The cost-effectiveness of metformin in the US diabetes prevention program trial: Simple interpretations need not apply.

Based on previously published US Diabetes Prevention Program (DPP) cost-effectiveness analyses (CEAs) metformin continues to be promoted as "cost-effective." We review the DPP within-trial CEA to assess this claim. Treatment alternatives included placebo (plus standard lifestyle advice), branded metformin and individual lifestyle modification. We added generic metformin as an alternative. Original published CEA data were taken as given and re-analyzed according to accepted principles for calculating incremental cost-effectiveness ratios (ICERs) in the economic evaluation field. With more than two treatments as in the DPP, these require attention to the rankings of interventions according to cost or effect prior to stipulating appropriate ICERs to calculate. With proper ICERs neither branded nor generic metformin was cost-effective, regardless of the value assumed for the willingness to pay for the quality-adjusted life year outcome assessed. Metformin alternatives were technically inefficient compared to placebo or the lifestyle modification alternative. Net loss calculations indicated substantial costs/health losses to using metformin instead of the optimal lifestyle alternative in response to metformin having been inaccurately labelled "cost-effective" in the original CEA. That CEA and subsequent analyses and citations of such analyses continue to claim that both metformin and lifestyle modification are cost-effective in diabetes prevention based on DPP data. Using metformin implies substantial costs and health losses compared to the cost-effective lifestyle modification. It may be that metformin has a role in cost-effective diabetes prevention, but this has yet to be shown based on DPP data.

An economic evaluation of a European cohort from a multinational trial of linezolid versus teicoplanin in serious Gram-positive bacterial infections: the importance of treatment setting in evaluating treatment effects.

In a recent multinational trial, hospital resource use and total cost of treatment were compared between linezolid and teicoplanin for severe Gram-positive bacterial infections among 227 European hospitalised patients. The results show that the linezolid group had a 3.2-day (6.3 for linezolid versus 9.5 for teicoplanin groups) shorter mean intravenous antibiotic treatment duration. Certain baseline variables, particularly the inpatient location at enrolment and the presence of outpatient/home parenteral antibiotic therapy (OHPAT), had substantial effects on length of stay (LOS) and cost of treatment. After adjusting for the between-treatment difference in these two variables and other baseline variables, the results showed non-significant shorter LOS and lower mean total cost of treatment for the linezolid group among patients with no access to OHPAT.

Comparison of linezolid with oxacillin or vancomycin in the empiric treatment of cellulitis in US hospitals.

In this decision-model analysis, the authors compared overall clinical efficacy and total cost of empiric treatment of hospitalized cellulitis patients prescribed linezolid and oxacillin or vancomycin. The authors hypothesized that, when used appropriately, empiric linezolid treatment is an effective, potentially cost-saving antibiotic compared with treatment initiated with oxacillin or vancomycin. Data on efficacy, duration of antibiotic treatment, and hospital stay for first-line treatment success were obtained from two clinical trials. Other medical resource use data were obtained from an expert panel of clinicians. US hospital direct medical costs were determined using standard costing techniques. Overall efficacy and total cost of treatment were estimated for combinations of the risk of being infected with methicillin-resistant pathogens. Sensitivity analyses were performed to test the impact of changes in major assumptions. Overall first-line efficacy is better for empiric treatment initiated with linezolid than with oxacillin or vancomycin across the spectrum of the risk of being infected with methicillin-resistant bacteria. The average total cost of treatment is lower for treatment initiated with linezolid than with vancomycin across the spectrum, or than with oxacillin when the risk of being infected with methicillin-resistant pathogens is 18.7 % or higher. Linezolid appears to be at least as effective as vancomycin or oxacillin for empiric treatment of hospitalized cellulitis patients. Linezolid is likely to be less costly compared with vancomycin at all resistance rates and with oxacillin when the risk of infection with methicillin-resistant pathogens is greater than 18.7 %, a resistance rate commonly seen in US hospitals.

Hospital resource use and cost of treatment with linezolid versus teicoplanin for treatment of serious gram-positive bacterial infections among hospitalized patients from South America and Mexico: results from a multicenter trial.

BACKGROUND: Linezolid is a novel oxazolidinone antibiotic that is effective for the treatment of gram-positive bacterial infections. The oral formulation has the potential to reduce length of stay (LOS) when used as a substitute for parenteral glycopeptide antibiotics. In a recent multinational trial comparing linezolid (i.v. followed by oral administration) with teicoplanin (i.v. alone or switched to i.m. administration), linezolid was found to have better efficacy (P = 0.005) and similar safety for treating serious gram-positive infections. OBJECTIVE: The purpose of this study was to compare hospital resource use (primarily LOS) and cost of treatment between linezolid and teicoplanin for hospitalized patients with serious gram-positive infections in South America and Mexico using data from the multinational trial. METHODS: In a multinational, Phase IIIb, open-label, comparator-controlled trial, data were collected from hospitalized patients in centers in 6 South America can countries and Mexico with suspected or confirmed serious gram-positive infections. Patients were randomly assigned to receive i.v. linezolid 600 mg BID (for the entire treatment period [7-28 days] or switched to oral linezolid 600 mg BID) or i.v. teicoplanin (for the entire treatment period or switched to i.m. teicoplanin) dosed per approved prescription information. Data on direct medical resource utilization were collected for each patient, including duration and doses of study medication, location of hospitalization and LOS, comedications, tests and procedures, and outpatient service usage. Unit costs for the medical resources were obtained from secondary sources. RESULTS: A total of 203 patients (97 treated with linezolid and 106 treated with teicoplanin) were enrolled from these 7 countries. The unadjusted results showed that compared with teicoplanin, patients treated with linezolid had a 3.1-day shorter mean i.v. antibiotic treatment duration (P < 0.001), a 2.0- to 2.2-day shorter median and mean LOS (P = 0.03), and a 311 US dollars lower mean total cost of treatment (P = NS). After controlling for age, race, sex, site of infection, inpatient location when the antibiotic treatment started, number of historical and current comorbidities, and whether the patient had a diagnosis of systemic inflammatory response syndrome or sepsis, the multivariate adjusted results were similar to the unadjusted results. The linezolid group had a 1.6-day shorter adjusted LOS or 66% greater odds of early discharge (P = 0.049) and a 335 US dollars lower adjusted mean total cost of treatment (P = NS). CONCLUSION: Linezolid was associated with shorter LOS and duration of IV antibiotic treatment than teicoplanin for serious gram-positive infections in the population studied. Linezolid therapy has the potential to reduce the total cost of treatment.

Effect of linezolid versus vancomycin on length of hospital stay in patients with complicated skin and soft tissue infections caused by known or suspected methicillin-resistant staphylococci: results from a randomized clinical trial.

BACKGROUND: Complicated skin and soft tissue infections are common surgical indications usually requiring patients to be hospitalized, and are often caused by gram-positive bacteria, including methicillin-resistant staphylococci such as MRSA. Vancomycin has been the standard treatment for methicillin-resistant staphylococcal infections in many countries, but its intravenous-only formulation for systemic infections often confines patients to the hospital for the treatment. Linezolid, a novel oxazolidinone antibiotic available in intravenous and 100% bioavailable oral forms, was shown in a randomized trial to be as efficacious as vancomycin for suspected or proven methicillin-resistant staphylococcal infections. To determine if oral linezolid can reduce length of hospital stay (LOS) when compared to vancomycin, we compared the LOS for the 230 complicated skin and soft tissue infection patients enrolled in this trial. MATERIALS AND METHODS: Patients received up to four weeks of linezolid (intravenous followed by optional oral) or vancomycin (intravenous only), followed by up to four weeks of observation. Unadjusted LOS was estimated using Kaplan-Meier survival functions, whereas the log-logistic survival analysis model was used to estimate the multivariate-adjusted LOS controlling for patient demographics and selected baseline clinical variables. Analysis was done on the intent-to-treat (n = 230) sample as well as on two subsamples of the clinically evaluable (n = 144) and surgical site infection (n = 114) patients. RESULTS: The unadjusted Kaplan-Meier median LOS was five days shorter for the linezolid group than the vancomycin group in the intent-to-treat sample (9 vs. 14 days, p = 0.052). It was eight days shorter (8 vs. 16 days, p = 0.0025) in the clinically evaluable sample, but the difference in the surgical site infection sample was not significant (10 vs. 14 days; p = 0.29). The linezolid group's unadjusted mean LOS was 1.7, 5.3 and 0.8 days shorter in the intentto-treat, clinically evaluable, and surgical site infection samples, respectively. After adjusting for age, gender, race, geographic region, bacteremia, type of inpatient location, and number of concurrent medical conditions using the log-logistic model, between-treatment differences in the multivariate-adjusted median LOS decreased to 3, 6, and 3 days, whereas the differences in mean LOS increased to 3.1, 6.5 and 2.5 days for the intent-to-treat, clinically evaluable, and surgical site infection samples (p < 0.01, < 0.01, and < 0.10), respectively. When the between-treatment differences in LOS were expressed as odds ratio of hospital discharges, multivariate-adjustment increased the odds ratios in favor of linezolid for all the three samples. CONCLUSION: Results from this randomized trial show that linezolid can significantly reduce LOS for patients with complicated skin and soft tissue infections from suspected or confirmed methicillin-resistant staphylococci.

Effects of linezolid on hospital length of stay compared with vancomycin in treatment of methicillin-resistant Staphylococcus infections. An application of multivariate survival analysis.

OBJECTIVES: This study was designed to estimate the effects of treatment with linezolid as compared with vancomycin, on the distribution of length of stay (LOS) for hospitalized patients with methicillin-resistant staphylococcal infections. Treatment with intravenous-oral linezolid may allow some patients to be discharged earlier than would treatment with intravenous vancomycin. METHODS: The analysis is based on the intention-to-treat sample from a randomized multinational phase 3 clinical trial of 460 patients showing that the treatments had equal efficacy. Given the nature of the LOS data, some censoring, and some imbalances between treatment groups, multivariate survival analysis was indicated. Cox proportional hazards assumptions were tested and failed, and accelerated failure time models were tested for best fit. The log-logistic model was selected and used as the basis for estimating the overall treatment effect on LOS. Two methods for multivariate corrections to the survivorship functions allowed more thorough description of the treatment effect on the distribution of LOS, including multivariate-adjusted Kaplan-Meier curves. RESULTS: The average reduction in LOS associated with linezolid treatment, based on the log-logistic model after correction for covariate effects, was 18.1% (p = .041) or 2.53 days at the median. This was consistent with differences at the medians of the adjusted survivorship functions, which were 2 or 3 days depending on the method used. Treatment-based differences exist at each decile of LOS and consistently favor linezolid. Estimated mean reduction in LOS due to linezolid was 1.62 days in both methods. CONCLUSIONS: In this study sample, linezolid treatment resulted in statistically significantly shorter hospital LOS as compared with vancomycin treatment. Appropriate use of multivariate survival analysis allows better examination of the nature of the treatment effect on LOS, which may be important for economic analysis.

Approaches to analysis of length of hospital stay related to antibiotic therapy in a randomized clinical trial: linezolid versus vancomycin for treatment of known or suspected methicillin-resistant Staphylococcus species infections.

As length of hospital stay (LOS) represents about 70-90% of the total cost of treating serious infections, it represents a key variable in analyzing the health economic differences between treatments for hospitalized patients. In a retrospective analysis using LOS data from a multinational, randomized, phase III clinical trial, we examined two methods (the log-logistic model and Kaplan-Meier survival function) and three approaches (unadjusted total LOS, total LOS adjusted for nontreatment factors, and adjusted LOS based on antibiotic treatment [the antibiotic treatment LOS]) for estimating antibiotic treatment effect on LOS and determined if these approaches could reduce the variation in LOS and control for the imbalance between treatment groups. The trial enrolled patients who were hospitalized with known or suspected Staphylococcus species infections who received at least one dose of linezolid or vancomycin (intent-to-treat sample) and who continued taking the study drug for at least 7 days (clinically evaluable sample). In the intent-to-treat sample, the linezolid group had a 2- (unadjusted) or 4-day (adjusted for nontreatment factors) shorter LOS at the 25th percentile; a 1- or 2-day advantage, respectively, at the 50th percentile (median); and a 0.6- or 1.6-day mean LOS advantage, compared with the vancomycin group. With the antibiotic treatment LOS approach, the linezolid group had mean and median LOS reductions comparable to or greater than those seen in the nontreatment-factor-adjusted results. Results for the clinically evaluable sample were similar to those of the intent-to-treat sample, but the differences between the treatment groups were greater. Linezolid-treated patients had significant LOS reductions that otherwise would be masked without the use of more appropriate, but less commonly used, methods.