Abstract Objective To develop and validate a single numerical comorbidity score for predicting short- and long-term mortality, by combining conditions in the Charlson and Elixhauser measures. Study ...Design and Setting In a cohort of 120,679 Pennsylvania Medicare enrollees with drug coverage through a pharmacy assistance program, we developed a single numerical comorbidity score for predicting 1-year mortality, by combining the conditions in the Charlson and Elixhauser measures. We externally validated the combined score in a cohort of New Jersey Medicare enrollees, by comparing its performance to that of both component scores in predicting 1-year mortality, as well as 180-, 90-, and 30-day mortality. Results C-statistics from logistic regression models including the combined score were higher than corresponding c-statistics from models including either the Romano implementation of the Charlson Index or the single numerical version of the Elixhauser system; c-statistics were 0.860 (95% confidence interval CI: 0.854, 0.866), 0.839 (95% CI: 0.836, 0.849), and 0.836 (95% CI: 0.834, 0.847), respectively, for the 30-day mortality outcome. The combined comorbidity score also yielded positive values for two recently proposed measures of reclassification. Conclusion In similar populations and data settings, the combined score may offer improvements in comorbidity summarization over existing scores.
The association between selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and risk of persistent pulmonary hypertension of the newborn (PPHN) has been controversial ...since the US Food and Drug Administration issued a public health advisory in 2006.
To examine the risk of PPHN associated with exposure to different antidepressant medication classes late in pregnancy.
Cohort study nested in the 2000-2010 Medicaid Analytic eXtract for 46 US states and Washington, DC. Last follow-up date was December 31, 2010.
A total of 3,789,330 pregnant women enrolled in Medicaid from 2 months or fewer after the date of last menstrual period through at least 1 month after delivery. The source cohort was restricted to women with a depression diagnosis and logistic regression analysis with propensity score adjustment applied to control for potential confounders. EXPOSURES FOR OBSERVATIONAL STUDIES: SSRI and non-SSRI monotherapy use during the 90 days before delivery vs no use.
Recorded diagnosis of PPHN during the first 30 days after delivery.
A total of 128,950 women (3.4%) filled at least 1 prescription for antidepressants late in pregnancy: 102,179 (2.7%) used an SSRI and 26,771 (0.7%) a non-SSRI. Overall, 7630 infants not exposed to antidepressants were diagnosed with PPHN (20.8; 95% CI, 20.4-21.3 per 10,000 births) compared with 322 infants exposed to SSRIs (31.5; 95% CI, 28.3-35.2 per 10,000 births), and 78 infants exposed to non-SSRIs (29.1; 95% CI, 23.3-36.4 per 10,000 births). Associations between antidepressant use and PPHN were attenuated with increasing levels of confounding adjustment. For SSRIs, odds ratios were 1.51 (95% CI, 1.35-1.69) unadjusted and 1.10 (95% CI, 0.94-1.29) after restricting to women with depression and adjusting for the high-dimensional propensity score. For non-SSRIs, the odds ratios were 1.40 (95% CI, 1.12-1.75) and 1.02 (95% CI, 0.77-1.35), respectively. Upon restriction of the outcome to primary PPHN, the adjusted odds ratio for SSRIs was 1.28 (95% CI, 1.01-1.64) and for non-SSRIs 1.14 (95% CI, 0.74-1.74).
Evidence from this large study of publicly insured pregnant women may be consistent with a potential increased risk of PPHN associated with maternal use of SSRIs in late pregnancy. However, the absolute risk was small, and the risk increase appears more modest than suggested in previous studies.
Objectives To evaluate the risk of all cause mortality associated with initiating compared with not initiating benzodiazepines in adults, and to address potential treatment barriers and confounding ...related to the use of a non-active comparator group.Design Retrospective cohort study.Setting Large de-identified US commercial healthcare database (Optum Clinformatics Datamart).Participants 1:1 high dimensional propensity score matched cohort of benzodiazepine initiators, and randomly selected benzodiazepine non-initiators with a medical visit within 14 days of the start of benzodiazepine treatment (n=1 252 988), between July 2004 and December 2013. To address treatment barriers and confounding, patients were required to have filled one or more prescriptions for any medication in the 90 days and 91-180 days before the index date (ie, the date of starting benzodiazepine treatment for initiators and the date of the selected medical visit for benzodiazepine non-initiators) and the high dimensional propensity score was estimated on the basis of more than 300 covariates.Main outcome measure All cause mortality, determined by linkage with the Social Security Administration Death Master File.Results Over a six month follow-up period, 5061 and 4691 deaths occurred among high dimensional propensity score matched benzodiazepine initiators versus non-initiators (9.3 v 9.4 events per 1000 person years; hazard ratio 1.00, 95% confidence interval 0.96 to 1.04). A 4% (95% confidence interval 1% to 8%) to 9% (2% to 7%) increase in mortality risk was observed associated with the start of benzodiazepine treatment for follow-ups of 12 and 48 months and in subgroups of younger patients and patients initiating short acting agents. In secondary analyses comparing 1:1 high dimensional propensity score matched patients initiating benzodiazepines with an active comparator, ie, patients starting treatment with selective serotonin reuptake inhibitor antidepressants, benzodiazepine use was associated with a 9% (95% confidence interval 3% to 16%) increased risk.Conclusions This large population based cohort study suggests either no increase or at most a minor increase in risk of all cause mortality associated with benzodiazepine initiation. If a detrimental effect exists, it is likely to be much smaller than previously stated and to have uncertain clinical relevance. Residual confounding likely explains at least part of the small increase in mortality risk observed in selected analyses.
Improvements in Long-Term Mortality After Myocardial Infarction and Increased Use of Cardiovascular Drugs After Discharge: A 10-Year Trend Analysis Soko Setoguchi, Robert J. Glynn, Jerry Avorn, ...Murray A. Mittleman, Raisa Levin, Wolfgang C. Winkelmayer The use of recommended cardiovascular medications after myocardial infarction (MI) has increased during the past decade. Little is known whether the increasing use of drugs contributed to the improvements in MI prognosis. Using data from Medicare and pharmacy programs in 2 states, we assessed trends in the mortality and the contribution to increasing medication use after MI in multivariate models. Among 21,484 MI patients, mortality decreased significantly with a 3% reduction in each year (1995 to 2004). Adjusting for the use of cardiovascular medications completely eliminated the mortality trend, suggesting that the mortality improvement is mainly due to increased use of these medications.
To propose standardized methods for measuring concurrent adherence to multiple related medications and to apply these definitions to a cohort of patients with diabetes mellitus.
Retrospective cohort ...study of 7567 subjects with diabetes prescribed 2 or more classes of oral hypoglycemic agents in 2005.
For each medication class, adherence for each patient was estimated using prescription-based and interval-based measures of proportion of days covered (PDC) from cohort entry until December 31, 2006. Concurrent adherence was calculated by applying these 2 measures in the following 3 ways: (1) the mean of each patient's average PDC, (2) the proportion of days during which patients had at least 1 of their medications available to them, and (3) the proportion of patients with a PDC of at least 80% for all medication classes. Because patients taking multiple related medications have distinct patterns of use, the analysis was repeated after classifying patients into mutually exclusive groups.
Concurrent medication adherence ranged from 35% to 95% depending on the definition applied. Interval-based measures provide lower estimates than prescription-based techniques. Definitions that require the use of at least 1 drug class categorize virtually all patients as adherent. Requiring patients to have a PDC of at least 80% for each of their drugs results in only 30% to 40% of patients being defined as adherent. The variability in adherence is greatest for patients whose treatment regimen changed the most during follow-up.
The variability in adherence estimates derived from different definitions may substantially impact qualitative conclusions about concurrent adherence to related medications. Because the measures we propose have different underlying assumptions, the choice of technique should depend on why adherence is being evaluated.
Background The bias implications of outcome misclassification arising from imperfect capture of mortality in claims-based studies are not well understood. Methods and Results We identified 2 cohorts ...of patients: (1) type 2 diabetes mellitus (n=8.6 million), and (2) heart failure (n=3.1 million), from Medicare claims (2012-2016). Within the 2 cohorts, mortality was identified from claims using the following approaches: (1) all-place all-cause mortality, (2) in-hospital all-cause mortality, (3) all-place cardiovascular mortality (based on diagnosis codes for a major cardiovascular event within 30 days of death date), or (4) in-hospital cardiovascular mortality, and compared against National Death Index identified mortality. Empirically identified sensitivity and specificity based on observed values in the 2 cohorts were used to conduct Monte Carlo simulations for treatment effect estimation under differential and nondifferential misclassification scenarios. From National Death Index, 1 544 805 deaths (549 996 35.6% cardiovascular deaths) in the type 2 diabetes mellitus cohort and 1 175 202 deaths (523 430 44.5% cardiovascular deaths) in the heart failure cohort were included. Sensitivity was 99.997% and 99.207% for the all-place all-cause mortality approach, whereas it was 27.71% and 33.71% for the in-hospital all-cause mortality approach in the type 2 diabetes mellitus and heart failure cohorts, respectively, with perfect positive predicted values. For all-place cardiovascular mortality, sensitivity was 52.01% in the type 2 diabetes mellitus cohort and 53.83% in the heart failure cohort with positive predicted values of 49.98% and 54.45%, respectively. Simulations suggested a possibility for substantial bias in treatment effects. Conclusions Approaches to identify mortality from claims had variable performance compared with the National Death Index. Investigators should anticipate the potential for bias from outcome misclassification when using administrative claims to capture mortality.
Although cyclooxygenase-2 inhibitors (coxibs) were developed to cause less gastrointestinal hemorrhage than nonselective nonsteroidal antiinflammatory drugs (NSAIDs), there has been concern about ...their cardiovascular safety. We studied the relative risk of acute myocardial infarction (AMI) among users of celecoxib, rofecoxib, and NSAIDs in Medicare beneficiaries with a comprehensive drug benefit.
We conducted a matched case-control study of 54 475 patients 65 years of age or older who received their medications through 2 state-sponsored pharmaceutical benefits programs in the United States. All healthcare use encounters were examined to identify hospitalizations for AMI. Each of the 10 895 cases of AMI was matched to 4 controls on the basis of age, gender, and the month of index date. We constructed matched logistic regression models including indicators for patient demographics, healthcare use, medication use, and cardiovascular risk factors to assess the relative risk of AMI in patients who used rofecoxib compared with persons taking no NSAID, taking celecoxib, or taking NSAIDs. Current use of rofecoxib was associated with an elevated relative risk of AMI compared with celecoxib (odds ratio OR, 1.24; 95% CI, 1.05 to 1.46; P=0.011) and with no NSAID (OR, 1.14; 95% CI, 1.00 to 1.31; P=0.054). The adjusted relative risk of AMI was also elevated in dose-specific comparisons: rofecoxib < or =25 mg versus celecoxib < or =200 mg (OR, 1.21; 95% CI, 1.01 to 1.44; P=0.036) and rofecoxib >25 mg versus celecoxib >200 mg (OR, 1.70; 95% CI, 1.07 to 2.71; P=0.026). The adjusted relative risks of AMI associated with rofecoxib use of 1 to 30 days (OR, 1.40; 95% CI, 1.12 to 1.75; P=0.005) and 31 to 90 days (OR, 1.38; 95% CI, 1.11 to 1.72; P=0.003) were higher than >90 days (OR, 0.96; 95% CI, 0.72 to 1.25; P=0.8) compared with celecoxib use of similar duration. Celecoxib was not associated with an increased relative risk of AMI in these comparisons.
In this study, current rofecoxib use was associated with an elevated relative risk of AMI compared with celecoxib use and no NSAID use. Dosages of rofecoxib >25 mg were associated with a higher risk than dosages < or =25 mg. The risk was elevated in the first 90 days of use but not thereafter.
The benefits of statins have been demonstrated for patients with a remote history of coronary artery bypass grafting (CABG); however, no investigation to date has evaluated whether initiation of ...statin therapy in the early months after surgery improves clinical outcomes.
A retrospective cohort of 7503 Medicare patients >/=65 years of age who underwent CABG (1995-2003) was assembled by use of linked hospital and pharmacy claims data. Rates of all-cause mortality and major adverse cardiovascular events were compared between patients who were (n=1745) and were not (n=5788) prescribed statins within 1 month of CABG discharge. Additional analyses evaluated the impact of statin initiation between 1 and 6 months after surgery. Multivariable and propensity score analysis demonstrated that statin use within 1 month of CABG discharge independently reduced the risk of all-cause mortality (adjusted hazard ratio 0.82, 95% confidence interval 0.72 to 0.94) compared with no statin use. Similarly, statin use within 1 month of CABG discharge independently reduced the risk of major adverse cardiovascular events (adjusted hazard ratio 0.89, 95% confidence interval 0.81 to 0.98). Initiation of statin therapy between 1 and 6 months after CABG discharge was also associated with reductions in major adverse cardiovascular events and mortality; however, outcome rates between early (</=1 month after CABG) and delayed (1 to 6 months after CABG) statin initiation were not significantly different.
Statin therapy initiated in the early months after hospital discharge independently reduces all-cause mortality and major adverse cardiovascular events after CABG. These findings validate the widespread practice of prescribing long-term statin therapy after CABG.
Low levels of statin adherence have been documented in patients with coronary artery disease (CAD), but whether coronary revascularization is associated with improved adherence rates has yet to be ...evaluated. We identified all Medicare beneficiaries enrolled in 2 statewide pharmacy assistance programs who were ≥65 years old, who had been hospitalized for CAD from 1995 through 2004, and who had been prescribed statin therapy within 90 days of discharge (n = 13,130). Statin adherence was measured based on the proportion of days covered with statin therapy after hospital discharge, and full adherence was defined as proportion of days covered ≥80%. Statin adherence was compared in patients with CAD treated with medical therapy (n = 3,714), percutaneous coronary intervention (n = 6,309), or coronary artery bypass graft surgery (n = 3,107). Statin adherence significantly increased over the period of the study from 70.5% to 75.4% (p <0.0001). After hospitalization for CAD, patients treated with percutaneous coronary intervention and coronary artery bypass graft surgery had full adherence rates of 70.6% and 70.2%, respectively. Full adherence rates were significantly lower for patients treated with coronary revascularization compared to patients treated with medical therapy (79.4%, p <0.0001). Independent predictors of higher statin adherence included treatment with medical therapy, later year of hospital admission, white race, previous statin use, and use of other cardiac medications after CAD hospitalization (p <0.01 for all comparisons). In conclusion, in patients receiving invasive coronary treatment, statin adherence remains suboptimal, despite strong evidence supporting their use. Given the health and economic consequences of nonadherence, these findings highlight the need for developing cost-effective strategies to improve medication adherence after coronary revascularization.