Evaluation of Adherence and Persistence Differences Between Adalimumab Citrate-Free and Citrate Formulations for Patients with Immune-Mediated Diseases in the United States.

INTRODUCTION: Our aim was to evaluate patient adherence and persistence with citrate-free adalimumab (ADA-CF), introduced in 2018 to reduce injection-site pain, compared with citrate-containing adalimumab (ADA-C). METHODS: This was a retrospective cohort study using a US claims database (IBM® MarketScan® Commercial and Medicare Supplemental Claims Database) from February 2018 to January 2020. Patients at least 18 years of age who were naïve to adalimumab 6 months before the index date (date of first adalimumab claim) and with at least 12 months of continuous medical and pharmacy coverage were eligible for the study. Adherence was assessed by determining the proportion of days covered (PDC) and the percentage of patients with PDC ≥ 80% during the 12-month follow-up period. Persistence was evaluated by measuring the rate of discontinuation and days to discontinuation (i.e., time on treatment) from the index date over the 12-month follow-up period. Continuous adherence outcomes (PDC) were evaluated using linear regression models. Binary adherence outcomes (PDC ≥ 80%) were assessed using logistic regression models. Kaplan-Meier analysis and Cox proportional hazards models were used to assess persistence outcomes. RESULTS: There were 2195 and 1005 patients in the ADA-CF and ADA-C cohorts, respectively, with most using adalimumab for rheumatoid arthritis (ADA-CF 29.7%, ADA-C 27.2%) and psoriasis (ADA-CF 24.5%, ADA-C 31.9%). Significantly greater adherence was achieved with ADA-CF compared with ADA-C (mean PDC [standard deviation] 0.68 [0.30] vs 0.61 [0.32], P < 0.0001). A significantly greater percentage of patients receiving ADA-CF (47.2%) vs ADA-C (39.6%) had PDC ≥ 80% (P < 0.0001). The discontinuation rate was significantly lower for the ADA-CF cohort (46.4%) compared with ADA-C (55.9%, P < 0.0001), resulting in a 27% lower likelihood of discontinuation during the 12-month follow-up period (hazard ratio 0.73; 95% confidence interval 0.66, 0.82; P < 0.0001) and longer time on treatment (260 vs 232 days, P < 0.0001). CONCLUSION: Adherence and persistence are significantly improved with ADA-CF compared with ADA-C.

Deep phenotyping of 34,128 adult patients hospitalised with COVID-19 in an international network study.

Comorbid conditions appear to be common among individuals hospitalised with coronavirus disease 2019 (COVID-19) but estimates of prevalence vary and little is known about the prior medication use of patients. Here, we describe the characteristics of adults hospitalised with COVID-19 and compare them with influenza patients. We include 34,128 (US: 8362, South Korea: 7341, Spain: 18,425) COVID-19 patients, summarising between 4811 and 11,643 unique aggregate characteristics. COVID-19 patients have been majority male in the US and Spain, but predominantly female in South Korea. Age profiles vary across data sources. Compared to 84,585 individuals hospitalised with influenza in 2014-19, COVID-19 patients have more typically been male, younger, and with fewer comorbidities and lower medication use. While protecting groups vulnerable to influenza is likely a useful starting point in the response to COVID-19, strategies will likely need to be broadened to reflect the particular characteristics of individuals being hospitalised with COVID-19.

Deep phenotyping of 34,128 patients hospitalised with COVID-19 and a comparison with 81,596 influenza patients in America, Europe and Asia: an international network study.

Background In this study we phenotyped individuals hospitalised with coronavirus disease 2019 (COVID-19) in depth, summarising entire medical histories, including medications, as captured in routinely collected data drawn from databases across three continents. We then compared individuals hospitalised with COVID-19 to those previously hospitalised with influenza. Methods We report demographics, previously recorded conditions and medication use of patients hospitalised with COVID-19 in the US (Columbia University Irving Medical Center [CUIMC], Premier Healthcare Database [PHD], UCHealth System Health Data Compass Database [UC HDC], and the Department of Veterans Affairs [VA OMOP]), in South Korea (Health Insurance Review & Assessment [HIRA]), and Spain (The Information System for Research in Primary Care [SIDIAP] and HM Hospitales [HM]). These patients were then compared with patients hospitalised with influenza in 2014-19. Results 34,128 (US: 8,362, South Korea: 7,341, Spain: 18,425) individuals hospitalised with COVID-19 were included. Between 4,811 (HM) and 11,643 (CUIMC) unique aggregate characteristics were extracted per patient, with all summarised in an accompanying interactive website (http://evidence.ohdsi.org/Covid19CharacterizationHospitalization/). Patients were majority male in the US (CUIMC: 52%, PHD: 52%, UC HDC: 54%, VA OMOP: 94%,) and Spain (SIDIAP: 54%, HM: 60%), but were predominantly female in South Korea (HIRA: 60%). Age profiles varied across data sources. Prevalence of asthma ranged from 4% to 15%, diabetes from 13% to 43%, and hypertensive disorder from 24% to 70% across data sources. Between 14% and 33% were taking drugs acting on the renin-angiotensin system in the 30 days prior to hospitalisation. Compared to 81,596 individuals hospitalised with influenza in 2014-19, patients admitted with COVID-19 were more typically male, younger, and healthier, with fewer comorbidities and lower medication use. Conclusions We provide a detailed characterisation of patients hospitalised with COVID-19. Protecting groups known to be vulnerable to influenza is a useful starting point to minimize the number of hospital admissions needed for COVID-19. However, such strategies will also likely need to be broadened so as to reflect the particular characteristics of individuals hospitalised with COVID-19.

Relationship of hospital-associated bleeding with length of stay and total hospitalization costs in patients hospitalized for atrial fibrillation.

BACKGROUND: While literature has focused on the impact of bleeding beginning outside the hospital setting among patients with atrial fibrillation (AF), there is little information regarding bleeding that first occurs within a hospital setting. This study was performed to determine the association between hospital-associated bleeding in patients admitted for AF on outcomes of length of stay (LOS) and total hospitalization cost. METHODS AND RESULTS: The Premier research database was queried to identify adult inpatients discharged between 2008-2011 having a primary diagnosis code for AF where a bleeding diagnosis code was not present on admission. Regression was used to adjust for baseline differences in patients to estimate outcomes comparing patients with and without a hospital-associated bleed. There were 143,287 patients that met the study criteria. There were 2991 (2.1%) patients identified with a hospital associated bleed. After adjustment for covariates, the mean estimated LOS was significantly greater in the bleed group, at 6.0 days (95% CI = 5.8-6.1) vs the no bleed group at 3.3 days (95% CI = 3.3-3.3) (p < 0.0001). Similarly, the adjusted mean estimated total hospitalization cost was also significantly greater in the bleed group, $12,069 (95% CI = $11,779-$12,366) vs $6561 (95% CI = $6538-$6583) in the no bleed group (p < 0.0001). CONCLUSIONS: After adjustments for baseline differences the data show that the 2.1% (n = 2991) of patients with hospital associated bleeding accounted for an estimated additional 8106 hospitalization days and $16.4 million dollars in cost over the study period compared to non-bleeders.

Comparison of hospital length of stay between hospitalized non-valvular atrial fibrillation patients treated with either apixaban or warfarin.

BACKGROUND: Hospital length of stay (LOS) is an important cost driver for hospitals and payers alike. Hospitalized non-valvular atrial fibrillation (NVAF) patients treated with apixaban may have shorter LOS than those treated with warfarin because of the absence of need for INR monitoring in apixaban. Thus, this study compared hospital LOS between hospitalized NVAF patients treated with either apixaban or warfarin. METHODS: This was a retrospective, observational cohort study based on a large US database including diagnosis, procedure, and drug administration information from >600 acute-care hospitals. Patients selected for study were aged ≥18 years and had a hospitalization record with an ICD-9-CM diagnosis code for atrial fibrillation (AF) in any position from 1 January 2013 to 28 February 2014 (index hospitalization). Patients with diagnoses indicative of rheumatic mitral valvular heart disease or a valve replacement procedure during index hospitalization were excluded. Patients were required to have been treated with either apixaban or warfarin, and not treated with rivaroxaban or dabigatran, during index hospitalization. Apixaban patients were propensity score (PS) matched to warfarin patients at a 1:1 ratio, using patient demographic/clinical and hospital characteristics. The study outcome was hospital LOS, calculated as discharge date minus admission date; a sensitivity analysis calculated hospital LOS as discharge date minus first anticoagulant administration date. Sub-analyses were conducted among patients with a primary diagnosis of AF. RESULTS: The study included 832 apixaban patients matched to 832 warfarin patients. Mean [standard deviation (SD)] and median hospital LOS were significantly (p < 0.001) shorter in apixaban patients (4.5 [4.2] and 3 days) than in warfarin patients (5.4 [5.0] and 4). Results were consistent in the sensitivity and sub-analyses. CONCLUSIONS: Among NVAF patients, apixaban treatment was associated with shorter hospital LOS when compared with warfarin treatment. These findings may have important clinical and economic implications for hospitals, payers, and patients.

Evaluation of medical costs avoided when new oral anticoagulants are used for extended treatment of venous thromboembolism based on clinical trial results.

This study evaluated avoidances in medical costs associated with clinical endpoints from randomized clinical trials that evaluated the efficacy and safety of the new oral anticoagulants (NOACs), dabigatran, rivaroxaban, and apixaban for extended treatment of patients with venous thromboembolism (VTE). Event rates of efficacy and safety endpoints from the clinical trials (RE-SONATE, EINSTEIN-EXT, and AMPLIFY-EXT) were obtained from published literature. Incremental annual medical costs among patients with clinical events from a US payer perspective were obtained from the literature or healthcare claims databases and inflation adjusted to 2013 costs. Differences in total medical costs associated with clinical endpoints for patients treated with NOACs versus placebo were then estimated. One-way univariate and Monte Carlo sensitivity analyses were additionally carried out. In all three NOAC trials lower rates of recurrent VTE occurred with NOAC use versus placebo. As a result of the reduction in VTE recurrence the overall medical costs avoided were -$2,794, -$2,948, -$4,249, and -$4,244 for VTE patients treated with dabigatran, rivaroxaban, apixaban 2.5 mg, and apixaban 5 mg respectively versus patients treated with placebo. Apixaban was associated with the greatest avoidance in medical costs, which was driven mainly by a greater reduced rate in recurrent VTE than other NOACs versus placebo and also a reduction in major bleeding rate. Further evaluation is needed to validate these results in the real-world setting.

The impact of ribavirin on real-world adherence rates in hepatitis C patients treated with sofosbuvir plus simeprevir.

BACKGROUND: Combination therapy with sofosbuvir (SOF) and simeprevir (SIM) is used to treat patients with hepatitis C virus infection. It is currently unknown whether adding ribavirin (RBV) to SOF + SIM, which raises the pill count from two up to eight pills a day, impacts adherence. The aim of this study is to examine the impact of pill count on real-world adherence rates in patients treated with SOF + SIM with and without RBV. METHODS: This retrospective study assessed composite adherence to SOF and SIM over 12 weeks of treatment for two cohorts of hepatitis C patients: one initiating SOF + SIM therapy, and the other initiating SOF + SIM + RBV therapy. Analyses were conducted using MarketScan(®) and Optum US commercial pharmacy claims and enrollment data. Adherence was adjusted by treatment regimen, age, sex, co-pay, presence/absence of cirrhosis, treatment history, and Charlson Comorbidity Index. RESULTS: There was a significant difference in composite unadjusted and adjusted adherence rates for SOF and SIM for the SOF + SIM vs SOF + SIM + RBV cohorts based on MarketScan data (unadjusted, 92.6% and 89.7%, respectively; P=0.0423; adjusted, 92.2% and 88.7%, respectively; P=0.0176), but not based on Optum data (unadjusted, 94.8% and 95.6%, respectively; P=0.5618; adjusted, 94.8% and 95.1%, respectively; P=0.8589). In the MarketScan and Optum databases, there were no statistical differences in unadjusted and adjusted adherence rates for SOF. Unadjusted and adjusted adherence rates for SIM were mixed, as they were for composite adherence. CONCLUSION: The impact of the addition of RBV to SOF + SIM therapy was mixed. The impact of RBV on SOF adherence was not significant in either database.

Comparison of Medical Costs of Patients With Atrial Fibrillation Unsuitable for Warfarin Treatment With Apixaban or Aspirin Based on AVERROES Trial.

BACKGROUND: The AVERROES trial name is the following: The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial demonstrated that apixaban reduced the risk of stroke relative to aspirin, without significantly increasing major bleeding risk in patients with atrial fibrillation (AF) considered unsuitable for warfarin therapy. Based on AVERROES trial results, this study compared the medical costs for clinical end points among patients with AF treated with either apixaban or aspirin. METHODS: Medical costs per patient-year for clinical events were determined. Based on clinical event rates for patients in the AVERROES trial, medical costs excluding drug costs were estimated for apixaban- and aspirin-treated patient groups. RESULTS AND CONCLUSIONS: Based on AVERROES trial results, among patients with AF unsuitable for warfarin therapy, apixaban use was estimated to be associated with a mean medical cost avoidance of US$735 in a patient-year relative to aspirin. The primary driver was the significant reduction in ischemic stroke rate. The medical cost reduction associated with apixaban use was consistent in sensitivity analyses.

Reviewing a clinical decision aid for the selection of anticoagulation treatment in patients with nonvalvular atrial fibrillation: applications in a US managed care health plan database.

PURPOSE: The Clinical Decision Aid was created to assist in selecting anticoagulant therapies for patients with nonvalvular atrial fibrillation. The aid incorporates a patient's absolute risk for stroke and bleeding, relative stroke risk reduction, and increase in relative bleeding risk to identify the agent with the lowest net risk. We describe theoretical implications of utilizing the aid at a US managed care population level. METHODS: This retrospective study used claims data from a large US managed care database including enrollees in commercial and Medicare Advantage plans. The distribution of patients across each possible combination of scores on the HAS-BLED scale (evidence of hypertension, abnormal renal or liver function, stroke, bleeding, labile INR, age >65 years, and drugs or alcohol abuse or dependence) and the CHA2DS2-VASc scale (CHADS2 [congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism] with additional nonmajor stroke risk factors, including age 65-74 years, female sex, and vascular disease) was generated. We assessed the correlation between the HAS-BLED and CHA2DS2-VASc scores and derived the optimal treatment options based on various bleeding ratios. FINDINGS: Data from 48,260 patients were included in the analysis. The MAPD subset had a higher mean HAS-BLED score (2.17 vs 1.39; P < 0.001) and a higher mean CHA2DS2-VASc score (3.35 vs 2.05; P < 0.001) than did the commercial subset. Pearson coefficients suggested a moderate to strong positive correlation between the HAS-BLED and CHA2DS2-VASc scores among the commercial (0.730; P < 0.001) and MAPD (0.568; P < 0.001) enrollees. Based on a 2:1 bleeding-to-stroke risk ratio, 70.50% of patients would be recommended treatment with apixaban; 25.86%, no treatment; 3.62%, acetylsalicylic acid; and 0.01%, dabigatran 150 mg, if the Clinical Decision Aid were to be used for anticoagulant treatment selection. IMPLICATIONS: Evidence-based clinical decision-making tools utilizing risk assessment for recommending a treatment may be valuable for not only health care providers but also health care payers in optimizing care at the population level.

Evaluation of medical costs associated with use of new oral anticoagulants compared with standard therapy among venous thromboembolism patients.

OBJECTIVE: This study evaluated differences in medical costs associated with clinical end-points from randomized clinical trials that compared the new oral anticoagulants (NOACs), dabigatran, rivaroxaban, apixaban, and edoxaban, to standard therapy for treatment of patients with venous thromboembolism (VTE). RESEARCH DESIGN AND METHODS: Event rates of efficacy and safety end-points from the clinical trials (RE-COVER, RE-COVER II, EINSTEIN-Pooled, AMPLIFY, Hokusai-VTE trial) were obtained from published literature. Incremental annual medical costs among patients with clinical events from a US payer perspective were obtained from the literature or healthcare claims databases and inflation adjusted to 2013 costs. Differences in total medical costs associated with clinical end-points for the NOACs vs standard therapy were then estimated. One-way and Monte Carlo sensitivity analyses were carried out. RESULTS: A lower rate of major bleedings was associated with use of any of the NOACs vs standard therapy. Except for dabigatran, use of NOACs was also associated with a lower rate of recurrent VTE/death. As a result of the reduction in clinical event rates, the overall medical cost differences were -$146, -$482, -$918, and -$344 for VTE patients treated with dabigatran, rivaroxaban, apixaban, and edoxaban, respectively, vs patients treated with standard therapy. CONCLUSIONS: When any of the four NOACs are used instead of standard therapy for acute VTE, treatment medical costs are reduced. Apixaban is associated with the greatest reduction in medical costs, which is driven by medical cost reductions associated with both efficacy and safety end-points. Further evaluation may be needed to validate these results in the real-world setting.

Depression monitoring and patient behavior in the Clinical Outcomes in MEasurement-Based Treatment (COMET) trial.

OBJECTIVE: In this secondary analysis of results of the Clinical Outcomes in MEasurement-Based Treatment (COMET) trial, patient behaviors that might account for the differences observed in clinical outcomes were examined. METHODS: Patients (N=914) diagnosed as having major depressive disorder participated in telephone interviews either monthly for six months (intervention) or at three and six months (usual care) asking about antidepressant medication-taking, use of psychotherapy or counseling, and participation in depression support groups. Physicians (N=83) in the intervention arm received monthly feedback regarding their patients' depression severity. RESULTS: A total of 664 (73%) patients completed the month 6 interview. The adjusted odds of current antidepressant use at six months were 85% greater (p=.01) for patients in the intervention (N=380) versus usual care (N=284) arms, according to multivariate regression analyses. CONCLUSIONS: More frequent measurement of depression symptoms was associated with greater medication persistence, which in turn may have mediated clinical improvements.

Estimation of the impact of warfarin's time-in-therapeutic range on stroke and major bleeding rates and its influence on the medical cost avoidance associated with novel oral anticoagulant use-learnings from ARISTOTLE, ROCKET-AF, and RE-LY trials.

Warfarin's time-in-therapeutic range (TTR) is highly variable among patients with nonvalvular atrial fibrillation (NVAF). The objective of this study was to estimate the impact of variations in wafarin's TTR on rates of stroke/systemic embolism (SSE) and major bleedings among NVAF patients in the ARISTOTLE, ROCKET-AF, and RE-LY trials. Additionally, differences in medical costs for clinical endpoints when novel oral anticoagulants (NOACs) were used instead of warfarin at different TTR values were estimated. Quartile ranges of TTR values and corresponding event rates (%/patient - year = %/py) of SSE and major bleedings among NVAF patients treated with warfarin were estimated from published literature and FDA documents. The associations of SSE and major bleeding rates with TTR values were evaluated by regression analysis and then the calculated regression coefficients were used in analysis of medical cost differences associated with use of each NOAC versus warfarin (2010 costs; US payer perspective) at different TTRs. Each 10 % increase in warfarin's TTR correlated with a -0.32%/py decrease in SSE rate (R(2) = 0.61; p < 0.001). Although, the rate of major bleedings decreased as TTR increased, it was not significant (-0.035%/py, p = 0.63). As warfarin's TTR increased from 30 to 90% the estimated medical cost decreased from -$902 to -$83 for apixaban, from -$506 to +$314 for rivaroxaban, and from -$596 to +$223 for dabigatran. Among NVAF patients there is a significant negative correlation between warfarin's TTR and SSE rate, but not major bleedings. The variations in warfarin's TTR impacted the economic comparison of use of individual NOACs versus warfarin.

Medical costs in the US of clinical events associated with oral anticoagulant (OAC) use compared to warfarin among non-valvular atrial fibrillation patients ≥75 and <75 years of age, based on the ARISTOTLE, RE-LY, and ROCKET-AF trials.

OBJECTIVES: Based on clinical trials the oral anticoagulants (OACs) apixaban, dabigatran, and rivaroxaban are efficacious for reducing stroke risk for non-valvular atrial fibrillation (NVAF) patients. Based on the clinical trials, this study evaluated the medical costs for clinical events among NVAF patients ≥75 and <75 years of age treated with individual OACs vs warfarin. METHODS: Rates for primary and secondary efficacy and safety outcomes (i.e., clinical events) among NVAF patients receiving warfarin or each of the OACs were determined for NVAF populations aged ≥75 years and <75 years of age from the OAC vs warfarin trials. One-year incremental costs among patients with clinical events were obtained from published literature and inflation adjusted to 2010 costs. Medical costs, excluding medication costs, for clinical events associated with each OAC and warfarin were then estimated and compared. RESULTS: Among NVAF patients aged ≥75, compared to warfarin, use of either apixaban or rivaroxaban was associated with a reduction in medical costs per patient year (apixaban = -$825, rivaroxaban =-$23), while dabigatran use was associated with increased medical costs of $180 per patient year. Among NVAF patients <75 years of age medical costs per patient year were estimated to be reduced -$254, -$367, and -$88, for apixaban, dabigatran, and rivaroxaban, respectively, in comparison to warfarin. LIMITATIONS: This economic analysis was based on clinical trial data and, therefore, the direct application of the results to routine clinical practice will require further assessment. CONCLUSIONS: Difference in medical costs between OAC and warfarin treated NVAF patients vary by age group and individual OACs. Although reductions in medical costs for NVAF patients aged ≥75 and <75 were observed for those using either apixaban or rivaroxaban vs warfarin, the reductions were greater per patient year for both the older and younger NVAF populations using apixaban.

Warfarin use and stroke risk among patients with nonvalvular atrial fibrillation in a large managed care population.

BACKGROUND: Stroke prevention is a goal of atrial fibrillation (AF) management, but discontinuation of warfarin anticoagulation therapy is common. OBJECTIVE: To investigate the association between warfarin discontinuation and hospitalization for stroke among nonvalvular AF (NVAF) patients enrolled in managed care. METHODS: Patients with NVAF who initiated warfarin therapy from January 2005 through June 2009 were included. Warfarin discontinuation was defined as a supply gap >60 days without evidence of International Normalized Ratio measurements. Follow-up, which was a variable time period from warfarin initiation until the earlier of death, disenrollment from the health plan, or June 30, 2010, was divided into periods of warfarin treatment and discontinuation. Stroke events were identified based on claims for inpatient stays with a primary diagnosis of stroke or transient ischemic attack. Cox proportional hazards models were constructed to assess the relationship between warfarin discontinuation and incident stroke while adjusting for baseline demographics, stroke and bleeding risk, and comorbidities, as well as time-dependent antiplatelet use, stroke, and bleeding events in the previous warfarin treatment period. RESULTS: Among warfarin initiators with NVAF (N = 16,253), 51.4% discontinued warfarin therapy at least once during a mean follow-up of 668 days. Stroke risk was significantly greater during warfarin discontinuation periods compared with therapy periods (hazard ratio = 1.60; 95% CI, 1.35-1.90; P < 0.001). CONCLUSIONS: More than half of patients on warfarin had treatment gaps or discontinued therapy. Therapy gaps were associated with increased stroke risk.

Dosing patterns of aripiprazole and quetiapine for adjunctive treatment of major depressive disorder (2006-2010).

The aim of this study was to investigate the dosing patterns of adjunctive quetiapine or adjunctive aripiprazole in the treatment of major depressive disorder from 2006 to 2010, and to evaluate the impact of Food and Drug Administration (FDA) approval on these dosing patterns. Patients included in the study were adults diagnosed with major depressive disorder, and treated with adjunctive aripiprazole or quetiapine between the years 2006 and 2010. The average daily dose and dose distribution were calculated and assessed statistically over the same time period. The mean daily dose for patients treated with adjunctive aripiprazole decreased from 13.5 mg/day in 2006 to 6.9 mg/day in 2010, whereas the mean daily dose for patients treated with quetiapine increased from 129 mg/day in 2006 to 139 mg/day in 2007, decreasing to 123 mg/day in 2010. The proportion of patients receiving FDA-recommended doses increased significantly for aripiprazole (86.3% in 2006 to 94.5% in 2010; P<0.001) and remained relatively stable for quetiapine (21.3% in 2006 to 24.0% in 2010; NS). The majority of patients treated with quetiapine received doses below those recommended by the FDA throughout the study period. Aripiprazole was mostly prescribed at therapeutic doses (pre-FDA and post-FDA approval), although the mean dose decreased significantly over time.

Medical Costs of Oral Anticoagulants vs Warfarin for Atrial Fibrillation Patients with Different Stroke Risks.

INTRODUCTION: The Apixaban for the Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE), Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY), and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trials demonstrated that the oral anticoagulants (OACs), apixaban, dabigatran, and rivaroxaban, respectively, are efficacious for stroke prevention among nonvalvular atrial fibrillation (NVAF) patients. Based on clinical trial results this study evaluated medical costs of clinical events associated with use of individual OACs relative to those of warfarin in NVAF patients with moderate and high stroke risk. METHODS: Rates for primary and secondary efficacy and safety outcomes (i.e., clinical events) among NVAF patients with CHADS2 = 2 and ≥3 were determined from the three OAC trials. One-year incremental costs among patients with clinical events from a US payer perspective were obtained from the literature and inflation adjusted to 2010 costs. Medical costs for clinical events associated with each OAC vs. warfarin were estimated and compared. RESULTS: For NVAF patients with moderate stroke risk (CHADS2 = 2) differences in clinical event medical costs vs. warfarin were -$298, -$143, and +$117 per patient year for apixaban, dabigatran (150 mg), and rivaroxaban, respectively (negative numbers indicate cost reduction). For NVAF patients with high stroke risk (CHADS2 ≥ 3) differences in clinical event medical costs vs. warfarin were -$697, +$2, and -$100 for apixaban, dabigatran (150 mg), and rivaroxaban, respectively. CONCLUSIONS: Medical cost differences associated with OACs vs. warfarin vary according to stroke risk. Of the three OACs, apixaban demonstrated consistent medical cost reductions vs. warfarin for NVAF patients with moderate and high stroke risks.

Exposure to potentially dangerous drug-drug interactions involving antipsychotics.

OBJECTIVE: Antipsychotic drug therapy is the cornerstone of treatment of persons with schizophrenia. Because most antipsychotics are metabolized by the hepatic cytochrome P450 system, concomitant use of an antipsychotic and medications that are competitively metabolized by the same system may cause a potentially harmful drug-drug interaction. This study used a large state's Medicaid claims database to examine the proportion of patients exposed to such interactions and the risk factors associated with exposure. METHODS: Claims from January 2000 through December 2003 for adult patients with a diagnosis of schizophrenia and at least one prescription for an antipsychotic (N=27,909) were examined for pairs of medications identified as potentially causing moderate or severe adverse drug effects. Logistic regression models were estimated to determine potential risk factors associated with exposure to the interaction pairs. RESULTS: A total of 6,417 (23%) patients were exposed to 14,213 potentially harmful interactions; 4,725 patients had at least one exposure from the same pharmacy, and 4,032 patients were exposed by the same physician. The greatest number of exposures (N=1,353) to potentially harmful combinations involved olanzapine and haloperidol. Patients prescribed risperidone were most likely to be exposed to an interaction (13.1%), followed by patients prescribed olanzapine (10.3%), quetiapine (3.3%), and clozapine (3.2%). A higher risk of exposure was associated with being female (odds ratio [OR]=.94), being white (OR=1.43), having depression (OR=1.21), or having impulse-control disorder (OR=1.98). CONCLUSIONS: Interventions by physicians and pharmacies to reduce the prescribing and dispensing of potentially harmful pairs of medications to patients with schizophrenia are recommended.

Why is warfarin underused for stroke prevention in atrial fibrillation? A detailed review of electronic medical records.

OBJECTIVE: Automated electronic queries of structured data fields in electronic medical records (EMR) found no barriers to warfarin in 42% of patients with atrial fibrillation or atrial flutter (AF) with moderate or high risk of stroke and no warfarin. A thorough manual review of records (including text reports) from the same EMR may better identify physicians' reasons for not using warfarin. METHODS: This was a cross-sectional, retrospective, manual EMR review. Patients identified in a previous automated EMR study with a CHADS2 (Chronic heart failure, Hypertension, Age >75 years, Diabetes mellitus, Stroke) score≥2, no record of warfarin, no barrier to warfarin use, and (in the present study) confirmation of AF diagnosis were included in the manual EMR review. A structured chart abstraction form was used to extract data visible in the clinicians' EMR user interface. Reasons why warfarin had not been prescribed were reported using descriptive statistics. RESULTS: Among 408 patients with 'no barriers' to warfarin in the automated EMR review, AF diagnosis was confirmed in 319 patients (mean age 74.8; 65% female). Forty-one percent (n=132) did not have chart records explaining why they were not on warfarin. Among the 59% (187) with a rationale against warfarin found in the records, the most common category (52%) was indicative of the risk of bleeding, either risk of fall or history of recent bleeding. The second most common category (16%) reflected that the patient was back in sinus rhythm. These findings are subject to inherent limitations of retrospective chart reviews. CONCLUSIONS: Many patients with AF and moderate-to-high risk of stroke are not treated with warfarin, and reasons for not using warfarin could not always be identified in patient records. Among patients with documented reasons, risk of bleeding (risk of fall or recent bleeding) was the most common category.

Clinical Outcomes in Measurement-based Treatment (Comet): a trial of depression monitoring and feedback to primary care physicians.

BACKGROUND: Despite the availability of effective treatments for depression, many patients under the care of primary care physicians do not achieve remission. Clinical Outcomes in Measurement-based Treatment (COMET) was designed to assess whether communicating patient-reported depression symptom severity to primary care physicians affects patient outcomes at 6 months. METHODS: Nine hundred fifteen patients (intervention: n = 503; control: n = 412) diagnosed with major depressive disorder were enrolled in a prospective trial in which physician practice sites were assigned to either the intervention or control study arm. Only patients who were prescribed an antidepressant by their physician were eligible, but medication type was independent of the study protocol. Intervention-arm physicians received monthly updates on their patients' depression severity, which was determined with the nine-item Patient Health Questionnaire (PHQ-9) administered during telephone interviews. Remission was defined as a PHQ-9 score <5 at 6 months; response was defined as a score reduction ≥50%. RESULTS: Among patients with baseline PHQ-9 score ≥5, 45.0% achieved remission (46.7% intervention versus 42.8% control) and 63.9% responded (67.0% intervention versus 59.7% control) at 6 months. After adjusting for baseline demographic and clinical variables, odds of remission (odds ratio [OR], 1.59 [95% CI, 1.07-2.37]) or response (OR, 2.02 [95% CI, 1.36-3.02]) were significantly greater for the intervention group than for control patients. CONCLUSIONS: This study demonstrated that regular patient symptom monitoring with feedback to physicians improved outcomes of depression treatment in the primary care setting. Determining reasons for the high observed nonremission rates requires further investigation.

Cost-effectiveness of adjunctive therapy with atypical antipsychotics for acute treatment of major depressive disorder.

BACKGROUND: While the clinical utility of atypical antipsychotics has been established in patients with major depressive disorder (MDD) who are refractory to antidepressant therapy, their cost-effectiveness is unknown. OBJECTIVE: To examine the cost-effectiveness of aripiprazole, quetiapine, and olanzapine/fluoxetine in adults with MDD who are refractory to antidepressant therapy. METHODS: Using techniques of decision analysis, we estimated expected outcomes and costs over 6 weeks in adults with MDD receiving (1) aripiprazole 2-20 mg/day and antidepressant therapy; (2) quetiapine 150 mg/day or 300 mg/day and antidepressant therapy; (3) the fixed-dose combination of olanzapine 6, 12, or 18 mg/day with fluoxetine 50 mg/day; or (4) antidepressant therapy alone. Cost-effectiveness was assessed in terms of the cost per additional responder at 6 weeks, defined as the ratio of the difference in the cost of MDD-related care over 6 weeks versus antidepressant therapy alone to the difference in the number of patients achieving clinical response by 6 weeks. We estimated the model using data from Phase 3 clinical trials of atypical antipsychotics along with other secondary data sources. RESULTS: With antidepressant therapy alone, the estimated clinical response rate at 6 weeks was 30%. Aripiprazole, quetiapine 150 mg/day, quetiapine 300 mg/day, and olanzapine/fluoxetine were estimated to increase clinical response at 6 weeks to 49%, 34%, 38%, and 45%, respectively. Costs of MDD-related care over 6 weeks were estimated to be $192 for antidepressant therapy, $847 for aripiprazole, $541 for quetiapine 150 mg/day, $672 for quetiapine 300 mg/day plus antidepressant therapy, and $791 for olanzapine/fluoxetine. Costs per additional responder (vs antidepressant therapy) over a 6-week period were estimated to be $3447 for aripiprazole, $8725 for quetiapine 150 mg/day, $6000 for quetiapine 300 mg/day, and $3993 for olanzapine/fluoxetine. CONCLUSIONS: Atypical antipsychotics substantially increase clinical response at 6 weeks. Cost per additional responder is lower for aripiprazole than for quetiapine or olanzapine/fluoxetine.