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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. 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. 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. In similar populations and data settings, the combined score may offer improvements in comorbidity summarization over existing scores.

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.

Advances in heart failure (HF) treatments have prolonged survival, but more patients die of HF than of any type of cancer. Little is known about the current practice in end-of-life (EOL) care in HF. Two EOL cohorts (HF and cancer) were identified using Medicare data linked with pharmacy and cancer registry data. We assessed use of hospice, opiates, and acute care services (hospitalizations, emergency department [ED] visits, intensive care unit [ICU] admissions, and death in acute care). Time trends and predictors of use were assessed using multivariate regression including demographics and cardiovascular and noncardiovasuclar comorbidities. Among 5,836 HF patients with median age of 85, 77% female and 4% black, 20% were referred to hospice compared to 51% of 7,565 cancer patients. A modest rise in hospice use over time was parallel in the 2 groups. Twenty-two percent of HF patients filled opiate prescriptions during 60 days before death compared to 46% of cancer patients. Use of acute care services in the 30 days before death was higher for HF (64% vs 39% for ED visits, 60% vs 45% for hospitalizations, and 19% vs 7% for ICU admission). More HF patients died during acute hospitalizations than cancer patients (39% vs 21%). Patients dying of HF were less likely to be supported by hospice and opiates but more likely to die in hospitals than patients with cancer. Our study suggests that opportunities may exist to improve hospice and opiate use in HF patients.

Purpose Claims data may be a suitable source studying associations between drugs and cancer. However, linkage between cancer registry and claims data including pharmacy-dispensing information is not always available. We examined the accuracy of claims-based definitions of incident cancers and their date of diagnosis. Methods Four claims-based definitions were developed to identify incident leukemia, lymphoma, lung, colorectal, stomach, and breast cancer. We identified a cohort of subjects aged >=65 (1997-2000) from Pennsylvania Medicare and drug benefit program data linked with the state cancer registry. We calculated sensitivity, specificity, and positive predictive values of the claims-based definitions using registry as the gold standard. We further assessed the agreement between diagnosis dates from two data sources. Results All definitions had very high specificity (>=98%), while sensitivity varied between 40% and 90%. Test characteristics did not vary systematically by age groups. The date of first diagnosis according to Medicare data tended to be later than the date recorded in the registry data except for breast cancer. The differences in dates of first diagnosis were within 14 days for 75% to 88% of the cases. Bias due to outcome misclassification of our claims-based definition of cancer was minimal in our example of a cohort study. Conclusions Claims data can identify incident hematologic malignancies and solid tumors with very high specificity with sufficient agreement in the date of first diagnosis. The impact of bias due to outcome misclassification and thus the usefulness of claims-based cancer definitions as cancer outcome markers in etiologic studies need to be assessed for each study setting.

Clinical trials have shown that tumor necrosis factor-α antagonists (TNFAs) confer little benefit, and some may cause potential harm in advanced heart failure (HF). Although TNFAs had significant benefits in treating rheumatoid arthritis (RA), little is known whether the drugs pose an increased risk of HF in older patients with RA. A cohort study was conducted using data from Medicare and drug benefit programs in 2 states (1994-2004). We identified patients with RA aged ≥65 who received TNFA or methotrexate (MTX). The cohort was divided into patients with and without previous HF. We considered demographic variables, cardiovascular risk factors, RA severity-related measures, and other comorbidities. The primary end point was hospitalization with HF. We used stratified Cox proportional hazards regression to estimate the adjusted effect of TNFAs on HF hospitalization. The cohort consisted of 1,002 TNFA users and 5,593 MTX users. There were 59 HF admissions during 1,680 person-years of TNFA use and 227 HF admissions during 10,623 person-years of MTX use. Comparing TNFA with MTX users, the adjusted hazard ratio for HF hospitalization was 1.70 (95% confidence interval 1.07-2.69). We found similar results in patients with and without previous HF. Among patients with previous HF, the adjusted hazard ratio for death was 4.19 (95% confidence interval 1.48-11.89). TNFAs may increase the risk of both first hospitalization and exacerbation of HF in elderly patients with RA. The potential for residual confounding in our study cannot be ruled out; larger and more detailed studies are needed to confirm the findings.

The Orphan Drug Act encourages drug development for rare conditions. However, some orphan drugs become top sellers for unclear reasons. We sought to evaluate the extent and cost of approved and unapproved uses of orphan drugs with the highest unit sales. We assessed prescription patterns for four top-selling orphan drugs: lidocaine patch (Lidoderm) approved for post-herpetic neuralgia, modafinil (Provigil) approved for narcolepsy, cinacalcet (Sensipar) approved for hypercalcemia of parathyroid carcinoma, and imatinib (Gleevec) approved for chronic myelogenous leukemia and gastrointestinal stromal tumor. We pooled patient-specific diagnosis and prescription data from two large US state pharmaceutical benefit programs for the elderly. We analyzed the number of new and total patients using each drug and patterns of reimbursement for approved and unapproved uses. For lidocaine patch, we subcategorized approved prescriptions into two subtypes of unapproved uses: neuropathic pain, for which some evidence of efficacy exists, and non-neuropathic pain. We found that prescriptions for lidocaine patch, modafinil, and cinacalcet associated with non-orphan diagnoses rose at substantially higher rates (average monthly increases in number of patients of 14.6, 1.45, and 1.58) than prescriptions associated with their orphan diagnoses (3.12, 0.24, and 0.03, respectively (p<0.001 for all)). By contrast, for imatinib, approved uses increased significantly over off-label (0.97 vs. 0.47 patients, p<0.001). Spending on off-label uses was highest for lidocaine patch and modafinil (>75%). Increases in lidocaine patch use for non-neuropathic pain far exceeded neuropathic pain (10.2 vs. 3.6 patients, p<0.001). In our sample, three of four top-selling orphan drugs were used more commonly for non-orphan indications. These orphan drugs treated common clinical symptoms (pain and fatigue) or laboratory abnormalities. We should continue to monitor orphan drug use after approval to identify products that come to be widely used for non-FDA approved indications, particularly those without adequate evidence of efficacy.

Hydroxyethyl starch and change in renal function in patients undergoing coronary artery bypass graft surgery. Several case reports and clinical lore have suggested that exposure to the colloid hydroxyethyl starch may impair renal function, but few studies have systematically addressed this issue, and several have produced conflicting results. We sought to study the question in a formal analysis of postoperative change in renal function in patients undergoing coronary artery bypass graft (CABG) surgery. We identified 238 consecutive patients who underwent CABG surgery at a large academic medical center. Glomerular filtration rate (GFR) was estimated using the Cockroft-Gault formula at baseline as well as on postoperative days 3 and 5. Linear regression analysis was used to study the relation between changes in GFR and intraoperative hydroxyethyl starch administration. Multivariate models controlled for potential demographic, clinical, and surgery-related confounders. Hydroxyethyl starch use was independently associated with a reduction in GFR on both postoperative days 3 and 5, with GFR declining by 7.2mL/min/1.73m2 on day 3 per unit of hydroxyethyl starch administered (95% CI, 1.7 to 12.7; P = 0.012), and by 6.6mL/min/1.73m2 on day 5 (95% CI, 1.2 to 11.9; P = 0.018). Intraoperative use of hydroxyethyl starch may be associated with modest impairment in renal function in patients undergoing CABG surgery. Randomized clinical trials will be necessary to confirm these findings and to further investigate their clinical implications.

Background: In the elderly (those aged ≥65 years), retail pharmacy claims are used to study drug use among the uninsured after drug policy changes, to prevent drug—drug interactions and duplication of therapy, and to guide medication therapy management. Claims include only prescriptions filled at 1 pharmacy location or within 1 pharmacy chain and do not include prescriptions filled at outside pharmacies, potentially limiting research accuracy and pharmacy-based safety interventions. Objectives: The aims of this study were to assess elderly patients' pharmacy loyalty and to identify predictors of using multiple pharmacies. Methods: Patients enrolled in the Pharmaceutical Assistance Contract for the Elderly (PACE) pharmacy benefit program with corresponding Medicare claims in the state of Pennsylvania comprised the study cohort. Among patients with pharmacy claims from all pharmacies used in 2004–2005, a primary pharmacy was defined as the pharmacy where at least 50% of a patient's prescriptions were filled. The number of pharmacies/chains used and prescriptions filled in 2005 was calculated. Predictors of using multiple pharmacies in 2005 were age, female gender, white race, urban residency, comorbidities, number of distinct chemical drugs (unique medications) used, and number of prescriptions filled, which were all assessed in 2004. Results: In total, pharmacy claims data from 182,116 patients (147,718 women [81.1%]; mean [SD] age, 78.8 [7.1] years; 168,175 white [92.3%]; 76,580 [42.1%] residing in an urban zip code area) were included. Of the 182,116 PACE patients in the study, a primary pharmacy was identified for 180,751 patients (99.3%). In 2005, patients filled an average of 59.3 prescriptions, with 57.0 prescriptions (96.1%) having been filled at the primary pharmacy. Compared with patients who used ≤5 unique medications in 2004, patients who used 6 to 9 unique medications had 1.38 times (95% CI, 1.34–1.43), and patients who used ≥15 unique medications had a 2.66 times (95% CI, 2.53–2.80) greater likelihood of using multiple pharmacies in 2005. Patients aged ≥85 years were 1.07 times (95% CI, 1.04–1.11) as likely to use multiple pharmacies compared with patients aged 65 to 74 years. Conclusions: This study found that patients aged ≥65 years were loyal to their primary pharmacy, offering reassurance to researchers and pharmacists who use retail pharmacy claims data to evaluate and/or to improve safe and appropriate medication use among the elderly. Care should be used in analyzing claims or managing the drug regimens of patients using multiple medications or patients aged ≥85 years; they are more likely to use multiple pharmacies and thus are more likely to have missing prescription information.

Clinical trials have helped clarify the efficacy of clopidogrel for the treatment and prevention of vascular disease. Costs for its use exceeded $5.9 billion in 2005, making it the second greatest source of drug expenditure in the world. However, little is known about the appropriateness of that use. Overuse of clopidogrel could have important implications for health care quality and drug expenditures. We conducted a retrospective cohort study linking all filled prescriptions to all clinical encounter data for Medicare beneficiaries enrolled in a large state-wide pharmacy assistance program. We identified all patients newly prescribed clopidogrel during a recent 2-year period and determined the proportion who had indications for clopidogrel, the mean number of tablets filled by patients with and without apparent indications in the year after starting therapy, and the costs associated with the observed patterns of clopidogrel use. We identified 4977 patients who were newly prescribed clopidogrel. Of these patients, only 47% had ≥1 documented indications for clopidogrel according to clinical trial findings. Using looser criteria, the number of patients with appropriate indications was 56%. During the first year of therapy, 43% ($2.05 million) of total clopidogrel expenditures for the patients studied was spent on patients without an indication that this agent was required, using the extended criteria for evidence-based use. More than 40% of the clopidogrel used in this population appears to have been prescribed to patients for whom the drug had no documented advantage over aspirin or no antiplatelet therapy. If the same proportion applies nationally, in 2005, it would represent almost $1.5 billion of potentially unnecessary health care expenditure.