neoplasms and death. ARIA was most likely to be sufficient for thromboembolic events, which have high positive predictive value in claims data alone and do not require supplemental clinical data. The lessons learned from this experience illustrate the continued challenges using administrative claims data, especially to define novel clinical outcomes. This analysis can help to identify where more granular clinical data are needed to fill gaps to improve the use of real‐world data for drug safety analyses and provide insights into what is needed to efficiently generate high‐quality real‐world evidence for efficacy. [ABSTRACT FROM AUTHOR]

Purpose: Develop and test a flexible, scalable tool using interrupted time series (ITS) analysis to assess the impact of Food and Drug Administration (FDA) regulatory actions on drug use. Methods: We applied the tool in the Sentinel Distributed Database to assess the impact of FDA's 2010 drug safety communications (DSC) concerning the safety of long‐acting beta2‐agonists (LABA) in adult asthma patients. We evaluated changes in LABA use by measuring the initiation of LABA alone and concomitant use of LABA and asthma controller medications (ACM) after the DSCs. The tool generated ITS graphs and used segmented regression to estimate baseline slope, level change, slope change, and absolute and relative changes at up to two user‐specified time point (s) after the intervention. We tested the tool and compared our results against prior analyses that used similar measures. Results: Initiation of LABA alone declined among asthma patients aged 18–45 years before FDA DSCs (−0.10% per quarter; 95%CI: −0.11% to −0.09%) and the downward trend continued after. Concomitant use of LABA and ACM was stable before FDA DSCs. After FDA DSCs, there was a small trend decrease of 0.006% per quarter (95% CI, −0.008% to −0.003%). We found similar results among those aged 46–64 years and patients with poorly‐controlled asthma. Our results were consistent with previous studies, confirming the performance of the new tool. Conclusions: We developed and tested a reusable ITS tool in real‐world databases formatted to the Sentinel Common Data Model that can assess the impact of regulatory actions on drug use. [ABSTRACT FROM AUTHOR]

Upstream open reading frames (uORFs) are known to negatively affect translation of the downstream ORF. The regulatory proteins involved in relieving this inhibition are however poorly characterized. In response to cellular stress, eIF2α phosphorylation leads to an inhibition of global protein synthesis, while translation of specific factors such as CHOP is induced. We analyzed a 105‐nt inhibitory uORF in the transcript of human CHOP (huORFchop) and found that overexpression of the zebrafish or human ENDOU poly(U)‐endoribonuclease (Endouc or ENDOU‐1, respectively) increases CHOP mRNA translation also in the absence of stress. We also found that Endouc/ENDOU‐1 binds and cleaves the huORFchop transcript at position 80G‐81U, which induces CHOP translation independently of phosphorylated eIF2α. However, both ENDOU and phospho‐eIF2α are nonetheless required for maximal translation of CHOP mRNA. Increased levels of ENDOU shift a huORFchop reporter as well as endogenous CHOP transcripts from the monosome to polysome fraction, indicating an increase in translation. Furthermore, we found that the uncapped truncated huORFchop‐69‐105‐nt transcript contains an internal ribosome entry site (IRES), facilitating translation of the cleaved transcript. Therefore, we propose a model where ENDOU‐mediated transcript cleavage positively regulates CHOP translation resulting in increased CHOP protein levels upon stress. Specifically, CHOP transcript cleavage changes the configuration of huORFchop thereby releasing its inhibition and allowing the stalled ribosomes to resume translation of the downstream ORF. SYNOPSIS: Heat or ER stress trigger a stress response involving eIF2α phosphorylation and induction of the transcription factor CHOP. Here, stress‐induced poly(U)‐specific endoribonuclease is found to specifically cleave CHOP mRNA, thereby releasing a uORF‐associated inhibitory structure and allowing its selective translation. Zebrafish Endouc and its human orthologue ENDOU positively regulate CHOP translation independently of phosphorylated eIF2α.Both ENDOU and phospho‐eIF2α are required for maximal translation of CHOP upon heat shock or ER stress.ENDOU binds the 105‐nt upstream uORF of the human CHOP transcript and cleaves it at position 80G‐81U.The truncated huORFchop‐81‐105 transcript does not contain IRES activity, while uncapped truncated huORFchop‐69‐105 transcript does. [ABSTRACT FROM AUTHOR]

The US Sentinel System and the Canadian Network for Observational Drug Effect Studies (CNODES) are two medical product safety surveillance networks. Using Sentinel's preprogrammed, parameterizable analytic tools, we reproduced two protocol‐based studies conducted by CNODES to assess the risks of acute pancreatitis and heart failure (HF) associated with the use of incretin‐based drugs, compared with use of ≥ 2 oral hypoglycemic agents. Results from the replication new‐user cohort analyses aligned with those from the CNODES nested case‐control studies. The adjusted hazard ratios were 0.95 (0.81–1.12; vs. 1.03 (0.87–1.22) in CNODES) for acute pancreatitis and 0.91 (0.84–1.00; vs. 0.82 (0.67–1.00) in CNODES) for HF among patients without HF history. The CNODES's common protocol approach allows studies tailored to specific safety questions, whereas the Sentinel's common data model plus pretested program approach enables more rapid analysis. Despite these differences, it is possible to obtain comparable results using both approaches. [ABSTRACT FROM AUTHOR]

Purpose The CHA2DS2‐VaSc and HAS‐BLED risk scores are commonly used in the studies of oral anticoagulants (OACs). The best ways to map these scores to the International Classification of Diseases, 10th Revision, Clinical Modification (ICD‐10‐CM) codes is unclear, as is how they perform in various types of OAC users. We aimed to assess the distributions of CHA2DS2‐VaSc and HAS‐BLED scores and C‐statistics for outcome prediction in the ICD‐10‐CM era using different mapping strategies. Methods: We compared the distributions of CHA2DS2‐VaSc and HAS‐BLED scores from various mapping strategies in atrial fibrillation patients before, during, and after ICD‐10‐CM transition. We estimated the C‐statistics predicting the 90‐day risk of hospitalized stroke (for CHA2DS2‐VaSc) or hospitalized bleeding (for HAS‐BLED) in patients identified at least 6 months after the ICD‐10‐CM transition, overall and by anticoagulant type. Results: Forward‐backward mapping produced higher CHA2DS2‐VaSc and HAS‐BLED scores in the ICD‐10‐CM era compared to the ICD‐9‐CM era: the mean difference was 0.074 (95% confidence interval 0.064‐0.085) for CHA2DS2‐VaSc and 0.055 (0.048‐0.062) for HAS‐BLED. Both scores had higher C‐statistics in patients taking no OACs (0.697 [0.677‐0.717] for CHA2DS2‐VaSc; 0.719 [0.702‐0.737] for HAS‐BLED) or direct OACs (0.695 [0.654‐0.735] for CHA2DS2‐VaSc; 0.700 [0.673‐0.728] for HAS‐BLED) than those taking warfarin (0.655 [0.613‐0.697] for CHA2DS2‐VaSc; 0.663 [0.6320.695] for HAS‐BLED). Conclusions: Existing mapping strategies generally preserved the distributions of CHA2DS2‐VaSc and HAS‐BLED scores after ICD‐10‐CM transition. Both scores performed better in patients on no OACs or direct OACs than patients on warfarin. [ABSTRACT FROM AUTHOR]

Background: Epidemiological study reporting is improving but is not transparent enough for easy evaluation or replication. One barrier is insufficient details about design elements in published studies. Methods: Using a previously conducted drug safety evaluation in claims as a test case, we investigated the impact of small changes in five key design elements on risk estimation. These elements are index day of incident exposure's determination of look‐back or follow‐up periods, exposure duration algorithms, heparin exposure exclusion, propensity score model variables, and Cox proportional hazard model stratification. We covaried these elements using a fractional factorial design, resulting in 24 risk estimates for one outcome. We repeated eight of these combinations for two additional outcomes. We measured design effects on cohort sizes, follow‐up time, and risk estimates. Results: Small changes in specifications of index day and exposure algorithm affected the risk estimation process the most. They affected cohort size on average by 8 to 10%, follow‐up time by up to 31%, and magnitude of log hazard ratios by up to 0.22. Other elements affected cohort before matching or risk estimate's precision but not its magnitude. Any change in design substantially altered the matched control‐group subjects in 1:1 matching. Conclusions: Exposure‐related design elements require attention from investigators initiating, evaluating, or wishing to replicate a study or from analysts standardizing definitions. The methods we developed, using factorial design and mapping design effect on causal estimation process, are applicable to planning of sensitivity analyses in similar studies. [ABSTRACT FROM AUTHOR]

The effect of treating comorbid depression to achieve optimal management of chronic obstructive pulmonary disease (COPD) has not yet empirically tested. We examined the association between antidepressant treatment and use of and adherence to COPD maintenance medications among patients with new-onset COPD and comorbid depression.Methods: Using 2006-2012 Medicare data, this retrospective cohort study identified patients with newly diagnosed COPD and new-onset major depression. Two exposures-antidepressant use (versus non-use) and adherence measured by proportion of days covered (PDC) (PDC ≥0.8 versus <0.8)-were assessed quarterly. We used marginal structural models to estimate the effects of prior antidepressant use and adherence on subsequent COPD maintenance inhaler use and adherence outcomes, accounting for time-varying confounders.Results: A total of 25 458 COPD-depression patients, 82% with antidepressant treatment, were followed for a median of 2.5 years. Nearly half (48%) used at least 1 COPD maintenance inhaler in any given quarter; among users, 3 in 5 (61%) had a PDC of <0.8. Compared to patients with no antidepressant treatment, those with antidepressant use were more likely to use (relative ratio [RR] = 1.15, 95% confidence interval [CI] = 1.12- 1.17) and adhere to (RR = 1.08, 95% = 1.03-1.14) their COPD maintenance inhalers. Patients who adhered to antidepressant treatment were more likely to use and adhere to COPD maintenance inhalers.Conclusion: Regularly treated depression may increase use of and adherence to necessary maintenance medications for COPD. Antidepressant treatment may be a key determinant to improving medication-taking behaviors among COPD patients comorbid with depression. [ABSTRACT FROM AUTHOR]

Purpose: To replicate the well-established association between angiotensinconverting enzyme inhibitors versus beta blockers and angioedema in the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) era. Methods: We conducted a retrospective, inception cohort study in a large insurance database formatted to the Sentinel Common Data Model. We defined study periods spanning the ICD-9-CM era only, ICD-10-CM era only, and ICD-9-CM and ICD-10-CM era and conducted simple-forward mapping (SFM), simple-backward mapping (SBM), and forward-backward mapping (FBM) referencing the General Equivalence Mappings to translate the outcome (angioedema) and covariates from ICD-9-CM to ICD-10-CM. We performed propensity score (PS)-matched and PSstratified Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: In the ICD-9-CM and ICD-10-CM eras spanning April 1 to September 30 of 2015 and 2016, there were 152 017 and 145 232 angiotensin-converting enzyme inhibitor initiators and 115 073 and 116 652 beta-blocker initiators, respectively. The PS-matched HR was 4.19 (95% CI, 2.82-6.23) in the ICD-9-CM era, 4.37 (2.92-6.52) in the ICD-10-CM era using SFM, and 4.64 (3.05-7.07) in the ICD-10-CM era using SBM and FBM. The PS-matched HRs from the mixed ICD-9-CM and ICD-10-CM eras ranged from 3.91 (2.69-5.68) to 4.35 (3.33-5.70). Conclusion: The adjusted HRs across different diagnostic coding eras and the use of SFM versus SBM and FBM produced numerically different but clinically similar results. Additional investigations as ICD-10-CM data accumulate are warranted. [ABSTRACT FROM AUTHOR]

Purpose: To describe the consistency in the frequency of 5 health outcomes across the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and Tenth Revision, Clinical Modification (ICD-10-CM) eras in the US. Methods: We examined the incidence of 3 acute conditions (acute myocardial infarction [AMI], angioedema, ischemic stroke) and the prevalence of 2 chronic conditions (diabetes, hypertension) during the final 5 years of the ICD-9-CM era (January 2010-September 2015) and the first 15 months of the ICD-10-CM era (October 2015-December 2016) in 13 electronic health care databases in the Sentinel System. For each health outcome reviewed during the ICD-10-CM era, we evaluated 4 definitions, including published algorithms derived from other countries, as well as simple-forward, simple-backward, and forward-backward mapping using the General Equivalence Mappings. For acute conditions, we also compared the incidence between April to December 2014 and April to December 2016. Results: The analyses included data from approximately 172 million health plan members. While the incidence or prevalence of AMI and hypertension performed similarly across the 2 eras, the other 3 outcomes did not demonstrate consistent trends for some or all the ICD-10-CM definitions assessed. Conclusions: When using data from both the ICD-9-CM and ICD-10-CM eras, or when using results from ICD-10-CM data to compare to results from ICD-9-CM data, researchers should test multiple ICD-10-CM outcome definitions as part of sensitivity analysis. Ongoing assessment of the impact of ICD-10-CM transition on identification of health outcomes in US electronic health care databases should occur as more data accrue. [ABSTRACT FROM AUTHOR]

Background Existing studies suggested that concomitant use of calcium channel blockers (CCBs) may interfere with the antiplatelet effect of clopidogrel. The objective of this study was to examine the effect of concomitant use of CCBs and clopidogrel on risks of acute coronary syndrome (ACS) re-hospitalization in patients receiving percutaneous coronary intervention. Methods Using the Taiwan National Health Insurance Research Database, we identified 51 925 patients who were admitted for newly diagnosed ACS, received percutaneous coronary intervention, and used clopidogrel within 1 year after discharge. We further stratified them into three groups based on their uses of guideline-recommended secondary prevention medications for ACS (fully, partially, and non-compliant groups) to assess the potential modification effect of guideline compliance. For each group, we conducted a 1:1 propensity score matching to minimize selection bias. Cox proportional hazard models were used to investigate the effect of concomitant use of CCBs (overall, subclasses, and individual CCBs) and clopidogrel on risks of ACS re-hospitalization. Results Concomitant use of CCBs in patients discharged with clopidogrel was significantly associated with a lower risk of ACS re-hospitalization in the fully compliant group (HRfully compliant = 0.82 [95% confidence interval 0.75-0.89], p < 0.001) but was associated with increased risk of ACS re-hospitalization in the non-compliant group (HRnon-compliant = 1.22 [1.03-1.45], p = 0.0252). Conclusions Different guideline compliance of secondary prevention medications could modify the potential drug-drug interaction between clopidogrel and CCBs. Concomitant use of CCBs and clopidogrel was significantly associated with increased risk of ACS re-hospitalization in ACS patients not compliant to guideline-recommended secondary prevention drugs. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objectives: Depression is a common comorbidity of chronic obstructive pulmonary disease (COPD) and is associated with increased exacerbations, healthcare utilization, and mortality. Among Medicare beneficiaries newly diagnosed with COPD, the objectives of this study were to (1) estimate the rate of new episodes of depression and (2) identify factors associated with depression.Methods: We identified beneficiaries with a first diagnosis of COPD during 2006-2012 using a 5% random sample of Medicare administrative claims data by searching for ICD-9-CM codes 490, 491.x, 492.x, 494.x, or 496. We identified episodes of depression using ICD-9-CM codes 296.2x, 296.3x, and 311.xx. We calculated incidence rates and their 95% confidence intervals (95% CI) and used a discrete time analysis to identify factors associated with development of depression.Results: Between 2006 and 2012, 125,348 beneficiaries meeting inclusion criteria were newly diagnosed with COPD. Twenty-three percent developed depression following COPD diagnosis. The annualized incidence rate of depression per 100 beneficiaries following COPD diagnosis was 9.4 (95% CI 9.3, 9.5). Rates were highest in the first 2 months following COPD diagnosis. COPD diagnosis was associated with increased risk of depression (risk ratio 1.76; 95% CI 1.73, 1.79) as were COPD-related hospitalizations (risk ratio 4.59; 95% CI 4.09, 5.15), a measure of COPD severity.Conclusions: Diagnosis of COPD increases the risk of depression. This study will aid in the allocation of resources to monitor and provide support for individuals with COPD at high risk of developing depression. [ABSTRACT FROM AUTHOR]

Objectives To examine disease-specific associations between antipsychotic dose and duration and all-cause mortality. Design Retrospective cohort study. Setting A 5% random sample of Medicare beneficiaries who had a Minimum Data Set 2.0 clinical assessment completed between 2007 and 2009. Participants Three mutually exclusive cohorts of new antipsychotic users with evidence of severe mental illness ( SMI, n = 5,621); dementia with behavioral symptoms (dementia + behavior) without SMI (n = 1,090); or delirium only without SMI or dementia + behavior (n = 2,100) were identified. Measurements Dose and duration of therapy with antipsychotics were assessed monthly with a 6-month look-back. Dose was measured as modified standardized daily dose ( mSDD), with a mSDD of 1 or less considered below or at recommended maximum geriatric dose. Duration was categorized as 30 or fewer, 31 to 60, 61 to 90, and 91 to 184 days for SMI and dementia + behavior and 7 or fewer, 8 to 30, 31 to 90, and 91 to 184 days for delirium. Complementary log-log models with mSDD and duration as time-dependent variables were used to estimate hazard ratios ( HRs) and 95% confidence intervals ( CIs) for mortality. Results In all three groups, new antipsychotic users with a mSDD of 1 or less had significantly lower mortality risk ( HRSMI = 0.77, 95% CI = 0.67-0.88; HRdementia+behavior = 0.52, 95% CI = 0.36-0.76; HRdelirium = 0.61, 95% CI = 0.44-0.85) than peers with a mSDD greater than 1. Individuals with longer duration of antipsychotic use (91-184 days for SMI and delirium) had significantly lower mortality than those with a short duration of use (≤30 days for SMI; ≤7 days for delirium). The interaction between dose and duration was statistically significant in the SMI cohort ( P < .001). Conclusion Lower mortality was observed with within-recommended dose ranges for dementia + behavior, SMI, and delirium and with long duration of antipsychotic use for the latter two disease groups. Prescribers should monitor antipsychotic dosage throughout the course of antipsychotic treatment and customize dose and duration regimens to an individual's indications. [ABSTRACT FROM AUTHOR]

Objectives To assess changes in behavioral symptoms associated with Alzheimer's disease and related dementias ( ADRDs) after antipsychotic ( AP) or antidepressant ( AD) treatment and to estimate the effect of treatment response on mortality risk. Design Retrospective cohort study using 2006-2009 Medicare administrative and prescription drug claims data linked to Minimum Data Set 2.0. Setting Long-stay (≥101 days) nursing home residents. Participants Continuously enrolled fee-for-service Medicare beneficiaries who had ADRDs, initiated (no use in prior 6 months) AP (n = 2,035) or AD (n = 1,661) treatment during or after one or more behavioral symptoms (verbally abusive, physically abusive, socially inappropriate or disruptive behavior) presented, and had reassessment of behavioral symptoms after 3 consecutive months of the initiated treatment. Measurements Behavioral symptom change was measured according to score (range 0-9, based on number and frequency of symptoms) change between baseline and reassessment (improved, <0; unchanged, 0; worsened, >0). Survival analyses were conducted on time to death after reassessment, comparing residents whose symptoms improved with those whose symptoms remained unchanged or worsened. Results APs and ADs were comparable in treatment effectiveness, as evidenced by more than 85% of the behavioral symptom episodes in each cohort improving or remaining stable. Mortality risk was lower in both cohorts ( AP: adjusted hazard ratio ( aHRAP) = 0.93, 95% confidence interval ( CI) = 0.81-1.07; AD: aHRAD = 0.82, 95% CI = 0.70-0.97) for residents whose symptoms improved than for those whose symptoms unchanged or worsened. Conclusion ADs may be reasonable pharmacological alternatives to APs in clinical management of ADRD-related behavioral symptoms. Initial treatment response may alter medication-associated mortality risk. Further study is needed to confirm findings using other data and behavioral symptom-specific instruments. [ABSTRACT FROM AUTHOR]

Objectives To examine the influence of quality measures of psychopharmacological medication ( PPM) prescribing on all-cause mortality in a Medicare long-stay nursing home ( NH) population. Design Longitudinal. Setting 2007-09 Medicare data linked to Minimum Data Set 2.0 files. Participants Four new-user cohorts of residents initiating antipsychotic (n = 13,105), antidepressant (n = 14,251), anxiolytic and sedative-hypnotic (n = 10,789), and any PPM (n = 14,568) medication. Measurements Three measures of PPM prescribing quality were assessed monthly with a 6-month look-back: evidence of appropriate indication, dose (modified standardized daily dose ( mSDD); below (<1), at (1), and above (>1) recommended geriatric dose), and duration of therapy (DOT; ≤30, 31-60, 61-90, 91-180 days from medication initiation). Complementary log-log models with quality measures as time-dependent variables were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality. Results Appropriate use of antidepressants, anxiolytics and sedative-hypnotics, and any PPMs, as evidenced by appropriate indications, was significantly associated with lower mortality risk (HRantidepressants = 0.81, 95% CI = 0.76-0.86; HRanxiolytics and sedative-hypnotics = 0.81, 0.75-0.88; HRPPM = 0.89, 0.83-0.95). Antipsychotic and anxiolytic and sedative-hypnotic users with a mSDD of less than 1 had lower mortality risk than those with a mSDD greater than 1, whereas a protective effect was observed in antidepressant users with a mSDD greater than 1. In all four cohorts, those with a DOT of 91 to 180 days had lower mortality than those with a DOT of 1 month or less; the lower risk of mortality was detected after antipsychotic use for 31 days or longer. Conclusion Optimal PPM prescribing quality, as measured by indication and duration, is associated with low mortality. The benefit related to drug dosage varied by therapeutic class. When prescribing PPMs to NH residents, providers should consider not only drug choice, but also dose and duration of prescribed regimens. [ABSTRACT FROM AUTHOR]

Porphyromonas gingivalis is a major pathogen in the initiation and progression of periodontal disease, which is recognized as a common complication of diabetes. ICAM-1 expression by human gingival fibroblasts ( HGFs) is crucial for regulating local inflammatory responses in inflamed periodontal tissues. However, the effect of P. gingivalis in a high-glucose situation in regulating HGF function is not understood. The P. gingivalis strain CCUG25226 was used to study the mechanisms underlying the modulation of HGF ICAM-1 expression by invasion of high-glucose-treated P. gingivalis ( HGPg). A high-glucose condition upregulated fimA mRNA expression in P. gingivalis and increased its invasion ability in HGFs. HGF invasion with HGPg induced increases in the expression of ICAM-1. By using specific inhibitors and short hairpin RNA ( shRNA), we have demonstrated that the activation of p38 MAPK and Akt pathways is critical for HGPg-induced ICAM-1 expression. Luciferase reporters and chromatin immunoprecipitation assays suggest that HGPg invasion increases NF-κ B- and Sp1- DNA-binding activities in HGFs. Inhibition of NF-κ B and Sp1 activations blocked the HGPg-induced ICAM-1 promoter activity and expression. The effect of HGPg on HGF signalling and ICAM-1 expression is mediated by CXC chemokine receptor 4 ( CXCR4). Our findings identify the molecular pathways underlying HGPg-dependent ICAM-1 expression in HGFs, providing insight into the effect of P. gingivalis invasion in HGFs. [ABSTRACT FROM AUTHOR]

Objectives To assess the effect of exposure to evidence-based medication after hospital discharge for Medicare beneficiaries with acute myocardial infarction ( AMI). Design A discrete-time hazard model was used to estimate time to outcome associated with exposure to four drug classes (angiotensin-converting enzyme inhibitors ( ACEIs)/angiotensin-II receptor blockers ( ARBs), beta-blockers ( BBs), statins, and clopidogrel) used for post- AMI secondary prevention of cardiovascular events and mortality. Setting Medicare administrative data for a 5% random sample of beneficiaries. Participants Medicare beneficiaries (N = 9,538) hospitalized for an AMI between April 1, 2006, and December 31, 2007, who survived for at least 30 days after discharge. The cohort was followed until death or December 31, 2008. Measurements Time-varying exposure was measured as proportion of days covered ( PDC) for each quarter during the follow-up period. PDC was classified into five categories (0-0.2, 0.2-0.4, 0.4-0.6, 0.6-0.8, 0.8-1.0). Outcomes were mortality and a composite outcome of death or post- AMI hospitalization. Results Over a median follow-up of 18 months, mean PDC rates ranged from 0.37 (clopidogrel) to 0.50 (statins). When comparing the highest versus lowest categories of exposure, the hazard of the composite outcome was significantly lower for all drug classes except BBs (statins, adjusted hazard ratio (a HR) = 0.71, ACEIs/ ARBs, a HR = 0.81, clopidogrel, a HR = 0.85, BBs, a HR = 0.93). All four drug classes were significantly associated with reductions in mortality; the magnitude of effect for the mortality outcome was largest for statins and smallest for BBs. Age modified the effect of statins on mortality. Conclusion Use of evidence-based medications for secondary prevention after AMI is suboptimal in the Medicare population, and low exposure rates are associated with significantly higher risk for subsequent hospitalization and death. [ABSTRACT FROM AUTHOR]