Developing a fit-for-purpose composite symptom score as a symptom burden endpoint for clinical trials in patients with malignant pleural mesothelioma.

We developed a composite symptom score (CSS) representing disease-related symptom burden over time in patients with malignant pleural mesothelioma (MPM). Longitudinal data were collected from an open-label Phase IIB study in which 239 patients completed the validated MD Anderson Symptom Inventory for MPM (MDASI-MPM). A blinded, independent review committee of external patient-reported outcomes experts advised on MDASI-MPM symptoms to include in the CSS. Through iterative analyses of potential symptom-item combinations, 5 MPM symptoms (pain, fatigue, shortness of breath, muscle weakness, coughing) were selected. The CSS correlated strongly with the full MDASI-MPM symptom set (0.92-0.94) and the Lung Cancer Symptom Scale-Mesothelioma (0.79-0.87) at each co-administration of the scales. The CSS also had good sensitivity to worsening disease and global quality-of-life ratings. The MDASI-MPM CSS can be used as an outcome in MPM clinical trials, including in responder analyses and at the individual patient level. It is brief enough to administer frequently, including electronically, to better capture symptom trajectories during and after a trial and in clinical practice. As a single score, the CSS addresses multiplicity issues that can arise when several symptoms increase due to worsening disease. Our process can be adapted to produce a CSS for other advanced-cancer trials.

Supporting Biomarker-Driven Therapies in Oncology: A Genomic Testing Cost Calculator.

BACKGROUND: Adoption of high-throughput, gene panel-based, next-generation sequencing (NGS) into routine cancer care is widely supported, but hampered by concerns about cost. To inform policies regarding genomic testing strategies, we propose a simple metric, cost per correctly identified patient (CCIP), that compares sequential single-gene testing (SGT) vs. multiplex NGS in different tumor types. MATERIALS AND METHODS: A genomic testing cost calculator was developed based on clinically actionable genomic alterations identified in the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets. Using sensitivity/specificity data for SGTs (immunohistochemistry, polymerase chain reaction, and fluorescence in situ hybridization) and NGS and marker prevalence, the number needed to predict metric was monetarized to estimate CCIP. RESULTS: At base case, CCIP was lower with NGS than sequential SGT for advanced/metastatic non-squamous non-small cell lung cancer (NSCLC), breast, colorectal, gastric cancers, and cholangiocarcinoma. CCIP with NGS was also favorable for squamous NSCLC, pancreatic, and hepatic cancers, but with overlapping confidence intervals. CCIP favored SGT for prostate cancer. Alternate scenarios using different price estimates for each test showed similar trends, but with incremental changes in the magnitude of difference between NGS and SGT, depending on price estimates for each test. CONCLUSIONS: The cost to correctly identify clinically actionable genomic alterations was lower for NGS than sequential SGT in most cancer types evaluated. Decreasing price estimates for NGS and the rapid expansion of targeted therapies and accompanying biomarkers are anticipated to further support NGS as a preferred diagnostic standard for precision oncology.

Transforming approaches to treating TRK fusion cancer: historical comparison of larotrectinib and histology-specific therapies.

OBJECTIVE: The results from basket trials utilized to gain regulatory approval of tumor-agnostic therapies can be difficult to interpret without the context of a comparator arm. We describe the role and efficacy of histology-based treatments to provide a historical comparison with larotrectinib. METHODS: A systematic literature review (SLR) was conducted on the clinical outcomes of current histology-based standard of care treatments used in non-small cell lung cancer, colorectal cancer, thyroid cancer, gliomas, soft tissue sarcoma, salivary gland cancer, and infantile fibrosarcoma (7 of the 21 tumor histologies in the larotrectinib trials). The review focused on advanced stage/metastatic disease to make a historical comparison with larotrectinib. RESULTS: Larotrectinib provides positive outcomes in both adult and pediatric patients with advanced or metastatic solid tumors known to harbor NTRK gene fusions across a wide range of tumor types. Although the numbers of patients per tumor type are limited, the results of this historical comparison demonstrated that larotrectinib is an efficacious treatment option when naïvely indirectly compared with historical treatments across all 7 reviewed tumor types, especially in comparison to later lines of therapy. CONCLUSIONS: Utilizing larotrectinib as a case example across these types of historical comparisons shows that larotrectinib provides positive efficacy outcomes in TRK fusion cancer across tumor histologies known to harbor NTRK gene fusions that may be preferable to historical treatments.

Evaluation of the psychometric properties and minimally important difference of the MD Anderson Symptom Inventory for malignant pleural mesothelioma (MDASI-MPM).

BACKGROUND: Symptom assessment requires psychometrically validated questionnaires that are easy to use, relevant to the disease, and quick to administer. The MD Anderson Symptom Inventory for malignant pleural mesothelioma (MDASI-MPM) was adapted from the general (core) MDASI to assess the severity of cancer-related and treatment-related symptoms specific to patients with this condition. The MDASI-MPM includes the 13 core MDASI symptoms, which are experienced by most cancer patients, and 6 MPM-specific items developed via qualitative interviewing, a method favored by the US Food and Drug Administration for instrument item generation and development. Qualitative interviewing that summarizes the item generation and development for the MDASI-MPM is detailed in a separate report. The psychometric study reported here was the next step in developing the validation dossier for the MDASI-MPM. RESULTS: In this secondary analysis of data from a Phase II trial, 248 patients provided MDASI-MPM data at multiple timepoints during therapy. Over time, fatigue, pain, shortness of breath, feeling of malaise, and muscle weakness were consistently the worst symptoms reported; symptoms interfered most with work and general activity and least with relations with others. Cronbach coefficient alpha values for all MDASI-MPM subscales were at least 0.88 at baseline and 0.91 during treatment, indicating good internal consistency reliability. Intraclass correlations of at least 0.86 for all MDASI-MPM subscales administered a cycle apart (n = 82) were indicative of good test-retest reliability. Correlations between MDASI-MPM subscales and LCSS-Meso scores were at least 0.70 (P < 0.001 for all comparisons). Patients with good performance status had significantly lower scores than did patients with poor performance status (all P < 0.05), supporting evidence for known-group validity and sensitivity. Effect-size differences were 0.69 and higher, indicating medium-to-large effects. The minimally important difference in the MDASI-MPM subscales ranged from 1.0 to 1.5 points on a 0-10 scale. CONCLUSIONS: Symptoms specific to a particular cancer, treatment method, or treatment site can be added to the core MDASI to create a tailored, "fit for purpose" instrument. We found the MDASI-MPM to be a valid, reliable, and responsive (sensitive) instrument for assessing the severity of symptoms of patients with MPM and their interference in patients' daily functioning.

Modification of existing patient-reported outcome measures: qualitative development of the MD Anderson Symptom Inventory for malignant pleural mesothelioma (MDASI-MPM).

PURPOSE: Malignant pleural mesothelioma (MPM) is an aggressive cancer of the lung pleura. The MD Anderson Symptom Inventory (MDASI) is a patient-reported outcome (PRO) measure of symptom burden, the combined impact of disease-related and treatment-related symptoms on functioning. Validated PRO measures may require modification for use in specific study populations. We sought to modify the MDASI for patients with MPM and create a fit-for-purpose symptom-burden measure for use in a clinical trial, according to US Food and Drug Administration guidance on PRO utilization to support labeling claims. METHODS: A literature review for MPM symptoms was conducted. Patients with MPM were qualitatively interviewed about experiences of disease and treatment. Descriptive analysis identified symptoms and interference with functioning to define MPM-related symptom burden. An expert panel rated the relevance of identified symptoms to patients with MPM. Patients who received the investigational drug in a previous Phase I study were interviewed for drug-specific symptoms. RESULTS: Literature review and interviews of 20 patients identified 31 MPM-related symptoms. A conceptual model of MPM-related symptom burden was developed. After expert-panel relevance review, five MPM-specific items and the 13 core MDASI symptoms met criteria for inclusion in a provisional MDASI-MPM for psychometric testing. Interviews with six patients identified six drug-specific symptoms; three were mentioned by multiple patients. Of these three, one was not in the core MDASI. CONCLUSIONS: The MDASI-MPM has established content validity and, with the addition of one symptom item, is ready for psychometric testing as fit-for-purpose for a clinical trial of an investigational agent.

Outcome assessment of an antipsychotic drug algorithm: effects of the Mississippi State Hospital algorithm project.

OBJECTIVE: This study evaluated a state psychiatric hospital's algorithm for prescribing antipsychotic drugs for inpatients with schizophrenia to determine whether its emphasis on cost efficiency is compatible with quality of care. METHODS: Outcomes were compared for patients who received medication that was algorithm adherent or nonadherent. Risperidone and ziprasidone were first-step oral antipsychotics. Documentation of clinical rationale was acceptable for nonpreferred drug use. Outcomes of interest were length of hospitalization and "much improved" or "very much improved" status on the Clinical Global Impression severity scale (CGI-S). RESULTS: Of 401 patients, 70% were male. The CGI-S modal rating of severity was "markedly ill." Duration of illness was longer for patients given algorithm-nonadherent (17.6±9.7 years) versus -adherent (14.9±11.6 years, p=.013) medication. No statistically significant between-group differences were observed for mean length of stay (51.4±35.5 days versus 43.8±27.4 days, adjusted difference p=.18) or median improvement time (adherent, 41 days; nonadherent, 42 days; CI=34-48 days for both group medians). CONCLUSIONS: Prescription algorithm adherence was not associated with significantly increased length of inpatient stay or delayed time to improvement.

A pilot study of antipsychotic prescribing decisions for acutely-Ill hospitalized patients.

BACKGROUND: Evidence on antipsychotic prescribing decisions is limited. This pilot study quantified factors considered in choosing an antipsychotic and evaluated the influence of metabolic status on treatment decisions. METHODS: Prescribing decisions by 4 psychiatrists were examined based on 80 adult patients initiated on antipsychotic medication diagnosed with schizophrenia, schizoaffective disorder or bipolar disorder by DSM-IV criteria, who were admitted to an acute inpatient psychiatric program of an urban Veterans Affairs Medical Center. The primary analysis examined the association between antipsychotic treatment choice and predictions of symptom control and metabolic risk. Secondary analyses included comparison of the chosen and next best treatments in predicted symptom control and metabolic risk, the frequency of reasons cited for drug choice, and the association between treatment choice and patients' baseline metabolic parameters. Mean differences and odds-ratios (OR) with 95% confidence intervals were used to compare relationships between treatment choice, ratings of risk and metabolic data. RESULTS: Antipsychotic choice correlated significantly with ratings of predicted symptom control (OR = .92, p = 0.02) and metabolic risk (OR = .88, p = 0.01). Mean differences between the chosen and next best drugs were significant but small in predicted symptom control (F = 2.81, df = 3, 76; p<0.05) compared with larger differences in anticipated metabolic risk (F = 14.80, df = 3, 76; p = 0.0001). Nevertheless, among 24 identified reasons influencing drug selection, anticipated metabolic risk of chosen antipsychotics was cited less often than efficacy measures. In contrast to psychiatrists' expectations of metabolic risk with selected treatments, we found that patients' actual baseline BMI, fasting glucose, blood pressure, and Framingham risk levels did not necessarily predict antipsychotic treatment choice independent of other factors. CONCLUSION: In the context of an acute psychiatric hospitalization, pilot data suggest that predictions of symptom control and metabolic risk correlated significantly with antipsychotic choice, but study psychiatrists were willing to assume relative degrees of metabolic risk in favor of effective symptom control. However, prescribing decisions were influenced by numerous patient and treatment factors. These findings support the potential utility of the ATCQ questionnaire in quantifying antipsychotic prescribing decisions. Further validation studies of the ATCQ questionnaire could enhance translation of research findings and application of treatment guidelines.

Findings of a U.S. national cardiometabolic screening program among 10,084 psychiatric outpatients.

OBJECTIVE: A national cardiometabolic screening program for patients in a variety of public mental health facilities, group practices, and community behavioral health clinics was funded by Pfizer Inc. between 2005 and 2008. METHODS: A one-day, voluntary metabolic health fair in the United States offered patients attending public mental health clinics free cardiometabolic screening and same-day feedback to physicians from a biometrics testing third party that was compliant with the Health Insurance Portability and Accountability Act. RESULTS: This analysis included 10,084 patients at 219 sites; 2,739 patients (27%) reported having fasted for over eight hours. Schizophrenia or bipolar disorder was self-reported by 6,233 (62%) study participants. In the overall sample, the mean waist circumference was 41.1 inches for men and 40.4 inches for women; 27% were overweight (body mass index [BMI] 25.0-29.9 kg/m(2)), 52% were obese (BMI >or=30.0 kg/m(2)), 51% had elevated triglycerides (>or=150 mg/dl), and 51% were hypertensive (>or=130/85 mm Hg). In the fasting sample, 52% had metabolic syndrome, 35% had elevated total cholesterol (>or=200 mg/dl), 59% had low levels of high-density lipoprotein cholesterol (<40 mg/dl for men or <50 mg/dl for women), 45% had elevated triglycerides (>or=150 mg/dl), and 33% had elevated fasting glucose (>or=100 mg/dl). Among the 1,359 fasting patients with metabolic syndrome, 60% were not receiving any treatment. Among fasting patients who reported treatment for specific metabolic syndrome components, 33%, 65%, 71%, and 69% continued to have elevated total cholesterol, low levels of high-density lipoprotein, high blood pressure, and elevated glucose levels, respectively. CONCLUSIONS: The prevalence of metabolic syndrome and cardiometabolic risk factors, such as overweight, hypertension, dyslipidemia, and glucose abnormalities, was substantial and frequently untreated in this U.S. national mental health clinic screening program.

Impact of real-world ziprasidone dosing on treatment discontinuation rates in patients with schizophrenia or bipolar disorder.

BACKGROUND: The purpose of this study is to evaluate the relationship between maximum dose of ziprasidone and time to discontinuation in the treatment of schizophrenia/schizoaffective disorder and bipolar disorder in clinical practice. METHOD: The 2001-2006 MarketScan Commercial and Medicare Databases were analyzed for maximum ziprasidone doses achieved in patients with schizophrenia/schizoaffective disorder or bipolar disorder. Ziprasidone maximum-dose groups were defined as low (20-60 mg/d), medium (61-119 mg/d), or high (120-160 mg/d). Patients receiving >160 mg/d were excluded. Mean time to discontinuation was evaluated across propensity score-matched dosing groups. Cox proportional hazard models were used to adjust for confounding when comparing the high- and medium-dose groups with the low-dose group. RESULTS: Data were available for 33,340 patients with schizophrenia/schizoaffective disorder, of whom 16.6% received low dose of ziprasidone, 22.0% medium dose, and 61.4% high dose. Of those subjects with bipolar disorder (n=27,751), 26.1% were receiving a low dose of ziprasidone, 25.7% a medium dose, and 48.3% a high dose. Among the propensity score-matched dosing groups, the respective mean time to discontinuation for low, medium, and high doses was 90.5, 117.2, and 201.6d within the schizophrenia/schizoaffective disorder cohort and 84.6, 110.7, and 173.2d within the bipolar cohort (p<0.0001 for all comparisons). The hazard ratios for discontinuing therapy were significantly lower for the medium- (0.84, 0.84) and high-dose (0.57, 0.60) groups relative to the low-dose group in schizophrenia/schizoaffective disorder and bipolar disorder, respectively. CONCLUSIONS: Patients with schizophrenia/schizoaffective or bipolar disorders receiving ziprasidone 120-160 mg/d experienced a statistically significant lower discontinuation rate compared with those receiving lower doses.

Metabolic screening after the American Diabetes Association's consensus statement on antipsychotic drugs and diabetes.

OBJECTIVE: Several second-generation antipsychotic (SGA) drugs have been associated with weight gain, hyperglycemia, and dyslipidemia. We evaluated whether glucose and lipid testing increased after the American Diabetes Association (ADA) consensus statement recommending metabolic monitoring for SGA-treated patients. RESEARCH DESIGN AND METHODS: Laboratory claims for serum glucose and lipid testing were identified for an incident cohort of 18,876 adults initiating SGA drugs in a U.S. commercial health plan (2001-2006) and a control group of 56,522 adults with diabetes not receiving antipsychotics. Interrupted time-series models were used to estimate the effect of ADA recommendations on baseline and annual testing trends after adjusting for differences in age, sex, mental health diagnoses, and cardiovascular risk using propensity score matching. RESULTS: Mean baseline testing rates for SGA-treated patients during the study period were 23% (glucose) and 8% (lipids). Among persistent users of SGA medication, annual testing rates were 38% (glucose) and 23% (lipid). Before the ADA statement, screening rates for SGA-treated patients were increasing (glucose: baseline 3.6% per year, annual 7.2% per year; lipid: baseline 1.2% per year, annual 4.8% per year; P < 0.001 for each trend). Increases were similar to background testing trends in control subjects. The ADA statement was not associated with an increase in screening rates. CONCLUSIONS: In a commercially insured population, glucose and lipid testing for SGA-treated adults was infrequent. A gradual increase in screening rates occurred over the 6-year period, but the changes were not temporally associated with the ADA statement. More effort is needed to improve diabetes and dyslipidemia screening in these at-risk patients.

Metabolic risk status and second-generation antipsychotic drug selection: a retrospective study of commercially insured patients.

BACKGROUND: Routine metabolic screening and consideration of patient metabolic status in the choice of a second-generation antipsychotic (SGA) medication are recommended. This study evaluated the association between abnormal blood glucose and lipid values and SGA prescribing patterns. MATERIALS AND METHODS: A retrospective cohort study using administrative data from 2 managed care plans in the United States evaluated 7904 adults initiating SGA therapy between 2001 and 2004. Baseline serum glucose, total cholesterol, and triglyceride values were available for 989 patients (12.5%), and follow-up assessments were done in 699 patients (8.8%). Abnormal values were defined as the following: total cholesterol, 200 mg/dL or higher; triglycerides, 200 mg/dL or higher; and glucose, 126 mg/dL or higher. The likelihood of abnormal laboratory values being associated with selection of a lower metabolic risk SGA drug (aripiprazole or ziprasidone) and with switching decisions was assessed using multivariate logistic regression models. RESULTS: Thirteen percent of the patients had glucose and lipid tests within 6 months of starting SGA therapy. The likelihood of starting a patient on an SGA drug with lower metabolic risk (ziprasidone: odds ratio, 3.26; 95% confidence interval, 1.25-8.47; aripiprazole: odds ratio, 2.13; 95% confidence interval, 0.77-5.88) was higher if the patient had elevated glucose values but was not associated with elevated cholesterol or triglyceride values or if the patient had preexisting diabetes or dyslipidemia. Abnormal glucose and lipid values were not associated with switching SGA medications in the first 6 months of therapy. Among patients who did switch SGA medications, elevated glucose and lipid values were not associated with a greater likelihood of switching to aripiprazole or ziprasidone. CONCLUSIONS: Low rates of recommended monitoring were observed. Abnormal metabolic parameters among those who were tested were not consistently associated with the selection of an SGA drug with lower metabolic risk.

Dose trends for second-generation antipsychotic treatment of schizophrenia and bipolar disorder.

BACKGROUND: Antipsychotic dosing used in clinical practice can differ from dosing originally recommended in product labeling. This has been reported for olanzapine and quetiapine, where higher doses are commonly used. This may be the case for ziprasidone as well. METHOD: To characterize changes over time in dosing for the initial and subsequent prescriptions of first-line second-generation antipsychotics used during treatment episodes for outpatients with schizophrenia and bipolar disorder, the 2001-2005 Thomson MarketScan Medicaid Database (Medicaid) and the 2001-2006 MarketScan Commercial Claims and Encounters Database (Commercial) were analyzed. Dose trends were evaluated using autoregressive time-series models. RESULTS: Data were available for 49180 treatment episodes of schizophrenia (4683 Commercial and 44497 Medicaid) and 83289 treatment episodes of bipolar disorder (57961 Commercial and 25328 Medicaid). The initial prescription mean daily and overall mean daily doses of ziprasidone in schizophrenia episodes significantly increased across the Medicaid and Commercial populations, with similar trends observed for bipolar episodes. The first (May 2001) and last (December 2005) observed 3-month mean daily doses for ziprasidone were 112 mg/d and 138 mg/d for patients with schizophrenia and 93 mg/d and 113 mg/d for those with bipolar disorder in the Medicaid cohort, with similar findings for the Commercial cohort. Consistently significant trends in dose changes were not observed for the other medications, although quetiapine and olanzapine doses generally increased while aripiprazole and risperidone doses generally decreased. CONCLUSIONS: There remains a need for controlled randomized clinical trials that test fixed doses of antipsychotics to ascertain the dose-response relationship within the dose range used in contemporary clinical practice.

Medical services for clients in community mental health centers: results from a national survey.

OBJECTIVE: This study provides national data on community mental health centers' (CMHCs') capacity to screen for and address their clients' general medical conditions. METHODS: A survey was distributed to members of the National Council for Community Behavioral Healthcare, the oldest and largest association of CMHCs. RESULTS: Among the 181 CMHCs responding to the survey, more than two-thirds reported having protocols or procedures to screen for common medical problems (hypertension, obesity, dyslipidemia, and diabetes). However, only one-half could provide treatment or referral for those conditions, and less than one-third could provide general medical services on site. Barriers to providing general medical services included problems in reimbursement, workforce limitations, physical plant constraints (for example, lack of available space or equipment), and lack of options for referrals to local community medical providers. CONCLUSIONS: Although most CMHCs had the capacity to screen for common medical conditions, they reported a variety of barriers to providing medical care for those problems either on site or via referral.

Comparison of cholinesterase inhibitor utilization patterns and associated health care costs in Alzheimer's disease.

BACKGROUND: Sustained treatment with a cholinesterase inhibitor (ChEI) is used in the management of the symptoms of Alzheimer's disease (AD). However, the characteristic declines in learning and memory seen in AD may erode the patient's ability to adhere to medication regimens with or without caregiver support. OBJECTIVES: To examine differences by type of ChEI in (1) monthly prevalence of use, (2) nonpersistence, (3) switching from the index drug to another ChEI, (4) number of days on therapy, (5) medication possession ratio (MPR), and (6) an estimate of the relationship of these characteristics to total annual health care expenditures. METHODS: Data were from the MarketScan Medicare Supplemental and Coordination of Benefits 2001-2003 database, which comprised 1.47 million Medicare beneficiaries during this 3-year time period. Inclusion criteria were: (1) aged 65 years or older; (2) at least 1 claim with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 331.0 for AD in any of 15 diagnosis fields on outpatient claims or any of 2 diagnosis fields on inpatient claims at any time during 18 months of observation; (3) at least 1 pharmacy claim for donepezil, galantamine, or rivastigmine preceded by a 6-month period without a ChEI claim; and (4) at least 12 months of follow-up data, for a minimum 18 months continuous enrollment. Multivariate analyses, including logistic regression and exponential conditional mean models, tested for cohort differences in ChEI utilization, controlling for demographics, region of the country, type of insurer, and the Charlson Comorbidity Index (comorbid diagnoses). Using exponential conditional mean models, we also examined the relationship between utilization characteristics and all-cause (i.e., not specific to AD) health care expenditures for a 12-month period, including inpatient and outpatient (physician) care, laboratory and radiology services, emergency room (ER) use, prescription drugs, and long-term care services (e.g., nursing home care, home health visits) paid by Medicare or private insurance, but excluding long-term care services paid by Medicaid. Expenditure was defined as allowed charge (i.e., the total payment received by the service provider including plan and patient paid amounts.) RESULTS: More than 70% of the patients who received ChEI therapy and who otherwise met the inclusion criteria were excluded from this study due to the absence of at least 1 claim with a diagnosis for AD. Of the 3,177 patients included in the study, the index ChEI was donepezil for 62.8% of the patients (n=1,994); 17.2% received galantamine (n=546) and 20.1% received rivastigmine (n=637). The total number of days of index therapy dispensed was greater for those starting on donepezil (mean [median, SD] days=226 [263, 115]) compared with rivastigmine (206 [233, 120], P<0.001), but was not significantly different compared with galantamine (216 [250, 119], P=0.085). Monthly prevalence of use was similar for the 3 drugs until month 5 when a smaller proportion of rivastigmine patients had index medication on hand (65.9%) compared with 72.1% of donepezil patients (P=0.003) and 72.7% of galantamine patients (P=0.012). At 12 months, the likelihood of receiving the index ChEI was higher for donepezil (61.1%) than for either rivastigmine (50.1%, P<0.001) or galantamine (56.4%, P=0.048) and was higher for galantamine than for rivastigmine (P=0.030). The rate of switching for donepezil patients was significantly lower (14.5%) than the switch rate for rivastigmine patients (21.5%, P<0.001) and was similar to the switch rate for galantamine patients (15.0%, P=0.781 for donepezil vs. galantamine; P=0.004 for galantamine vs. rivastigmine). Rates of nonpersistence, measured as having at least 1 gap in therapy of 30 days or more during the 1-year follow-up, were 63.5% for donepezil, 63.7% for galantamine (P=0.933 for donepezil vs. galantamine), and 68.0% for rivastigmine (P=0.042 for donepezil vs. rivastigmine). MPRs and total days supply of any ChEI did not significantly differ among the 3 drugs. Results of multivariate models showed that, controlling for index ChEI drug, each additional month of ChEI treatment was associated with a reduction of 1% in total all-cause health care costs. The mean (SD) total all-cause 1-year health care costs for patients initiated on the 3 ChEIs were not significantly different: $12,112 ($16,437) for donepezil, $12,137 ($19,154) for galantamine (P=0.978), and $12,853 ($14,543) for rivastigmine (P=0.278). CONCLUSIONS: During the first year following initiation of ChEI therapy, patients initiated on donepezil had a greater days supply of the index medication than did patients initiated on rivastigmine. At 12 months following treatment initiation, the proportion of patients in therapy was higher for donepezil than for either rivastigmine or galantamine and was higher for galantamine than for rivastigmine. Patients treated with either donepezil or galantamine were less likely to switch from the index drug to another ChEI than were patients treated with rivastigmine. All-cause 1-year health care costs for patients initiated on the 3 ChEIs were not significantly different.

Efficacy of disease-modifying therapies in relapsing remitting multiple sclerosis: a systematic comparison.

The treatment of relapsing-remitting multiple sclerosis (RRMS) has become more effective over the last decade with the advent of the currently available disease-modifying therapies (DMTs). Pivotal clinical studies differ in many characteristics, such that cross-comparisons of relative risk reductions are of limited value and can be misleading. Our objective was to compare the clinical efficacy of currently approved first-line DMTs in patients with RRMS, applying an evidence-based medicine approach. We reviewed all phase III pivotal trials of DMTs. Six clinical trials of Avonex, Betaseron, Copaxone, Rebif and Tysabri in patients with RRMS were identified for analysis. Only randomized, placebo-controlled, double-blind studies were included. The clinical efficacy endpoints compared were: proportion of relapse-free patients at 1 and 2 years; annualized relapse rate at 2 years; proportion of progression-free patients at 2 years, and proportion of patients free of gadolinium-enhancing lesions at 1 year or 9 months. Based on these analyses, Betaseron, Rebif, and Tysabri show comparable effects, whereas for several endpoints Avonex or Copaxone did not significantly differ from placebo. In the absence of head-to-head studies for all products used to treat RRMS, it still may be possible to compare treatment effects by applying evidence-based medicine principles.

Risk of discontinuation of atypical antipsychotic agents in the treatment of schizophrenia.

OBJECTIVES: To compare discontinuation rates of atypical antipsychotic agents in patients with schizophrenia. METHOD: Adult Maryland Medicaid patients with schizophrenia were categorized based on initial atypical antipsychotic drug received: aripiprazole (n=446); olanzapine (n=1705); quetiapine (n=1467); risperidone (n=1580); and ziprasidone (n=700). Discontinuation was measured using refill patterns, allowing 14-day gaps between refill dates. Using olanzapine as the reference drug, the hazard of discontinuation within the first year of follow-up was compared across atypicals using Cox proportional hazard models adjusted for demographic and clinical covariates. Sensitivity analysis tested the robustness of results by using different definitions of the index date. RESULTS: At one-year follow-up, most patients discontinued their antipsychotic medication (90.4% adjusted mean discontinuation). The hazard ratio (HR) for discontinuing therapy in patients starting treatment on aripiprazole, risperidone, or ziprasidone was not significantly different from olanzapine [HR 1.047, 0.973 and 0.990, respectively]. Quetiapine was associated with significantly higher hazard of discontinuation [HR 1.130] than olanzapine. Covariates associated with significantly lower discontinuation were being male [HR 0.899], older age [HR 0.997] and being on concurrent medication when initiating therapy [HR 0.225]; having a previous hospitalization was associated with significantly higher discontinuation hazard [HR 1.276]. Results were robust in the sensitivity analysis. CONCLUSIONS: Discontinuation rates were high at one-year follow-up and did not differ significantly for patients on aripiprazole, olanzapine, risperidone, or ziprasidone. The higher hazard of discontinuation associated with quetiapine when compared to olanzapine is consistent with that observed in Phase I of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).

Monitoring patient improvement and treatment outcomes in managed behavioral health.

This study examined the use of outcome reports sent to clinicians by a managed behavioral healthcare organization to monitor patient progress and its relation to treatment outcome. Results showed that clinicians who reported using outcome information had patients who also reported greater improvement at 6 months from baseline. Improvement per session was greatest among patients whose clinicians reported reading the outcome report and using outcome measures in their clinical practice. Using baseline and ongoing measures to assess patient improvement can provide clinicians with feedback during treatment, which may lead to better clinical outcomes and enable quality management systems in managed care to flag high-risk cases and identify failure of adequate improvement.

Change in framingham risk score in patients with schizophrenia: a post hoc analysis of a randomized, double-blind, 6-week trial of ziprasidone and olanzapine.

OBJECTIVE: To examine the change in Framingham risk score (FRS) arising from short-term treatment with ziprasidone or olanzapine. METHOD: Hospitalized adults with a primary DSM-IV diagnosis of schizophrenia or schizo-affective disorder were randomly assigned to 6 weeks of double-blind treatment with ziprasidone or olanzapine from November 21, 1998 to September 28, 2000. Data on fasting lipid levels were collected at screening and endpoint, and blood pressure was measured at screening and baseline and weekly until week 6 of treatment (or last visit). FRS for patients aged ≥30 years was calculated using an algorithm derived from the Framingham Heart Study. Baseline-to-endpoint least-squares mean changes in age-adjusted FRS by gender were compared using analysis of covariance (baseline adjusted). RESULTS: Men who received olanzapine demonstrated a mean increase in their total cholesterol levels (+18.5 mg/dL; N = 53) and low-density lipoprotein cholesterol levels (+13.0 mg/dL; N = 45), whereas men who received ziprasidone demonstrated a mean decrease in their total cholesterol levels (-8.5 mg/dL; N = 44) and low-density lipoprotein cholesterol levels (-7.2 mg/dL; N = 40) (p = .0006 and p = .004, respectively). Additionally, men who received olanzapine showed an increase in baseline FRS (+7.69%; N = 53), whereas men who received ziprasidone showed a decrease in baseline FRS (-11.06%; N = 42) (p = .09). In women, treatment differences in FSR numerically favored ziprasidone but were not statistically significant. Neither treatment had a significant effect on blood pressure. CONCLUSION: In short-term treatment, olanza-pine was associated with a significant worsening of lipid profile compared with ziprasidone, with a consequent increase in FRS versus ziprasidone. These findings, coupled with the significant weight gain in patients treated with olanzapine versus ziprasidone, warrant investigation in longer-term trials.

The acceptability and effectiveness of patient-reported assessments and feedback in a managed behavioral healthcare setting.

OBJECTIVE: To determine whether providing clinicians with the results of a patient-reported mental health assessment would have a significant impact on patients' mental health outcomes. STUDY DESIGN: The study used a portion of the SCL-90 (Symptom Checklist-90) to track the perceived mental health of 1374 patients in a managed behavioral healthcare system over 6 weeks. METHODS: Participants were randomized into a feedback group whose clinicians received clinical feedback reports at intake and at 6 weeks, and a control group whose clinicians received no report. RESULTS: Patients in the feedback group achieved statistically significant improvement in clinical status relative to controls. CONCLUSIONS: Overall, the study suggests that patient-reported mental health assessments have the potential both to become acceptable to clinicians and to improve the effectiveness of clinical care.

Treatment for substance use disorders in a privately insured population under managed care: costs and services use.

The study investigated the relationship of substance use disorders, concurrent psychiatric disorders, and patient demographics to patterns of treatment use and spending in behavioral health and medical treatment sectors. We examined claims data for individuals covered by the same organization. Services spending and use were examined for 1899 individuals who received substance use disorder treatment in 1997. Medical and pharmacy spending was assessed for 590 individuals (31.1%). The most prevalent services were outpatient, intensive outpatient, residential, and detoxification. Average mental health/substance abuse (MHSA) care spending conditional on use was highest for those with concurrent alcohol and drug disorders (US 5235 dollars) compared to those with alcohol (US 2507 dollars) or drugs (US 3360 dollars) alone; other psychiatric illness (US 4463 dollars) compared to those without (US 1837 dollars); and employees' dependents (US 4138 dollars) compared to employees (US 2875 dollars) or their spouses (US 2744 dollars). A significant minority also sought MHSA services in the medical sector. Understanding services use and associated costs can best be achieved by examining services use across treatment sectors.