A pooled analysis of exenatide use and risk of acute pancreatitis.

OBJECTIVE: To estimate the association between exenatide BID use and acute pancreatitis across two claims-based studies. RESEARCH DESIGN AND METHODS: We pooled two cohort studies within separate commercial health insurance databases. We included initiators of exenatide BID and all other antihyperglycemic drugs without prior pancreatitis from 2005-2008. Poisson regression models provided rate ratios (RRs) and 95% confidence intervals (CIs) of the association of exenatide BID with acute pancreatitis adjusted for quintiles of propensity scores. MAIN OUTCOME MEASURES: Primary inpatient diagnoses of acute pancreatitis with correction for misclassification via a validation sub-study. RESULTS: There were 49,956 initiators of exenatide BID and 692,333 initiators of other antihyperglycemic drugs. Patients in the two studies were similar on many demographic and clinical characteristics. Exenatide BID initiators had a higher prevalence of diagnoses consistent with diabetes complications (e.g. peripheral neuropathy) and cardiovascular risk factors (e.g. hypertension). In both studies, current exenatide BID use was not associated with uncorrected outcomes of acute pancreatitis (pooled RR 1.0; CI 0.8-1.3). PPV correction resulted in a slightly higher point estimate for current use (pooled RR 1.3; CI 1.0-1.7) and past use (pooled RR 1.6; 95% CI 1.2-2.1). CONCLUSIONS: These data are consistent with little or no higher risk of acute pancreatitis associated with current exenatide BID use relative to nonuse. Although previous work identified non-causal mechanisms, an increased incidence of acute pancreatitis following cessation of treatment remains a possibility. Bias due to residual confounding or outcome misclassification may remain, and should be considered a potential explanation for these findings.

Branching and capping determine the force-velocity relationships of branching actin networks.

A branching actin network is the major engine that drives cell motility. A measure of the effectiveness of an engine is the velocity the engine is able to produce at a given resistance-the force-velocity relationship. Concave force-velocity relationships consist of a force-insensitive region, indicative of an adaptive response. In contrast, convex force-velocity relationships would reflect a passive response. Even in in vitro experiments, branching actin networks can exhibit both concave and convex force-velocity curves. However, the exact mechanism that can explain both force-velocity curves is not yet known. We carried out an agent-based stochastic simulation to explore such a mechanism. We discovered an emergent behavior of a branching actin network: Upon resistance, it remodels itself by increasing the number of filaments growing in contact with the load. The remodeling is favored by branching events and limited by capping. The force-velocity relationship hinges on the relative time-scale between the intrinsic kinetics of the branching actin network and the loading. Shortly after encountering resistance (∼seconds), the force-velocity relationship of the actin network is always convex, as it does not have enough time to remodel itself. A concave force-velocity relationship requires network remodeling at longer time-scales (∼tens of seconds to minutes) and the faster branching event relative to capping. Furthermore, our model explains the observed hysteresis in the force-velocity relationship of actin networks. Our model thus establishes a unified mechanism that can account for both convex and concave force-velocity relationships observed in branching actin networks.

MDMS: Molecular Dynamics Meta-Simulator for evaluating exchange type sampling methods.

Replica exchange methods have become popular tools to explore conformational space for small proteins. For larger biological systems, even with enhanced sampling methods, exploring the free energy landscape remains computationally challenging. This problem has led to the development of many improved replica exchange methods. Unfortunately, testing these methods remains expensive. We propose a Molecular Dynamics Meta-Simulator (MDMS) based on transition state theory to simulate a replica exchange simulation, eliminating the need to run explicit dynamics between exchange attempts. MDMS simulations allow for rapid testing of new replica exchange based methods, greatly reducing the amount of time needed for new method development.

Patient Out-of-Pocket Payments for Oral Oncolytics: Results From a 2009 US Claims Data Analysis.

PURPOSE: Oral oncolytics are an increasingly important treatment option for cancer. These agents often fall within the pharmacy benefit, with the potential for increased out-of-pocket (OOP) cost burden for patients. The purpose of this study was to evaluate patient OOP payments for oral oncolytic therapies in US managed care plans. MATERIALS AND METHODS: Patients age ≥ 18 years who received one of 21 oral oncolytics were identified in 2009 US claims; the first oral therapy was the index therapy. OOP payments were calculated as the allowed amount (dollar amount a health plan allows for a therapy, including member liability) minus the paid amount (dollar amount paid by a health plan). Patient characteristics were provided, and per-claim OOP payments were evaluated for each of the 21 therapies in aggregate and stratified by payer type and index therapy. RESULTS: A total of 6,094 patients who received at least one oral oncolytic therapy were identified. Mean age was 53 years; 54% were women; 77% had a commercial payer; prevalent cancer diagnoses included breast, colorectal, glioblastoma, and lung. Mean OOP payments were highest for dasatinib ($527; median, $36) and lowest for cyclophosphamide ($15; median, $10). Medicare Risk patients had higher mean OOP payments for most therapies compared with commercial, Medicaid, and self-insured patients. CONCLUSION: Among 21 oral oncolytics, average OOP cost ranged from $15 to > $500. These results confirm previous findings showing OOP payments differing widely among oral oncolytic options. As cost for therapy becomes a greater part of treatment decisions, an understanding of patient OOP cost will be critical in informing choices.

Patient out-of-pocket payments for oral oncolytics: results from a 2009 US claims data analysis.

OBJECTIVES: Oral oncolytics are an increasingly important treatment option for cancer. These agents often fall within the pharmacy benefit, with the potential for increased out-of-pocket (OOP) cost burden for patients. The purpose of this study was to evaluate patient OOP payments for oral oncolytic therapies in US managed care plans. MATERIALS AND METHODS: Patients aged >18 years who received 1 of 21 oral oncolytics were identified in 2009 US claims; the first oral therapy was the index therapy. OOP payments were calculated as the allowed amount (dollar amount a health plan allows for a therapy, including member liability) minus the paid amount (dollar amount paid by a health plan). Patient characteristics were provided, and per-claim OOP payments were evaluated for each of the 21 therapies in aggregate and stratified by payer type and index therapy. RESULTS: A total of 6094 patients who received at least 1 oral oncolytic therapy were identified. Mean age was 53 years; 54% were women; 77% had a commercial payer; prevalent cancer diagnoses included breast, colorectal, glioblastoma, and lung. Mean OOP payments were highest for dasatinib ($527; median, $36) and lowest for cyclophosphamide ($15; median, $10). Medicare Risk patients had higher mean OOP payments for most therapies compared with commercial, Medicaid, and self-insured patients. CONCLUSIONS: Among 21 oral oncolytics, average OOP cost ranged from $15 to >$500. These results confirm previous findings showing OOP payments differing widely among oral oncolytic options. As cost for therapy becomes a greater part of treatment decisions, an understanding of patient OOP cost will be critical in informing choices.

Effect of a continuous measure of adherence with infliximab maintenance treatment on inpatient outcomes in Crohn's disease.

BACKGROUND: To assess the impact of a continuous measure of adherence with infliximab maintenance treatment in Crohn's disease (CD) during the first year of treatment on CD-related health care utilization, CD-related hospitalizations, inpatient costs, and length of hospital stay. PATIENTS AND METHODS: A retrospective claims analysis using the IMS LifeLink Health Plan Claims Database (September 1, 2004, to June 30, 2009) was conducted. Continuous enrollment for 12 months before and 12 months after the index date was required. Patients were required to have at least two claims with an International Classification of Diseases, 9th Revision, Clinical Modification diagnosis code for CD (555.xx) pre-index and be aged ≥ 18 years at index. Patients with three infusions during the first 56 days post-index and at least one infusion following day 56 post-index were considered to have maintenance therapy. Adherence and nonadherence were defined as a medication possession ratio of ≥ 80% and < 80%, respectively. RESULTS: Four hundred forty-eight patients were included in the analysis (mean age, 42.6 years; 56% female; mean ± standard deviation [SD] and median number of infliximab infusions, 7.35 ± 1.60 and 8). The number of patients who met the definition of adherence was 344 (77%). CD-related health care utilization was not significantly impacted by adherence except for ancillary services and radiology. Fewer adherent patients were hospitalized compared with nonadherent patients (9% versus 16%; P = 0.03). Adherent patients had fewer mean ± SD and median days in the hospital (5.5 ± 3.4 and 5 days) compared with nonadherent patients (13.1 ± 14.2 and 8 days; P = 0.01). Mean ± SD and median hospital costs were significantly greater for nonadherent patients ($40,822 ± $49,238 and $28,864) compared with adherent patients ($13,704 ± $10,816 and $9938; P = 0.002). CONCLUSION: Adherence with maintenance infliximab over 12 months was associated with lower rates of CD-related hospitalizations and inpatient costs and a shorter length of hospital stay.

Impact of infliximab adherence on Crohn's disease-related healthcare utilization and inpatient costs.

INTRODUCTION: Few published reports have described the impact of adherence with biologic agents on hospitalizations and inpatient costs in Crohn's disease (CD). METHODS: A retrospective claims analysis using the IMS LifeLink Health Plan Claims Database between September 1, 2004 and June 30, 2009 was conducted. Continuous enrollment for 12 months before and 12 months after the index date was required. Patients were required to have ≥2 claims with an International Classification of Diseases, 9th Edition, Clinical Modification diagnosis code for CD (555.xx) preindex, be ≥18 years of age at index, and have ≥4 infliximab infusions with a gap no greater than 12 weeks between each infusion. Patients with 7-9 infliximab infusions (12 months postindex) were considered adherent; patients with 4-6 infliximab infusions were considered nonadherent. RESULTS: In total, 638 patients were included in the analyses (mean age, 43 years; 58% female in the adherent group and 53% in the nonadherent group). The number of patients who met the definition of adherence was 466 (73%). A smaller proportion of adherent patients had a CD-related emergency room visit, compared with nonadherent patients (11% vs. 17%, P=0.029). A smaller proportion of adherent patients required CD-related hospitalization, compared with nonadherent patients (8% vs. 12%, P=0.117). Among those hospitalized, adherent patients had fewer mean [median] days in the hospital (5.9 [5] days), compared with nonadherent patients (12.8 [8] days, P=0.015). Mean [median] hospital costs were significantly lower for adherent patients ($13,427 [$9,352]), compared with nonadherent patients ($37,783 [$28,864], P=0.001). Multivariate analyses confirmed lower inpatient (P<0.001) costs for adherent versus nonadherent patients. CONCLUSION: Adherence with infliximab therapy during the first year of treatment in patients with CD was associated with a shorter hospital length of stay and lower inpatient costs compared with nonadherent patients. Strategies for increasing adherence rates to infliximab maintenance therapy may be valuable in reducing hospitalizations and inpatient costs in patients with CD.

Impact of persistence with infliximab on hospitalizations in ulcerative colitis.

OBJECTIVES: To assess infliximab infusion patterns in ulcerative colitis (UC) and assess the impact of persistence with infliximab maintenance therapy on UC-related hospitalizations, lengths of stay, and inpatient costs. STUDY DESIGN: Retrospective analysis of medical claims for UC patients newly initiating infliximab treatment. METHODS: Patients were aged >18 years and had 2 UC diagnosis codes, an infliximab index date between September 1, 2005, and January 31, 2008, and continuous enrollment for >12 months before and >14 months after the index date. Infliximab induction (first 56 days postindex) and maintenance (>56 days and <12 months postinduction) patterns were evaluated. Of patients with maintenance treatment, persistence was defined as a medication possession ratio (MPR) of >80%, and this group was compared with those without persistence (<80% MPR). RESULTS: Overall, 420 patients were included in the analysis; 84.3% (n = 354) continued to maintenance therapy. Maintenance infusion patterns were consistent with recommended prescribing information. A smaller proportion of patients with maintenance therapy persistence required hospitalization compared with patients without persistence (3.0% vs 20.4%; P <.001). Hospitalized patients with maintenance therapy persistence had significantly lower mean inpatient costs ($14,243 vs $32,745; P = .046), with a trend toward shorter mean lengths of stay (6.67 vs 9.71 days; P = .147) than patients without persistence. CONCLUSIONS: Infliximab maintenance therapy persistence in UC was associated with significantly fewer hospitalizations. Once hospitalized, patients with therapeutic persistence had significantly decreased inpatient costs.

Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the LifeLink database.

OBJECTIVE: To test the hypothesis that exenatide twice daily reduces the relative incidence of cardiovascular disease (CVD) events among patients with type 2 diabetes compared with other glucose-lowering agent(s). RESEARCH DESIGN AND METHODS: A retrospective database analysis was performed of the LifeLink database of medical and pharmaceutical insurance claims for June 2005 through March 2009. Patients with no history in the preceding 9 months of myocardial infarction, ischemic stroke, or coronary revascularization procedure were assigned to the exenatide-initiated or non-exenatide-initiated cohorts based on the first new prescription filled and reassigned if exenatide was prescribed or discontinued. Incident CVD events (myocardial infarction, ischemic stroke, or coronary revascularization procedure) were identified by ICD-9-CM diagnosis codes. Patient outcomes were adjusted for differences in clinical and demographic characteristics and compared using propensity score-weighted discrete time survival analysis with time-varying exposure to exenatide. RESULTS: A total of 39,275 patients with type 2 diabetes were treated with exenatide twice daily, and 381,218 patients were treated with other glucose-lowering therapies. Patients who initiated exenatide were more likely to have prior ischemic heart disease, obesity, hyperlipidemia, hypertension, and/or other comorbidities at baseline. Exenatide-treated patients were less likely to have a CVD event than non-exenatide-treated patients (hazard ratio 0.81; 95% CI 0.68-0.95; P = 0.01) and lower rates of CVD-related hospitalization (0.88; 0.79-0.98; P = 0.02) and all-cause hospitalization (0.94; 0.91-0.97; P < 0.001). CONCLUSIONS: Exenatide twice-daily treatment was associated with a lower risk of CVD events and hospitalizations than treatment with other glucose-lowering therapies.

Comparing adherence and persistence across 6 chronic medication classes.

BACKGROUND: The National Quality Forum recently endorsed the proportion of days covered (PDC)-a measure of medication adherence-as an indicator of quality in drug therapy management. OBJECTIVE: To inform initial efforts to improve the quality of drug therapy management, we compared PDC and persistence among new users of 6 commonly used chronic medication categories. METHODS: A retrospective analysis of pharmacy claims in a database of more than 64 million members enrolled in 100 health plans assessed persistence and adherence to drug therapy in 6 chronic conditions. Patients were included in the analysis if they initiated a prescription drug of interest in any of 6 drug classes-prostaglandin analogs, statins, bisphosphonates, oral antidiabetics, angiotensin II receptor blockers (ARBs), and overactive bladder (OAB) medications-between January 1 and December 31, 2005. The first claim for a drug of interest during this period was considered a patient's index date. Patients were required to have a minimum of 12 months of continuous enrollment both preceding and following their index date. New users of a treatment were identified by excluding patients who filled a prescription for any drug in the same class during the previous 12 months and were followed for a minimum of 12 months. Nonpersistence was defined as discontinuation of the therapy class following an allowed gap between refills-30-, 60-, and 90-day refill gaps were used. Adherence was defined as a continuous measure of the proportion of days covered (PDC) during the 12-month post-index period. Logistic regression analyses predicted (a) nonpersistence during the 12-month post-index period and (b) adherence (PDC) of at least 80%, with drug class as the predictor variable of interest, controlling for demographic variables, insurance and plan type, history of hospitalization, Charlson comorbidity score, copayment for index medication, and number of medications at index. RESULTS: A total of 167,907 patients were identified across 6 cohorts. Using the 60-day gap, 6-month persistence rates were prostaglandin analogs 47%, statins 56%, bisphosphonates 56%, oral antidiabetics 66%, ARBs 63%, and OAB medications 28%. After the first 90 days of therapy, relative persistence was stable across cohorts, and rates declined consistently from 6 months post-index to study end. Logistic regression models showed that oral antidiabetic users had a 59%, 36%, 37%, and 79% decreased risk of nonpersistence in a 12-month follow-up period compared with patients taking prostaglandin analogs, statins, bisphosphonates, or OAB medications, respectively. Risk of nonpersistence decreased with increasing age. Mean (SD) 12-month adherence rates were: prostaglandin analogs 37% (26%), statins 61% (33%), bisphosphonates 60% (34%), oral antidiabetics 72% (32%), ARBs 66% (32%), and OAB medications 35% (32%). Logistic regression indicated that oral antidiabetic use was a significant predictor of adherence (PDC) of at least 80% compared with other therapy classes. Adjusted odds ratios for oral antidiabetics were 17.60 (95% confidence interval [CI] = 15.38-20.14) versus prostaglandin analogs, 2.06 (95% CI = 1.99-2.12) versus statins, 1.92 (95% CI = 1.83-2.02) versus bisphosphonates, 1.29 (95% CI = 1.24-1.34) versus ARBs, and 5.77 (95% CI = 5.38-6.19) versus OAB medications. CONCLUSION: This analysis of adherence (PDC) and persistence across a sample of 6 chronic therapies found variable but uniformly suboptimal medication use. Adherence to prostaglandin eye drops and OAB medications was lower than to cardiovascular, oral antidiabetic, and oral osteoporosis therapies. These findings provide useful baseline information for the development of initiatives to improve the quality of drug therapy management.

Survival and changes in comorbidities after bariatric surgery.

OBJECTIVE: To evaluate survival rates and changes in weight-related comorbid conditions after bariatric surgery in a high-risk patient population as compared with a similar cohort of morbidly obese patients who did not undergo surgery. SUMMARY BACKGROUND DATA: Morbid obesity is increasingly becoming a major public health issue. Existing studies are limited in their ability to assess the risks and benefits of bariatric surgery because few studies compare surgical patients to a similar, morbidly obese, nonsurgical cohort, especially in high-risk populations like the elderly and disabled. METHODS: A retrospective cohort analysis using Medicare fee-for-service patients from 2001 to 2004. Survival rates and diagnosed presence of 5 conditions commonly comorbid with morbid obesity were examined for morbidly obese patients who did and did not undergo bariatric surgery, with up to 2 years follow-up. RESULTS: Morbidly obese Medicare patients who underwent bariatric surgery had increased survival rates over the 2 years of this study when compared with a similar morbidly obese nonsurgical group (P < 0.001). For patients under the age of 65, this survival advantage started at 6 months postoperatively and for patients over age 65, at 11 months. The surgical group also experienced significant improvements in the diagnosed prevalence of 5 weight-related comorbid conditions (diabetes, sleep apnea, hypertension, hyperlipidemia, and coronary artery disease) relative to the nonsurgical cohort after 1 year postsurgery (P < 0.001). CONCLUSIONS: Bariatric surgery appears to increase survival even in the high-risk, Medicare population, both for individuals aged 65 and older and those disabled and under 65. In addition, the diagnosed prevalence of weight-related comorbid conditions declined after bariatric surgery relative to a control cohort of morbidly obese patients who did not undergo surgery.