Adjustment of publication bias using a cumulative meta-analytic framework.

OBJECTIVES: Publication bias has the potential to adversely impact clinical decision making and patient health if alternative decisions would have been made had there been complete publication of evidence. METHODS: The objective of our analysis was to determine if earlier publication of the complete evidence on rosiglitazone's risk of myocardial infarction (MI) would have changed clinical decision making at an earlier point in time. We tested several methods for adjustment of publication bias to assess the impact of potential time delays to identifying the MI effect. We then performed a cumulative meta-analysis (CMA) for both published studies (published-only data set) and all studies performed (comprehensive data set). We then created an adjusted data set using existing methods of adjustment for publication bias (Harbord regression, Peter's regression, and the nonparametric trim and fill method) applied to the limited data set. Finally, we compared the time to the decision threshold for each data set using CMA. RESULTS: Although published-only and comprehensive data sets did not provide notably different final summary estimates [OR = 1.4 (95 percent confidence interval [CI]: .95-2.05) and 1.42 (95 percent CI: 1.03-1.97)], the comprehensive data set reached the decision threshold 36 months earlier than the published-only data set. All three adjustment methods tested did not show a differential time to decision threshold versus the published-only data set. CONCLUSIONS: Complete access to studies capturing MI risk for rosiglitazone would have led to the evidence reaching a clinically meaningful decision threshold 3 years earlier.

Level of asthma control and healthcare utilization in Latin America.

The purpose of this study was to investigate whether uncontrolled asthma was associated with healthcare outcomes among Latin American patients with asthma. We used data from 2168 patients with asthma who participated in the 2011 Latin America Asthma Insights and Management (AIM) survey. Using Global Initiative for Asthma (GINA) guidelines, patients were categorized as having asthma that was well-controlled, partly controlled, or uncontrolled. Overall, 7% of the patients surveyed had asthma that was classified as well-controlled. Patients whose asthma was not well-controlled were significantly more likely to report use of asthma medications (ORs ranging from 1.6-41) and to have had emergency healthcare visits or hospitalizations for their asthma in the previous year (ORs ranging from 2.1 to 5.9). They also reported decreases in their productivity compared to patients with well-controlled asthma. These associations suggest that emphasis on improving asthma control could have substantial effects on patient productivity and utilization of healthcare resources.

Skeletal health in men with chronic lung disease: rates of testing, treatment, and fractures.

UNLABELLED: To advance our understanding of the burden of fractures among men, we studied a group of men at high risk for low bone strength due to lung disease. We found high rates of fractures but low rates of bone density testing that could predict fracture before it occurs. INTRODUCTION: To advance understanding of the burden of fragility fractures and attention to bone health among men with chronic obstructive lung disease (COPD), we quantified rates of fragility fracture, bone density testing, and anti-resorptive treatment and calculated the number needed to screen (NNS) to prevent one hip fracture in a cohort of men with COPD. METHODS: Veterans Administration (VA) and VA-Medicare administrative data permitted a retrospective cohort study of 87,360 men aged 50 and older, newly diagnosed with COPD between 1999 and 2003. Logistic regression models including patient characteristics, morbidities, and medication use assessed the effect of covariates on fracture and probability of testing or treatment. RESULTS: Mean age was 66.8. Hip and wrist fracture rates were 3.99 and 1.31 per 1,000 person years, respectively. Mean follow-up was 2.67 years; 4.4% underwent bone densitometry; 2.8% filled anti-resorptive prescriptions. Age, white race/ethnicity, more COPD exacerbations, barbiturate use, and anti-Parkinson's drug use were significantly associated with fracture. Age, and systemic corticosteroids were most significantly associated with testing or treatment. Based on published adherence and treatment effects, the cohort's calculated NNS to prevent one hip fracture is 432. CONCLUSIONS: Fracture rate was high and testing and treatment uncommon. The NNS of 432 to prevent one hip fracture is smaller than 731, the NNS for women aged 65-69 for whom universal screening is recommended. Attention to the bone health of this population is warranted. Future research must determine how testing and treatment impact overall quality of life and mortality of men with COPD.

The costs and consequences of omalizumab in uncontrolled asthma from a USA payer perspective.

BACKGROUND: Omalizumab, an anti-immunoglobulin E antibody, reduces exacerbations and symptoms in uncontrolled allergic asthma. The study objective was to estimate the costs and consequences of omalizumab compared to usual care from a US payer perspective. METHODS: We estimated payer costs, quality-adjusted survival (QALYs), and the incremental cost-effectiveness ratio (ICER) of omalizumab compared to usual care using a state-transition simulation model that included sensitivity analyses. Every 2 weeks, patients could transition between chronic asthma and exacerbation health states. The best available evidence informed the clinical and cost input estimates. Five years of omalizumab treatment followed by usual care was assumed to estimate a lifetime horizon. Omalizumab responders (60.5% of treated) were modeled as a separate scenario where nonresponders reverted back to usual care after 16 weeks of active treatment. RESULTS: The mean lifetime discounted costs and QALYs were $83,400 and 13.87 for usual care and $174,500 and 14.19 for omalizumab plus usual care resulting in $287 200/QALY (95% interval: $219,300, $557, 900). The ICER was $172 300/QALY when comparing omalizumab to usual care in the responder scenario. One-way sensitivity analyses indicated that the results were sensitive to the difference in treatment-specific utilities for the chronic state, exacerbation-associated mortality, omalizumab price, exacerbation rates, and response definition. CONCLUSIONS: The results suggest that adding omalizumab to usual care improves QALYs at an increase in direct medical costs. The cost-effectiveness of omalizumab is similar to other chronic disease biologics. The value increases when omalizumab response is used to guide long-term treatment.

Present and future costs of COPD in Iceland and Norway: results from the BOLD study.

The Burden of Obstructive Lung Disease (BOLD) initiative provides standardised estimates of the burden of chronic obstructive pulmonary disease (COPD) worldwide. We estimate the current and future economic burden of COPD in Reykjavik, Iceland and Bergen, Norway using data from the BOLD initiative. Data on utilisation of healthcare resources were gathered from the BOLD survey, existing literature and unit costs from national sources. Economic data were applied to a Markov model using transition probabilities derived from Framingham data. Sensitivity analyses were conducted varying unit costs, utilisation and prevalence of disease. The cost of COPD was 478 euro per patient per yr in Iceland and 284 euro per patient per yr in Norway. The estimated cumulative costs of COPD for the population aged > or = 40 yrs, were 130 million euro and 1,539 million euro for the following 10 yrs in Iceland and Norway, respectively. Costs of COPD accounted for 1.2 and 0.7% of healthcare budgets in Iceland and Norway, respectively. Sensitivity analyses showed estimates were most sensitive to changes in exacerbation frequency. COPD has a significant economic burden in both Iceland and Norway and will grow in the future. Interventions aimed at avoiding exacerbations will have the most impact on costs of COPD over the next 20 yrs.

Health economics of asthma: assessing the value of asthma interventions.

The aim of this systematic review was to summarize and assess the quality of asthma intervention health economic studies from 2002 to 2007, compare the study findings with clinical management guidelines, and suggest avenues for future improvement of asthma health economic studies. Forty of the 177 studies met our inclusion criteria. We assessed the quality of studies using The Quality of Health Economic Studies validated instrument (total score range: 0-100). Six studies (15%) had quality category 2, 26 studies (65%) achieved quality category 3, and the remaining eight (20%) studies were scored as the highest quality level, category 4. Overall, the findings from this review are in line with the Global Initiative for Asthma clinical guidelines. Many asthma health economic studies lacked appropriate long term time horizons to match the chronic nature of the disease and suffered from using effectiveness measures that did not capture all disease related risks and benefits. We recommend that new asthma simulation models: be flexible to allow for long term time horizons, focus on using levels of asthma control in their structure, and estimate both long term asthma specific outcomes like well-controlled time as well as generic outcomes such as quality adjusted survival.

The impact of an ambulatory CPOE system on medication errors.

Few studies have evaluated the impact of an ambulatory computerized physician order entry (CPOE) system on medication errors. We conducted a retrospective analysis of 10,172 prescriptions to evaluate the impact of a basic CPOE system on prescribing-related medication errors, and found a significant decrease in the occurrence of errors.

A new perspective on concepts of asthma severity and control.

Concepts of asthma severity and control are important in the evaluation of patients and their response to treatment but the terminology is not standardised and the terms are often used interchangeably. This review, arising from the work of an American Thoracic Society/European Respiratory Society Task Force, identifies the need for separate concepts of control and severity, describes their evolution in asthma guidelines and provides a framework for understanding the relationship between current concepts of asthma phenotype, severity and control. "Asthma control" refers to the extent to which the manifestations of asthma have been reduced or removed by treatment. Its assessment should incorporate the dual components of current clinical control (e.g. symptoms, reliever use and lung function) and future risk (e.g. exacerbations and lung function decline). The most clinically useful concept of asthma severity is based on the intensity of treatment required to achieve good asthma control, i.e. severity is assessed during treatment. Severe asthma is defined as the requirement for (not necessarily just prescription or use of) high-intensity treatment. Asthma severity may be influenced by the underlying disease activity and by the patient's phenotype, both of which may be further described using pathological and physiological markers. These markers can also act as surrogate measures for future risk.

The response to combination therapy treatment regimens in severe/difficult-to-treat asthma.

The aim of the present study was to assess the response of high-dose salmeterol/fluticasone combination (SFC) and low-dose SFC compared with regimens without inhaled corticosteroid (ICS) plus long-acting beta-agonist (LABA) in a large cohort with severe or difficult-to-treat asthma. Subjects were administered low-dose SFC (100/50 or 250/50 microg) or high-dose SFC (500/50 microg), and a control group received medications that could include ICS or LABA but not both. The present authors calculated unadjusted and propensity score-adjusted differences in outcomes consistent with components of asthma control, comparing high-dose and low-dose SFC cohorts with controls. The low-dose SFC cohort had higher asthma-related quality of life and fewer asthma control problems compared with controls. The high-dose SFC cohort had higher forced expiratory volume in one second but higher odds of having severe asthma compared with controls. The present results support the evidence that some asthmatics achieve better outcomes while receiving a low-dose salmeterol/fluticasone combination, but also suggest that those on a high-dose salmeterol/fluticasone combination fail to achieve significant improvement in many control-related health outcomes as compared with similar patients not receiving salmeterol/fluticasone combination. These findings suggest a limited value of high-dose salmeterol/fluticasone combination compared with the alternatives. While additional studies are needed, the present findings call for alternative therapeutic approaches in severe/difficult-to-treat asthma for those unable to attain asthma control with or without salmeterol/fluticasone combination.

Cost effectiveness of therapy with combinations of long acting bronchodilators and inhaled steroids for treatment of COPD.

BACKGROUND: Little is known about the combination of different medications in chronic obstructive pulmonary disease (COPD). This study determined the cost effectiveness of adding salmeterol (S) or fluticasone/salmeterol (FS) to tiotropium (T) for COPD. METHODS: This concurrent, prospective, economic analysis was based on costs and health outcomes from a 52 week randomised study comparing: (1) T 18 microg once daily + placebo twice daily (TP group); (2) T 18 microg once daily + S 25 microg/puff, 2 puffs twice daily (TS group); and (3) T 18 microg once daily + FS 250/25 microg/puff, 2 puffs twice daily (TFS group). The incremental cost effectiveness ratios (ICERs) were defined as incremental cost per exacerbation avoided, and per additional quality adjusted life year (QALY) between treatments. A combination of imputation and bootstrapping was used to quantify uncertainty, and extensive sensitivity analyses were performed. RESULTS: The average patient in the TP group generated CAN$2678 in direct medical costs compared with $2801 (TS group) and $4042 (TFS group). The TS strategy was dominated by TP and TFS. Compared with TP, the TFS strategy resulted in ICERs of $6510 per exacerbation avoided, and $243,180 per QALY gained. In those with severe COPD, TS resulted in equal exacerbation rates and slightly lower costs compared with TP. CONCLUSIONS: TFS had significantly better quality of life and fewer hospitalisations than patients treated with TP but these improvements in health outcomes were associated with increased costs. Neither TFS nor TS are economically attractive alternatives compared with monotherapy with T.

An evaluation of the cost-effectiveness of omalizumab for the treatment of severe allergic asthma.

Omalizumab is the first licensed anti-immunoglobulin (Ig) E antibody shown to be effective for treatment of allergic (IgE-mediated) asthma. Recent international guidelines recommend omalizumab as add-on treatment to fixed dose inhaled corticosteroid (ICS) and long-acting beta(2)-agonist (LABA) combination therapy. However, omalizumab is more expensive than other current asthma treatments and health and reimbursement authorities are increasingly demanding evidence of economic benefit to support pricing and formulary listing. The aims of this article are to (i) summarize data on the human and economic burden of severe asthma, (ii) summarize the efficacy data obtained for omalizumab in clinical trials in patients with inadequately controlled severe persistent allergic asthma despite high-dose ICS plus a LABA, and (iii) discuss the cost-effectiveness evidence published for omalizumab in this patient population. A wealth of evidence exists highlighting that the health, economic and societal burden of asthma is considerable and is highly skewed towards patients with severe asthma, particularly when asthma is inadequately controlled. Omalizumab is clinically beneficial in patients with severe persistent allergic asthma despite high-dose ICS plus a LABA, particularly in a subgroup of patients who respond to therapy. In patients who respond to therapy, the cost-effectiveness of omalizumab compares well with other biologic treatments for chronic illness.

Outcomes for COPD pharmacological trials: from lung function to biomarkers.

The American Thoracic Society/European Respiratory Society jointly created a Task Force on "Outcomes for COPD pharmacological trials: from lung function to biomarkers" to inform the chronic obstructive pulmonary disease research community about the possible use and limitations of current outcomes and markers when evaluating the impact of a pharmacological therapy. Based on their review of the published literature, the following document has been prepared with individual sections that address specific outcomes and markers, and a final section that summarises their recommendations.

Global strategy for asthma management and prevention: GINA executive summary.

Asthma is a serious health problem throughout the world. During the past two decades, many scientific advances have improved our understanding of asthma and ability to manage and control it effectively. However, recommendations for asthma care need to be adapted to local conditions, resources and services. Since it was formed in 1993, the Global Initiative for Asthma, a network of individuals, organisations and public health officials, has played a leading role in disseminating information about the care of patients with asthma based on a process of continuous review of published scientific investigations. A comprehensive workshop report entitled "A Global Strategy for Asthma Management and Prevention", first published in 1995, has been widely adopted, translated and reproduced, and forms the basis for many national guidelines. The 2006 report contains important new themes. First, it asserts that "it is reasonable to expect that in most patients with asthma, control of the disease can and should be achieved and maintained," and recommends a change in approach to asthma management, with asthma control, rather than asthma severity, being the focus of treatment decisions. The importance of the patient-care giver partnership and guided self-management, along with setting goals for treatment, are also emphasised.

The cost of treating ribavirin-induced anemia in hepatitis C: the impact of using recombinant human erythropoietin.

OBJECTIVE: Ribavirin-induced anemia (RIA) is a common adverse effect of chronic hepatitis C treatment. Studies have shown that the use of epoetin decreases the need for ribavirin dose reduction or discontinuation. The primary objective was to calculate the incremental cost of treating hepatitis C in those without versus with RIA, using either the strategy of ribavirin dose reduction/discontinuation or epoetin. The secondary objective was to calculate the incremental cost of using epoetin versus no epoetin to treat RIA, per ribavirin dose reduction/discontinuation averted. METHODS: Estimates from the literature and decision-analytic techniques were used to model treatment patterns and estimate the cost of managing RIA in genotype 1, 2, and 3 subjects. Sensitivity analyses were used to address uncertainty. RESULTS: Clinically significant RIA, a reduction in hemoglobin of > or = 2 g/dL (1.2 mmol/L), developed in 72% of patients in observational studies. The incremental cost of treating chronic hepatitis C decreased when employing the strategy of ribavirindose reduction/discontinuation to treat RIA, and increased by 5.7% (genotype 1) or 34.4% (genotype 2 or 3), when using epoetin. Using one-way sensitivity analyses, the cost of using epoetin per ribavirin dose reduction/discontinuation averted was $39,579-$52,023. Generalizability may be limited to settings in which a similar proportion of patients develop RIA. CONCLUSIONS: The proportional cost of treating hepatitis C when using epoetin to treat RIA is significant in genotype 2 or 3 patients. The cost of using epoetin per ribavirin dose reduction/discontinuation averted is substantial in patients with genotypes 1, 2, or 3; and varies with the probability of response to epoetin. These findings suggest that additional studies are warranted that will determine the effect of epoetin on treatment outcomes and its role as supportive therapy in patients with RIA.

Association of control and risk of severe asthma-related events in severe or difficult-to-treat asthma patients.

BACKGROUND: Clinical tools for predicting poor outcomes in asthma patients are lacking. This study investigated the association of asthma control and subsequent severe asthma-related healthcare events in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. METHODS: The extent of asthma control problems was determined from baseline values of the Asthma Therapy Assessment Questionnaire (ATAQ). Patients self-reported the presence of severe asthma-related events at 6- and 12-month follow up. Poisson regression models determined the adjusted association between baseline control and the likelihood of severe asthma-related events. RESULTS: At baseline, 2942 patients (mean age, 49.6 years; female, 71.9%) had an ATAQ score (no control problems, 17.0%; 1 control problem, 20.0%; 2 control problems, 30.8%; 3 or 4 control problems, 32.2%) and at least one severe asthma-related event. After adjustment, subjects with three or four control problems were at greater risk for unscheduled office visits [relative risk (RR) = 2.8; 95% confidence interval (CI): 2.4-3.2], course of oral steroids (RR = 2.9; 95% CI: 2.5-3.3), emergency room visits (RR = 4.1; 95% CI: 2.7-6.2) or hospitalization (RR = 13.6; 95% CI: 7.4-24.9), vs no control problems. Progressively poorer levels of asthma control are associated with increasing risk of severe asthma-related events. CONCLUSIONS: This study provides evidence of an association between poor asthma control and future severe asthma-related healthcare events. A validated questionnaire may help clinicians identify patients requiring intervention to prevent future severe asthma-related events.

Extent, patterns, and burden of uncontrolled disease in severe or difficult-to-treat asthma.

BACKGROUND: Characterization of uncontrolled asthma burden in a natural treatment setting can influence treatment recommendations and clinical practice. The objective was to characterize and compare the economic burden of severe or difficult-to-treat asthma in uncontrolled and controlled patients. METHODS: Baseline patient data (age > or = 13 years; n = 3916) were obtained from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study. Disease control was assessed using two approaches: (i) applying criteria for control based on the Gaining Optimal Asthma Control study, and (ii) using the Asthma Therapy Assessment Questionnaire (ATAQ) to identify the number of asthma control problems. Assessments were performed at baseline, and at months 12 and 24. Monetary values were assigned to productivity loss and medical resource use. Direct and indirect costs were aggregated over 24 months and compared using Student's t-test for continuous measures and chi-squared for categorical variables. RESULTS: Throughout the study, most patients had uncontrolled asthma (83% uncontrolled; 16% inconsistent control; 1.3% controlled). Controlled patients experienced fewer work or school absences and less healthcare resource use than uncontrolled patients at all study time points. Using the multilevel ATAQ control score, asthma costs increased directly with the number of asthma control problems. Costs for uncontrolled patients were more than double those of controlled patients throughout the study (14,212 vs 6,452 US Dollars; adjusted to 2002 Dollars; P < 0.0001). CONCLUSIONS: This study demonstrated that few severe or difficult-to-treat asthma patients achieved control over a 2-year period and the economic consequence of uncontrolled disease is substantial.

Cost effectiveness of inhaled steroid withdrawal in outpatients with chronic obstructive pulmonary disease.

BACKGROUND: The evidence for the effectiveness and safety of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) is inconclusive. This study determined the cost effectiveness of withdrawing fluticasone propionate (FP) in outpatients with COPD. METHODS: The cost effectiveness analysis was based on a randomised, placebo controlled FP withdrawal study. After a 4 month run in period on FP, patients were randomly assigned to continue FP 500 microg twice daily or to receive placebo for 6 months. A decision analytical model evaluated the 6 month incremental cost effectiveness of the ICS versus ICS withdrawal strategy. One way sensitivity analyses and a Monte Carlo simulation were performed to evaluate the robustness of the findings. RESULTS: The average patient with COPD in the FP group generated 511 in direct medical costs, including 238 for FP. The cost of the placebo strategy was 456. The higher direct drug cost of 212 per patient for the FP strategy during the 6 month follow up period compared with the placebo group was partially offset by a lower exacerbation and hospital admission cost of 157. The 6 month incremental cost effectiveness of the FP strategy compared with placebo was 110 per exacerbation prevented and 1286 per hospital admission prevented. CONCLUSIONS: Over a 6 month period, withdrawing FP in a pre-selected trial population of COPD patients led to absolute cost savings but with a higher rate of exacerbations and hospital admissions.