Noninvasive Prenatal Testing for Trisomies 21, 18, and 13, Sex Chromosome Aneuploidies, and Microdeletions in Average-Risk Pregnancies: A Cost-Effectiveness Analysis.

OBJECTIVE: The cost effectiveness of noninvasive prenatal testing (NIPT) has been established for high-risk pregnancies but remains unclear for pregnancies at other risk levels. The aim was to assess the cost effectiveness of NIPT in average-risk pregnancies from the perspective of a provincial public payer in Canada. METHODS: A model was developed to compare traditional prenatal screening (TPS), NIPT as a second-tier test (performed only after a positive TPS result), and NIPT as a first-tier test (performed instead of TPS) for trisomies 21, 18, and 13; sex chromosome aneuploidies; and microdeletions in a hypothetical annual population cohort of average-risk pregnancies (142 000 to 148,000) in Ontario, Canada. A probabilistic analysis was conducted with 5000 repetitions. RESULTS: Compared with TPS, NIPT as a second-tier test detected more affected fetuses with trisomies 21, 18, and 13 (188 vs. 158), substantially reduced the number of diagnostic tests (i.e., chorionic villus sampling and amniocentesis) performed (660 vs. 3107), and reduced the cost of prenatal screening ($26.7 million vs. $27.6 million) annually. Compared with second-tier NIPT, first-tier NIPT detected an additional 80 cases of trisomies 21, 18, and 13 at an additional cost of $33 million. The incremental cost per additional affected fetus detected was $412 411. Extending first-tier NIPT to include testing for sex chromosome aneuploidies and 22q11.2 deletion would increase the total screening cost. CONCLUSIONS: NIPT as a second-tier test is cost-saving compared with TPS alone. Compared with second-tier NIPT, first-tier NIPT detects more cases of chromosomal anomalies but at a substantially higher cost.

A Non-inferiority Framework for Cost-Effectiveness Analysis.

BACKGROUND: Traditional decision rules have limitations when a new technology is less effective and less costly than a comparator. We propose a new probabilistic decision framework to examine non-inferiority in effectiveness and net monetary benefit (NMB) simultaneously. We illustrate this framework using the example of repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT) for treatment-resistant depression. METHODS: We modeled the quality-adjusted life-years (QALYs) associated with the new intervention (rTMS), an active control (ECT), and a placebo control, and we estimated the fraction of effectiveness preserved by the new intervention through probabilistic sensitivity analysis (PSA). We then assessed the probability of cost-effectiveness using a traditional cost-effectiveness acceptability curve (CEAC) and our new decision-making framework. In our new framework, we considered the new intervention cost-effective in each simulation of the PSA if it preserved at least 75 percent of the effectiveness of the active control (thus demonstrating non-inferiority) and had a positive NMB at a given willingness-to-pay threshold (WTP). RESULTS: rTMS was less effective (i.e., associated with fewer QALYs) and less costly than ECT. The traditional CEAC approach showed that the probabilities of rTMS being cost-effective were 100 percent, 39 percent, and 14 percent at WTPs of $0, $50,000, and $100,000 per QALY gained, respectively. In the new decision framework, the probabilities of rTMS being cost-effective were reduced to 23 percent, 21 percent, and 13 percent at WTPs of $0, $50,000, and $100,000 per QALY, respectively. CONCLUSIONS: This new framework provides a different perspective for decision making with considerations of both non-inferiority and WTP thresholds.

Mechanical Thrombectomy in Acute Ischemic Stroke: A Systematic Review.

Although intravenous thrombolysis increases the probability of a good functional outcome in carefully selected patients with acute ischemic stroke, a substantial proportion of patients who receive thrombolysis do not have a good outcome. Several recent trials of mechanical thrombectomy appear to indicate that this treatment may be superior to thrombolysis. We therefore conducted a systematic review and meta-analysis to evaluate the clinical effectiveness and safety of new-generation mechanical thrombectomy devices with intravenous thrombolysis (if eligible) compared with intravenous thrombolysis (if eligible) in patients with acute ischemic stroke caused by a proximal intracranial occlusion. We systematically searched seven databases for randomized controlled trials published between January 2005 and March 2015 comparing stent retrievers or thromboaspiration devices with best medical therapy (with or without intravenous thrombolysis) in adults with acute ischemic stroke. We assessed risk of bias and overall quality of the included trials. We combined the data using a fixed or random effects meta-analysis, where appropriate. We identified 1579 studies; of these, we evaluated 122 full-text papers and included five randomized control trials (n=1287). Compared with patients treated medically, patients who received mechanical thrombectomy were more likely to be functionally independent as measured by a modified Rankin score of 0-2 (odds ratio, 2.39; 95% confidence interval, 1.88-3.04; I2=0%). This finding was robust to subgroup analysis. Mortality and symptomatic intracerebral hemorrhage were not significantly different between the two groups. Mechanical thrombectomy significantly improves functional independence in appropriately selected patients with acute ischemic stroke.

Atypical ductal hyperplasia diagnosed at sonographically guided core needle biopsy: frequency, final surgical outcome, and factors associated with underestimation.

OBJECTIVE: The purposes of this article were to review the mammographic and sonographic features of breast masses yielding atypical ductal hyperplasia (ADH) at sonographically guided biopsy, evaluate the surgical pathology outcome of these lesions, and determine whether clinical or imaging features can be used to predict upgrade to malignancy. MATERIALS AND METHODS: Among 6325 sonographically guided biopsies (2003- 2010) (14-gauge cores), 56 yielded the diagnosis of ADH (0.9%). Six patients were excluded (lost to follow-up). Fifty lesions were surgically excised in 45 patients. Mammographic and sonographic features were analyzed in consensus by two radiologists using the BI-RADS lexicon. RESULTS: Forty-five patients (mean age, 56 years; 12 < 50 years; six with synchronous breast carcinoma) had 50 ADH lesions (median size, 0.6 cm). Surgical excision yielded malignancy in 28 cases (56% underestimation rate). Among 42 mammograms (47 lesions), 30 lesions were identified (30/47, 64%) as masses (12/30, 40%), asymmetric densities (10/30, 33%), microcalcifications (4/30, 13%), and architectural distortions (4/30, 13%). Sonographically, most lesions appeared as hypoechoic masses (64%, 30/47) with irregular shape (51%, 24/47), microlobulated margins (49%, 23/47), no posterior acoustic feature (25/47, 53%), abrupt interface (70%, 33/47), and parallel orientation (57%, 27/47). No mammographic and sonographic features were associated with malignant outcome, whereas age less than 50 years (p = 0.03) and synchronous malignancy (p = 0.03) were associated with malignant outcome. CONCLUSION: ADH diagnosed at sonographically guided 14-gauge core needle biopsy shows a high underestimation rate. Synchronous carcinoma or age less than 50 years is associated with malignant outcome.

Simplified Methods for Modelling Dependent Parameters in Health Economic Evaluations: A Tutorial.

BACKGROUND: In health economic evaluations, model parameters are often dependent on other model parameters. Although methods exist to simulate multivariate normal (MVN) distribution data and estimate transition probabilities in Markov models while considering competing risks, they are technically challenging for health economic modellers to implement. This tutorial introduces easily implementable applications for handling dependent parameters in modelling. METHODS: Analytical proofs and proposed simplified methods for handling dependent parameters in typical health economic modelling scenarios are provided, and implementation of these methods are illustrated in seven examples along with the SAS and R code. RESULTS: Methods to quantify the covariance and correlation coefficients of correlated variables based on published summary statistics and generation of MVN distribution data are demonstrated using examples of physician visits data and cost component data. The use of univariate normal distribution data instead of MVN distribution data to capture population heterogeneity is illustrated based on the results from multiple regression models with linear predictors, and two examples are provided (linear fixed-effects model and Cox proportional hazards model). A conditional probability method is introduced to handle two or more state transitions in a single Markov model cycle and applied in examples of one- and two-way state transitions. CONCLUSIONS: This tutorial proposes an extension of routinely used methods along with several examples. These simplified methods may be easily applied by health economic modellers with varied statistical backgrounds.

Systematic review and meta-analysis of a urine-based pneumococcal antigen test for diagnosis of community-acquired pneumonia caused by Streptococcus pneumoniae.

Standard culture methods for diagnosis of Streptococcus pneumoniae pneumonia take at least 24 h. The BinaxNOW urine-based test for S. pneumoniae (BinaxNOW-SP) takes only 15 min to conduct, potentially enabling earlier diagnosis and targeted treatment. This study was conducted to assess whether the use of BinaxNOW-SP at the time of hospital admission would provide adequate sensitivity and specificity for diagnosis of community-acquired pneumonia (CAP) in adult patients. We searched PubMed, EMBASE/OVID, Cochrane Collaboration, Centre for Reviews and Dissemination, INAHTA, and CADTH for diagnostic or etiologic studies of hospitalized predominately adult patients with clinically defined CAP that reported the diagnostic performance of BinaxNOW-SP versus cultures. Two authors independently extracted study details and diagnostic two-by-two tables. We found that 27 studies met our inclusion criteria, and three different reference standards were used between them. A bivariate meta-analysis of 12 studies using a composite of culture tests as the reference standard estimated the sensitivity of BinaxNOW-SP as 68.5% (95% credibility interval [CrI], 62.6% to 74.2%) and specificity as 84.2% (95% CrI, 77.5% to 89.3%). A meta-analysis of all 27 studies, adjusting for the imperfect and variable nature of the reference standard, gave a higher sensitivity of 74.0% (CrI, 66.6% to 82·3%) and specificity of 97.2% (CrI, 92.7% to 99.8%). The analysis showed substantial heterogeneity across studies, which did not decrease with adjustment for covariates. We concluded that the higher pooled sensitivity (compared to culture) and high specificity of BinaxNOW-SP suggest it would be a useful addition to the diagnostic workup for community-acquired pneumonia. More research is needed regarding the impact of BinaxNOW-SP on clinical practice.

Invasive ductal carcinoma of the breast: correlation between tumor grade determined by ultrasound-guided core biopsy and surgical pathology.

OBJECTIVE: The purpose of this article is to evaluate the concordance between tumor grade found on ultrasound-guided core biopsies of invasive ductal carcinomas of the breast and subsequent excision specimens. MATERIALS AND METHODS: We retrospectively studied 300 consecutive invasive ductal carcinomas (274 women) that were biopsied under sonographic guidance, using 14-gauge core needles exclusively, and that were subsequently excised surgically. A minimum of four cores were taken per lesion. Core biopsy grades were compared with final surgical grades (reference standard). Tumor grade was assigned using the standard modified Scarff-Bloom-Richardson system. The agreement rate was expressed in percentages and in kappa statistics; the rates of overestimation and underestimation were also assessed. The correlation between tumor size (small, ≤ 0.5 cm; medium, 0.6-2.4 cm; and large, ≥ 2.5 cm) and agreement rate was also evaluated. RESULTS: The overall agreement between core biopsy and surgical pathology grade was 69% (simple κ = 0.46; 95% CI, 0.36-0.54). Agreement by biopsy grade was 86% (55/64) for grade 3, 66% (118/180) for grade 2, and 55% (23/42) for grade 1. Core biopsy underestimated 24% (70/286) and overestimated 7% (20/286) of the lesions. When discordant, core biopsy differed from excision by no more than one grade. Large tumors were more likely to show underestimation rather than overestimation when discordant (rate of underestimation, 92% for large, 81% for medium, and 33% for small tumors; p < 0.0031). CONCLUSION: Ultrasound-guided core biopsy accurately predicts high-grade breast tumors but is moderately accurate for lower-grade lesions. Large tumor size negatively impacts the accuracy of tumor grade found on biopsy and is associated with underestimation.

Understanding bias in probabilistic analysis in model-based health economic evaluation.

Guidelines of economic evaluations suggest that probabilistic analysis (using probability distributions as inputs) provides less biased estimates than deterministic analysis (using point estimates) owing to the non-linear relationship of model inputs and model outputs. However, other factors can also impact the magnitude of bias for model results. We evaluate bias in probabilistic analysis and deterministic analysis through three simulation studies. The simulation studies illustrate that in some cases, compared with deterministic analyses, probabilistic analyses may be associated with greater biases in model inputs (risk ratios and mean cost estimates using the smearing estimator), as well as model outputs (life-years in a Markov model). Point estimates often represent the most likely value of the parameter in the population, given the observed data. When model parameters have wide, asymmetric confidence intervals, model inputs with larger likelihoods (e.g., point estimates) may result in less bias in model outputs (e.g., costs and life-years) than inputs with lower likelihoods (e.g., probability distributions). Further, when the variance of a parameter is large, simulations from probabilistic analyses may yield extreme values that tend to bias the results of some non-linear models. Deterministic analysis can avoid extreme values that probabilistic analysis may encounter. We conclude that there is no definitive answer on which analytical approach (probabilistic or deterministic) is associated with a less-biased estimate in non-linear models. Health economists should consider the bias of probabilistic analysis and select the most suitable approach for their analyses.

Evaluating the correlations of cost and utility parameters from summary statistics for probabilistic analysis in economic evaluations.

OBJECTIVES: The correlations between economic modeling input parameters directly impact the variance and may impact the expected values of model outputs. However, correlation coefficients are not often reported in the literature. We aim to understand the correlations between model inputs for probabilistic analysis from summary statistics. METHODS: We provide proof that for correlated random variables X and Y (e.g. inpatient visits and outpatient visits), the Pearson correlation coefficients of sample means and samples are equal to each other (corrX,Y=corrX-,Y-). Therefore, when studies report summary statistics of correlated parameters, we can quantify the correlation coefficient between parameters. RESULTS: We use examples to illustrate how to estimate the correlation coefficient between the incidence rates of non-severe and severe hypoglycemia events, and the common coefficient of five cost components for patients with diabetic foot ulcers. We further introduce three types of correlations for utilities and provide two examples to estimate the correlations for utilities based on published data. We also evaluate how correlations between cost parameters and utility parameters impact the cost-effectiveness results using a Markov model for major depression. CONCLUSION: Incorporation of the correlations can improve the precision of cost-effectiveness results and increase confidence in evidence-based decision-making. Further empirical evidence is warranted.

Examining the correlation between treatment effects in clinical trials and economic modeling.

INTRODUCTION: Many diseases have a sequential treatment pathway. Compared with patients without previous treatment, patients who fail initial treatment may have lower success rates with a second treatment. This phenomenon can be explained by a correlation between treatment effects. METHODS: We developed a statistical model of covariance for the underlying unobserved correlation between treatments and established a mathematical expression for the magnitude of the latent correlation term. We conducted a simulation study of clinical trials to investigate the correlation between two treatments and explored clinical examples based on published literature to illustrate the identification and evaluation of these correlations. RESULTS: Our simulation study confirmed that a treatment correlation reduces the probability of success for the second treatment, compared with no correlation. We found that treatment correlations may be observable in clinical trials, such as for depression and lung cancer, and the magnitude of correlation may be estimated. We illustrated that treatment correlations can be incorporated into an economic model, with possible impacts on cost-effectiveness results. Additional applications of correlation concepts are also discussed. CONCLUSIONS: We evaluated the correlation between treatment effects and our approach can be applied to clinical trial design and economic modeling of sequential clinical treatment pathways.

Developing Economic Models for Assessing the Cost-Effectiveness of Multiple Diagnostic Tests: Methods and Applications.

BACKGROUND: Clinical pathways with multiple diagnostic tests are complex to model, but problematic and simplistic approaches are often used in economic evaluations. METHODS: We analyzed statistical methods of handling multiple diagnostic tests and provided guidance on applying these methods in economic modeling. We first introduced a statistical model to quantify the correlations between 2 tests and how those correlations can be incorporated within an economic model. We also presented the general form of conditional dependence among multiple tests. We then introduced net reclassification improvement (NRI), a measure that evaluates the added value of a new risk factor (e.g., biomarker) for risk prediction. We further provided 2 examples to illustrate the application of these methods. RESULTS: Our first example illustrated how to model an add-on test to an existing test, in the absence of a perfect reference standard. After accounting for the imperfect nature of both tests and the conditional dependence between tests, the potential health benefits from the additional test were reduced. This led to differential cost-effectiveness results when comparing models using the perfect test and conditional independence assumptions. The second example illustrated how to evaluate the added value of a new risk factor using the NRI measure. Using the new risk classification provides greater precision in risk prediction, and in the example, the strategy using the new risk classification with treatment for selected individuals led to more favorable cost-effectiveness results. CONCLUSIONS: These innovative methods for handling multiple diagnostic tests have improved the methodology within the field and should be adopted to provide more accurate estimates within cost-effectiveness analyses. HIGHLIGHTS: Economic evaluations of multiple diagnostic tests often apply problematic simplistic approaches, such as ignoring conditional dependence between 2 tests or assuming a perfect final test in the diagnostic pathway. We provided guidance on how to apply improved methods for economic modeling.We introduced methods to model conditional dependence between 2 imperfect tests. We used an example to illustrate how assumptions about perfect diagnostic test accuracy and conditional independence between tests affect cost-effectiveness.Compared with the results of the area under the receiver-operating-characteristic curve, net reclassification improvement has distinct advantages in measuring the added value of a new risk factor for model-based economic evaluation.Economic evaluations that appropriately account for the complexities of diagnostic test pathways can help decision makers ensure efficient use of resources.

Developing a cross-validation tool for evaluating economic evidence in rapid literature reviews.

Background: Rapid economic reviews efficiently summarize economic evidence. However, reporting main findings without assessing quality and credibility can be misleading. The objective of this study was to develop a rapid cross-validation screening tool to evaluate economic evidence when conducting rapid economic literature reviews. Methods: This article outlines our reasoning and the theoretical concepts for developing the screening tool. Results: This cross-validation tool is a qualitative approach under a Bayesian framework that uses prior health economic evidence to gauge the credibility of the rapid economic review's findings. This article describes an application of this tool and highlights practical considerations for its development and deployment. Conclusion: This tool can provide a valuable screening instrument to evaluate the quality and credibility of the economic evidence.

Review and estimation of disutility for joint health states of severe and nonsevere hypoglycemic events in diabetes.

Aim: Many economic evaluations used linear or log-transformed additive methods to estimate the disutility of hypoglycemic events in diabetes, both nonsevere (NSHEs) and severe (SHEs). Methods: We conducted a literature search for studies of disutility for hypoglycemia. We used additive, minimum and multiplicative methods, and the adjusted decrement estimator to estimate the disutilities of joint health states with both NSHEs and SHEs in six scenarios. Results: Twenty-four studies reported disutilities for hypoglycemia in diabetes. Based on construct validity, the adjusted decrement estimator method likely provides less biased estimates, predicting that when SHEs occur, the additional impact from NSHEs is marginal. Conclusion: Our proposed new method provides a different perspective on the estimation of quality-adjusted life-years in economic evaluations of hypoglycemic treatments.

Percutaneous radiofrequency ablation for the treatment of early stage hepatocellular carcinoma: a health technology assessment.

OBJECTIVES: The aim of this study was to compare the clinical effectiveness and cost of percutaneous radiofrequency ablation (PRFA) and surgical resection (SRS) for the management of early stage Hepatocellular Carcinoma. METHODS: A systematic literature search of articles in English, French, and Chinese was performed using online databases. Only articles with patients classified as Child-Pugh Class A or B, with tumor size <5 cm were included. A meta-analysis was carried out to estimate the survival rate and disease-free survival rate following PRFA or SRS treatments. The cost of each treatment was estimated from the third party perspective. Univariate sensitivity analyses were used to study the relative importance of each component cost. RESULTS: We identified six studies (one randomized controlled trial (RCT) and five comparative cohort studies) meeting our inclusion criteria. There is good evidence that among Child-Pugh A patients for whom both SRS and PRFA are available options, survival rates following either procedure are comparable, while complications are more frequent and hospitalization longer following SRS. The evidence concerning recurrence rates and disease-free survival is less clear. Whereas the RCT indicates comparable outcomes with either procedure up to 3 years, the results of five cohort studies (with possible selection bias), particularly those with a mix of Child-Pugh A and B patients, favor the surgical option. SRS, costs approximately Canadian $8,275 more per case than PRFA. CONCLUSIONS: Continuing doubts on this issue can only be resolved by a substantial RCT. Meanwhile, for early stage HCC patients classified as Child-Pugh A, who despite a possibly higher recurrence rate, prefer the less invasive PRFA to open surgery with its attendant risks, there is sufficient evidence to justify such a choice. For those classified as Child-Pugh (B) it is possible that overall survival is equally good with PRFA, but the evidence is less certain.

Comparison of the expected rewards between probabilistic and deterministic analyses in a Markov model.

Objectives: In Markov models that evaluate the cost-effectiveness of health-care technologies, it is generally recommended to use probabilistic analysis instead of deterministic analysis. We sought to compare the performance of probabilistic and deterministic analysis in estimating the expected rewards in a Markov model.Methods: We applied Jensen's inequality to compare the expected Markov rewards between probabilistic and deterministic analysis and conducted a simulation study to compare the bias and accuracy between the two approaches.Results: We provided mathematical justification why probabilistic analysis is associated with greater Markov rewards (life-years and quality-adjusted life-years) compared with deterministic analysis. In our simulations, probabilistic analyses tended to generate greater life-years, bias, and mean square error for the estimated rewards compared with deterministic analyses. When the expected values of transition probabilities were the same, weaker evidence derived from smaller sample sizes resulted in larger Markov rewards compared with stronger evidence derived from larger sample sizes. When longer time horizons were applied in cases of weak evidence, there was a substantial increase in bias where the rewards in both probabilistic and deterministic analysis were overestimated.Conclusion: Authors should be aware that probabilistic analysis may lead to increased bias when the evidence is weak.

The cost-effectiveness of Maze procedures using ablation techniques at the time of mitral valve surgery.

BACKGROUND: The classic cut and sew surgical Maze procedure has been shown to reduce atrial fibrillation (AF), and recently newer surgical ablation techniques with reduced technical complexity have been introduced. This study sought to systematically review the efficacy and safety of these newer techniques and to evaluate their long-term cost-effectiveness at the time of scheduled mitral valve (MV) surgery. METHODS: A systematic literature search and meta-analysis was performed to generate the most reliable efficacy and safety parameter estimates for a Markov decision analysis model comparing MV surgery alone to MV surgery plus an ablation Maze procedure. Both basic and probabilistic sensitivity analyses were conducted. RESULTS: Based on the six randomized controlled trials (RCTs) identified, the pooled 1-year estimate of AF after surgery alone was 71 percent (95 percent confidence interval [CI], 64 percent to 78 percent). The pooled risk ratio of AF after surgical ablation treatment at the time of mitral valve surgery relative to valve surgery alone was 0.33 (95 percent CI, 0.19 to 0.55). The pooled analyses showed that no statistical significant increases in operative mortality, permanent pacemaker implantation, and postoperative bleeding with the ablative Maze procedures. An ablation-based Maze procedure at the time of mitral valve surgery had an incremental cost-effectiveness ratio (ICER) of $4,446CAD ($3,850US) per quality-adjusted life-year (QALY) compared with valve surgery alone. Specifically costs were an extra $900CAD but with improved clinical outcomes (0.20 QALYs), including a prolonged life expectancy of 0.10 life-years. In one-way sensitivity analyses, survival time after MV surgery had the largest impact on ICER. Other variables influencing the ICER included the risk ratio of AF, utility, and cost estimates. Probabilistic sensitivity analysis suggests that 58.1 percent, 73.9 percent, and 89.3 percent of the simulations of the Maze strategy are cost-effective at willingness to pay thresholds of $20,000, $50,000, and $100,000CAD per QALY gained, respectively. CONCLUSIONS: Our meta-analysis suggests that a Maze surgical ablation procedure at the time of MV surgery is associated with a reduced postoperative AF risk. Our economic model further suggests that the surgical ablation strategy at the time of mitral valve surgery is likely a cost-effective intervention, provided patients have a good long-term postsurgical prognosis.

Microvolt T-wave alternans and the selective use of implantable cardioverter defibrillators for primary prevention: a cost-effectiveness study.

OBJECTIVES: Implantable cardioverter defibrillators (ICDs) are an effective but expensive treatment for the prevention of sudden cardiac deaths in patients with severe left-ventricular dysfunction. Recent studies suggest that microvolt T-wave alternans (MTWA) predicts mortality and severe arrhythmic events in this population. However, the impact of MTWA on ICD cost-effectiveness is unknown. METHODS: A Markov decision-analysis model evaluated three treatment strategies for primary prevention in patients with severe left-ventricular dysfunction: (i) medical therapy for all; (ii) ICD therapy for all; and (iii) selective ICD therapy based on non-negative (positive or indeterminate) MTWA test results. Incremental cost-effectiveness ratios (ICER) were calculated from the perspective of a third party payer using a 10-year time horizon. Sensitivity analyses examined the robustness of the estimates. RESULTS: A treatment strategy involving ICD therapy in all patients was associated with an ICER of $121,800/quality-adjusted life-year (QALY) compared with medical therapy, whereas a treatment strategy involving the selective use of ICDs based on MTWA test results was associated with an ICER of $108,900/QALY compared with medical therapy. Sensitivity analyses suggest that, under most scenarios, the selective use of ICDs based on MTWA results does not decrease the ICER to below $100,000/QALY. CONCLUSION: MTWA only marginally improves the cost-effectiveness of ICDs for primary prevention in patients with severe left-ventricular dysfunction. There remains a need for improved means to effectively identify which patients will derive the greatest benefit from ICD implantation.

Cost-utility analysis of intensive blood glucose control with metformin versus usual care in overweight type 2 diabetes mellitus patients in Beijing, P.R. China.

OBJECTIVE: The UKPDS 34 and 51 showed that intensive blood glucose control with metformin is cost-saving and increases life expectancy in overweight type 2 diabetic patients in the United Kingdom. Diabetes is becoming an important health problem in urban China. This study addresses the effects and costs of intensive blood glucose control in this setting, aimed at supporting decision-making on the allocation of scarce resources. METHODS: A decision analytic model was developed to estimate the costs and effectiveness of intensive blood glucose control in overweight type 2 diabetes patients in Beijing, compared with usual care in accordance with clinical practice. The analysis was carried out from a health-care perspective. RESULTS: The base-case analysis (3% discount rate) shows that the average incremental costs of 11 years of intensive treatment with metformin are 126.6 K RMB (16.4 K US$) per quality-adjusted life year (QALY) gained. The incremental cost-effectiveness ratio (ICER) is sensitive to the costs of medication alternatives for metformin in the intensive treatment group and to the discount rate used (0%: 105.6 K RMB (13.7 K US$) per QALY gained; 5%: 171.0 K RMB (22.2 K US$) per QALY gained). After 20 and 30 years (lifetime) follow-up, the ICERs become increasingly favorable, 90.1 K RMB (11.7 K US$) and 74.3 K RMB (9.6 K US$), respectively. The ICER is most sensitive to the costs of medication alternatives for metformin in the intensive treatment group, and to the discount rate. CONCLUSIONS: Interpretation of the findings depends on the maximum willingness to pay for a QALY in China, which has not officially been defined. If this would be three times the gross domestic product per capita, a value that has been suggested in the literature, lifetime intensive blood glucose control is likely to be cost-effective. Our findings differ from the UKPDS studies and emphasize that generalizing the results of studies across countries requires considerable adaptation to the local context.

The Impact of the Underlying Risk in Control Group and Effect Measures in Non-Inferiority Trials With Time-to-Event Data: A Simulation Study.

BACKGROUND: We designed a simulation study to assess how the conclusions of a non-inferiority trial (NIT) will change if the observed risk is different from the expected risk. METHODS: We simulated Weibull distribution time-to-event data with a true hazard ratio (HR) being equal or close to 1. The empirical margins and sample size of a hypothetical trial were chosen based on a systematic review. Setting the significance level at 5% for the two-sided confidence interval (CI), we examined the statistical power (i.e., the probabilities of the upper limit of the 95% CI falling within the margin) of using two measures at various underlying risk in the control group. RESULTS: Using the empirical margins, HRs of 1.2, 1.35 or 1.5, the statistical power is lower than 0.22 when the underlying risk in the control group is less than 10%, but the power increases along with the higher underlying risk. The predicted upper limit of the 95% CI of the difference in two Kaplan-Meier estimators (DTKME) is low when risk is low (< 20%) or high (> 80%), but reaches the highest value when risk is around 50%. When the underlying risk in the control group is lower than 10%, measures of DTKME resulted in much higher power than HR. CONCLUSIONS: When HR is the effect measure, the probability of concluding non-inferiority will increase as the underlying risk in the control group increases. When DTKME is the effect measure, the probability of concluding non-inferiority will decrease as the underlying risk in the control increases. In this case, the probability of concluding non-inferiority is at a minimum when the control risk reaches about 50%. When the risk in the control arm is less than 10%, the conclusion of an NIT is sensitive to the choice of effect measure.

Some issues for the evaluation of noninferiority trials.

Although published noninferiority trials (NITs) generally conclude that the experimental intervention being studied is noninferior compared with standard therapy or active control, NIT quality is often not satisfactory. We have proposed 14 questions to assist in evaluating the clinical evidence of the experimental versus standard therapy. The aim of these questions is to critically appraise NITs and support proper interpretation of study results. Readers should not only consider whether the confidence interval of the primary effect measure falls within the prespecified noninferiority margin (thus concluding noninferiority), but also assess the similarities between primary and secondary outcomes for the experimental and standard therapy. To conclude noninferiority conceptually is to synthesize evidence from both the current NIT comparing experimental therapy with standard therapy and historical data comparing standard therapy with placebo control. Therefore, readers should use external data sources (e.g., historical data) to validate the study design (e.g., selection of standard therapy, effect measure and the noninferiority margin), and assess the uncertainty of findings due to differences between the observed and expected incidence rates, follow-up time, effects of adjuvant therapy and the secondary outcomes of therapies. Following an explanation of the 14 questions, we then apply the questions to a NIT on intraoperative radiation therapy for early stage breast cancer, as an example.