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.

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.

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.

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.

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.

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.

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.

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 potential clinical and economic benefits of silver alloy urinary catheters in preventing urinary tract infection.

BACKGROUND: Catheter-associated urinary tract infection (UTI) is associated with increased morbidity, mortality, and costs. A recent meta-analysis concluded that silver alloy catheters reduce the incidence of UTI by 3-fold; however, clinicians must decide whether the efficacy of such catheters is worth the extra per unit cost of $5.30. OBJECTIVE: To assess the clinical and economic impact of using silver alloy urinary catheters in hospitalized patients. METHODS: The decision model, performed from the health care payer's perspective, evaluated a simulated cohort of 1000 hospitalized patients on general medical, surgical, urologic, and intensive care services requiring short-term urethral catheterization (2-10 days). We compared 2 catheterization strategies: silver alloy catheters and standard (noncoated) urinary catheters. Outcomes included the incidence of symptomatic UTI and bacteremia and direct medical costs. RESULTS: In the base-case analysis, use of silver-coated catheters led to a 47% relative decrease in the incidence of symptomatic UTI from 30 to 16 cases per 1000 patients (number needed to treat = 74) and a 44% relative decrease in the incidence of bacteremia from 4.5 to 2.5 cases per 1000 patients (number needed to treat = 500) compared with standard catheters. Use of silver alloy catheters resulted in estimated cost savings of $4.09 per patient compared with standard catheter use ($20.87 vs $16.78). In a multivariate sensitivity analysis using Monte Carlo simulation, silver-coated catheters provided clinical benefits over standard catheters in all cases and cost savings in 84% of cases. CONCLUSIONS: Using silver alloy catheters in hospitalized patients requiring short-term urinary catheterization reduces the incidence of symptomatic UTI and bacteremia, and is likely to produce cost savings compared with standard catheters.

The efficacy of silver alloy-coated urinary catheters in preventing urinary tract infection: a meta-analysis.

PURPOSE: Indwelling urinary catheters are implicated in most cases of nosocomial urinary tract infection. Silver-coating of catheters may reduce the risk of these infections; however, trials have provided mixed results. We performed a meta-analysis to estimate the effectiveness of silver-coated urinary catheters. SUBJECTS AND METHODS: Published or unpublished articles were sought using MEDLINE, reference review, and correspondence with original authors, catheter manufacturers, and experts. Trials using silver-coated urinary catheters in the treatment group and uncoated urinary catheters in the control group were included. Bacteriuria, as evaluated by urine culture, was the outcome variable used to indicate urinary tract infection. Summary odds ratios (OR) and 95% confidence intervals (CI) were calculated using Mantel-Haenszel methods with a fixed-effects model. RESULTS: Of 117 reports retrieved, eight trials with a total of 2,355 patients satisfied inclusion criteria. The summary OR for urinary tract infection was 0.59 (95% CI, 0.42 to 0.84) indicating a significant benefit in the patients receiving silver-coated catheters. A test of heterogeneity, however, indicated that the odds ratios varied significantly among studies. Silver alloy catheters (OR = 0.24; 95% CI, 0.11 to 0.52) were significantly more protective against bacteriuria than silver oxide catheters (OR = 0.79; 95% CI, 0.56 to 1.10). CONCLUSIONS: This meta-analysis clarifies discrepant results among trials of silver-coated urinary catheters by revealing that silver alloy catheters are significantly more effective in preventing urinary tract infections than are silver oxide catheters. Though silver alloy urinary catheters cost about $6 more than standard urinary catheters, they may be worth the extra cost since catheter-related infection is a common cause of nosocomial infection and bacteremia.

Incidence and long-term cost of steroid-related side effects after renal transplantation.

Corticosteroids are an essential component of most immunosuppressive regimens currently used in renal transplantation because of their efficacy in reducing acute rejection and improving graft survival. Steroids, however, are associated with numerous side effects that lead to increased patient morbidity and mortality. The incidence and economic cost of steroid-related side effects have not been quantitatively assessed. Thus, based on a systematic review of the published literature, we estimated the incidence of steroid-related hypertension (15%), posttransplantation diabetes mellitus (10%), peripheral fractures (2% per year), avascular necrosis of the hip (8%), and cataracts (22%). In addition, we estimated that approximately 5% of patients who have cataracts or avascular necrosis of the hip require surgery. We used these literature-based estimates in a model to project the costs of treating side effects over a 10-year posttransplantation time frame for a 50-patient cohort that represented an average-sized renal transplant center. Steroid-induced hypertension and its complications were the most expensive side effect ($93,900), followed closely by posttransplantation diabetes ($89,700) and avascular necrosis of the hip ($61,700). Cataracts and peripheral bone fractures were less costly ($16,300 and $4,300, respectively). The cumulative projected 10-year cost of all side effects for the 50-patient cohort was $265, 900, or $5,300 per transplant patient. Steroid-related side effects add to the long-term cost of medical care of renal transplant recipients. These costs provide a rationale for further investigation of steroid-sparing immunosuppression protocols.

The medical cost of undiagnosed sleep apnea.

Obstructive sleep apnea is an under-diagnosed, but common disorder with serious adverse consequences. Cost data from the year prior to the diagnosis of sleep-disordered breathing in a consecutive series of 238 cases were used to estimate the potential medical cost of undiagnosed sleep apnea and to determine the relationship between the severity of sleep-disordered breathing and the magnitude of medical costs. Among cases, mean annual medical cost prior to diagnosis was $2720 versus $1384 for age and gender matched controls (p<0.01). Regression analysis showed that the reciprocal of the apnea hypopnea index among cases was significantly related to log-transformed annual medical costs after adjusting for age, gender, and body mass index (p<0.05). We conclude that patients with undiagnosed sleep apnea had considerably higher medical costs than age and sex matched individuals and that the severity of sleep-disordered breathing was associated with the magnitude of medical costs. Using available data on the prevalence of undiagnosed moderate to severe sleep apnea in middle-aged adults, we estimate that untreated sleep apnea may cause $3.4 billion in additional medical costs in the U.S. Whether medical cost savings occur with treatment of sleep apnea remains to be determined.

The economic burden of COPD.

COPD is one of the leading causes of morbidity and mortality worldwide and imparts a substantial economic burden on individuals and society. Despite the intense interest in COPD among clinicians and researchers, there is a paucity of data on health-care utilization, costs, and social burden in this population. The total economic costs of COPD morbidity and mortality in the United States were estimated at $23.9 billion in 1993. Direct treatments for COPD-related illness accounted for $14.7 billion, and the remaining $9.2 billion were indirect morbidity and premature mortality estimated as lost future earnings. Similar data from another US study suggest that 10% of persons with COPD account for > 70% of all medical care costs. International studies of trends in COPD-related hospitalization indicate that although the average length of stay has decreased since 1972, admissions per 1,000 persons per year for COPD have increased in all age groups > 45 years of age. These trends reflect population aging, smoking patterns, institutional factors, and treatment practices.

The costs of treating COPD in the United States.

STUDY OBJECTIVES: COPD affects millions of people in the United States. The purpose of this study was to describe the medical resource use and costs incurred by persons with COPD in the United States in 1987. DESIGN: Data for this study were derived from the 1987 National Medical Expenditure Survey. A societal perspective was adopted for this analysis. PATIENTS OR PARTICIPANTS: All persons > or = 40 years old with resource use or expenditures for chronic bronchitis, emphysema, or nonspecific chronic airway obstruction were included in this study. RESULTS: Mean per-person direct medical expenditures among persons with COPD were $6,469 (1987 US dollars), about 25% of which was COPD related. Approximately 68% of direct medical expenditures in persons with COPD were for inpatient hospitalization. CONCLUSIONS: COPD causes a large societal burden of illness that is expected to increase. This study provides a valuable foundation and historical measure against which to compare other estimates.

Economic analysis of lung volume reduction surgery as part of the National Emphysema Treatment Trial. NETT Research Group.

BACKGROUND: In today's cost-conscious health care environment, obtaining timely and accurate economic information regarding new medical technologies has become extremely important. The National Emphysema Treatment Trial, a multicenter, randomized controlled trial of lung volume reduction surgery (LVRS) plus medical therapy, versus medical therapy for patients with severe emphysema, includes a parallel cost-effectiveness analysis. METHODS: The analysis is designed to determine the cost-effectiveness of LVRS versus medical therapy for those who are eligible for the procedure. After describing theoretical foundations of cost-effectiveness analysis as they apply to this study, we describe the economic and quality of life data that are being collected alongside the clinical trial, methods of analysis, and approach to presenting the results. RESULTS: The cost-effectiveness of LVRS relative to medical therapy will be presented as costs per quality-adjusted life years gained. CONCLUSIONS: This analysis will provide timely economic data that can be considered alongside the clinical results of the National Emphysema Treatment Trial. As one of the largest clinical trials to include a parallel, prospective cost-effectiveness analyses, this study will also provide valuable practical information about conducting an economic analysis alongside a multicenter clinical trial.