Quality-adjusted Survival Time Research Articles

Quality-adjusted survival time without symptoms or toxicity of acalabrutinib with or without obinutuzumab in patients with treatment-naive chronic lymphocytic leukemia

Acalabrutinib monotherapy (A) and acalabrutinib plus obinutuzumab (A + O) demonstrated improved efficacy and safety versus chlorambucil plus obinutuzumab (C + O) among treatment-naive patients with chronic lymphocytic leukaemia (CLL) in the ELEVATE-TN trial. The relative risk-benefit at a median follow-up of 47 months was assessed using Quality-adjusted Time Without Symptoms and Toxicity (Q-TWiST) methodology. Patient data were partitioned into 3 states: time with toxicity (TOX); time without symptoms or toxicity (TWiST); and time after relapse (REL). Mean Q-TWiST was estimated by summing the mean time in each state, multiplied by its respective utility weight. Patients receiving A or A + O experienced significantly longer Q-TWiST versus C + O when toxicity was defined as grade 3–4 adverse events (AEs) (41.79 vs 34.56 months; 42.07 vs 34.56 months) and grade 2–4 AEs (35.07 vs 30.64 months; 34.21 vs 30.64 months). Overall, patients with treatment-naive CLL treated with A or A + O experienced significant gains in Q-TWiST compared with C + O.

Net-benefit regression with censored cost-effectiveness data from randomized or observational studies.

Cost-effectiveness analysis is an essential part of the evaluation of new medical interventions. While in many studies both costs and effectiveness (eg, survival time) are censored, standard survival analysis techniques are often invalid due to the induced dependent censoring problem. We propose methods for censored cost-effectiveness data using the net-benefit regression framework, which allow covariate-adjustment and subgroup identification when comparing two intervention groups. The methods provide a straightforward way to construct cost-effectiveness acceptability curves with censored data. We also propose a more efficient doubly robust estimator of average causal incremental net benefit, which increases the likelihood that the results will represent a valid inference in observational studies. Lastly, we conduct extensive numerical studies to examine the finite-sample performance of the proposed methods, and illustrate the proposed methods with a real data example using both survival time and quality-adjusted survival time as the measures of effectiveness.

Quality-adjusted Time Without Symptoms or Toxicity (Q-TWiST) for Lenvatinib plus Everolimus Versus Everolimus Monotherapy in Patients with Advanced Renal Cell Carcinoma

BackgroundThe lenvatinib (LEN) plus everolimus (EVE) combination demonstrated improved progression-free survival over everolimus alone in a phase 2 trial (Study-205). ObjectiveTo compare quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) between LEN + EVE and EVE alone among patients with advanced renal cell carcinoma (RCC) following one prior antiangiogenic therapy. Design, setting, and participantsThis was a post hoc analysis of Study-205. Outcome measurements and statistical analysisSurvival time was partitioned into three mutually exclusive health states: time with grade 3/4 toxicity (TOX); time before disease progression and without grade 3/4 toxicity (TWiST); and time after disease progression (REL). The mean time in each state was weighted by utility measures and summed to calculate Q-TWiST. Nonparametric bootstrapping generated 95% confidence intervals (CIs). In the base case, utility for TWiST, TOX, and REL was assigned as 1.0, 0.5, and 0.5, respectively. Sensitivity analyses applied alternative utility values for REL, TOX, and TWiST. A relative gain in Q-TWiST of ≥10% and ≥15% has been established as clinically important and clearly clinically important, respectively. Results and limitationsPatients receiving LEN + EVE (n = 51) had a significant mean Q-TWiST gain of 3.7 mo (14.7 vs 11.0 mo; 95% CI for difference 1.3–6.3), with a relative gain of 24% compared to EVE alone. In a sensitivity analysis using alternative utility values for TWiST (varied from 0.55 to 0.9) with utility set to 0.5 for both TOX and REL, the relative Q-TWiST gain was maintained (ranging from 11.0% to 21.2%; all significant) across varying utility values. Limitations include the sample size, the absence of utility estimates, and the length of adverse events from the trial. ConclusionsLEN + EVE showed a significant and clearly clinically important improvement in quality-adjusted survival time versus EVE alone. Patient summaryPatients with advanced kidney cancer who had received other previous treatments experienced a clearly clinically important improvement in quality survival time when treated with lenvatinib plus everolimus compared to everolimus alone.

Prolonged Improvement in Patient-Reported Outcomes (PROs) and Well-being in Older Patients With Treatment-Naïve (TN) Chronic Lymphocytic Leukemia Treated With Ibrutinib (Ibr): 3-Year Follow-up of the RESONATE-2 Study

Prolonged Improvement in Patient-Reported Outcomes (PROs) and Well-being in Older Patients With Treatment-Naïve (TN) Chronic Lymphocytic Leukemia Treated With Ibrutinib (Ibr): 3-Year Follow-up of the RESONATE-2 Study

Balancing efficacy and quality of life measurements among metastatic renal cell carcinoma (RCC) studies.

Metastatic renal cell carcinoma (mRCC) treatments have rapidly evolved in the last few years. While vascular endothelial growth factor (VEGF) inhibition had previously been the mainstay of treatment for first-line advanced RCC therapy in the past decade, it has now rapidly changed into combination checkpoint inhibitors with or without VEGF TKIs, although there remains a role for VEGF tyrosine kinase inhibitor monotherapy for patients with favorable-risk disease and for those with intermediate and poor-risk disease with the use of cabozantinib. Perspectives on the Quality-adjusted survival Time without Symptoms of disease or Toxicity (Q-TWiST) analysis for the CABOSUN trial, as well as different aspects of efficacy regarding different first-line therapy for advanced or metastatic RCC are discussed herein.

Patient-Centered Outcomes in ARIEL3, a Phase III, Randomized, Placebo-Controlled Trial of Rucaparib Maintenance Treatment in Patients With Recurrent Ovarian Carcinoma.

PURPOSETo investigate quality-adjusted progression-free survival (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST) in a post hoc exploratory analysis of the phase III ARIEL3 study of rucaparib maintenance treatment versus placebo.PATIENTS AND METHODSPatients with platinum-sensitive, recurrent ovarian carcinoma were randomly assigned to rucaparib (600 mg twice per day) or placebo. QA-PFS was calculated as progression-free survival function × the 3-level version of the EQ-5D questionnaire (EQ-5D-3L) index score function. Q-TWiST analyses were performed defining TOX as the mean duration in which a patient experienced grade ≥ 3 treatment-emergent adverse events (TEAEs) or the mean duration in which a patient experienced grade ≥ 2 TEAEs of nausea, vomiting, fatigue, and asthenia. Q-TWiST was calculated as μTOX × TOX + TWiST, with μTOX calculated using EQ-5D-3L data.RESULTSThe visit cutoff was Apr 15, 2017. Mean QA-PFS was significantly longer with rucaparib versus placebo in the intent-to-treat (ITT) population (375 randomly assigned to rucaparib v 189 randomly assigned to placebo; difference, 6.28 months [95% CI, 4.85 to 7.47 months]); BRCA-mutant cohort (130 rucaparib v 66 placebo; 9.37 months [95% CI, 6.65 to 11.85 months]); homologous recombination deficient (HRD) cohort (236 rucaparib v 118 placebo; 7.93 months [95% CI, 5.93 to 9.53 months]); and BRCA wild-type/loss of heterozygosity (LOH) low patient subgroup (107 rucaparib v 54 placebo; 2.71 months [95% CI, 0.31 to 4.44 months]). With TOX defined using grade ≥ 3 TEAEs, the difference in mean Q-TWiST (rucaparib v placebo) was 6.88 months (95% CI, 5.71 to 8.23 months), 9.73 months (95% CI, 7.10 to 11.94 months), 8.11 months (95% CI, 6.36 to 9.49 months), and 3.35 months (95% CI, 1.66 to 5.40 months) in the ITT population, BRCA-mutant cohort, HRD cohort, and BRCA wild-type/LOH low patient subgroup, respectively. Q-TWiST with TOX defined using select grade ≥ 2 TEAEs also consistently favored rucaparib.CONCLUSIONThe significant differences in QA-PFS and Q-TWiST confirm the benefit of rucaparib versus placebo in all predefined cohorts.

Quality-Adjusted Survival With nab-Paclitaxel Versus Standard Paclitaxel in Metastatic Breast Cancer: A Q-TWiST Analysis

BackgroundIn this analysis we compared quality-adjusted survival outcomes between nab-paclitaxel (nab-P) and standard paclitaxel (Pac) using data from the nab-P phase III registration trial in metastatic breast cancer. Patients and MethodsQuality-adjusted overall survival was estimated using the quality-adjusted time without symptoms or toxicity (Q-TWiST) approach. Overall survival was partitioned into time without progression/Grade ≥ 3 adverse events (AEs) toxicity (TWiST), time with Grade ≥ 3 AE toxicity (TOX), and time after relapse (REL). Q-TWiST was calculated by multiplying mean time in each health state by its assigned utility (base-case utility values: time without symptoms of disease progression or toxicity of Grade ≥ 3 adverse events [TWiST] = 1.0, TOX = 0.5, and REL = 0.5). In threshold analyses, TOX and REL varied from 0.0 to 1.0 whereas TWiST was maintained at 1.0. Comparisons were made for the intent-to-treat population and the subset of patients initiating the study drugs as second or subsequent lines (2L+) of chemotherapy (per approved nab-P indication; 2L+ subpopulation). A ≥ 15% relative Q-TWiST gain (vs. mean Pac overall survival) was considered clearly clinically important. ResultsIn the intent-to-treat population, nab-P (n = 229) versus Pac (n = 225) resulted in nonsignificant gains of 1.4 months of mean Q-TWiST (11.6 vs. 10.2 months; 95% confidence interval [CI], −0.03 to 2.8). In the 2L+ subpopulation, nab-P (n = 132) versus Pac (n = 136) resulted in a statistically significant gain of 2.2 months of mean Q-TWiST (10.5 vs. 8.4 months; 95% CI, 0.6-3.8), with a 17.1% relative Q-TWiST gain (threshold analysis range, 14.0%-19.5%, both figures significant). ConclusionIn its approved indication for metastatic breast cancer, nab-P showed a statistically significant and clearly clinically important improvement in quality-adjusted survival time versus Pac in the 2L+ subpopulation.

Comparative quality-adjusted survival analysis between radiation therapy alone and radiation with androgen deprivation therapy in patients with locally advanced prostate cancer: a secondary analysis of Radiation Therapy Oncology Group 85-31 with novel decision analysis methods.

BackgroundAndrogen deprivation therapy in addition to radiation therapy (RT + ADT) has shown benefits in local control and progression-free survival compared with RT alone for patients with locally advanced prostate cancer in Radiation Therapy Oncology Group 85-31. However, the survival gain may be diluted with increased toxicity of ADT. The aim of the study is to compare quality-adjusted life years (QALYs) values between two groups.MethodsWe developed “quality-adjusted survival analysis using duration” (QASAD) and “quality-adjusted survival analysis using probability” (QASAP) to estimate the quality-adjusted survival time. The QASAD uses the median duration in each health state to weight the utilities, whereas the QASAP uses the proportional probability of being in each state for weighting. The survival and complication rates were reconstructed based on published Kaplan–Meier survival curves, and the utility values for states were obtained from the previous literature.ResultsQALYs values for RT + ADT were generally higher than those for RT. The QASAD resulted in a QALY value of 4.93 [95% bootstrapped confidence interval (CI) = 4.12–5.71] for RT and of 5.60 (95% CI = 4.30–6.48) for RT + ADT. QASAP resulted in a QALY value of 4.85 (95% CI = 4.16–5.39) for RT and 4.96 (95% CI = 3.73–5.78) for RT + ADT.ConclusionsWe showed that RT + ADT provided slightly better quality-adjusted survival outcome than RT alone. The QASAD and QASAP methods may help the decision of optimal treatment balancing between survival gain and unfavorable quality of life.

QTWiST analysis of the RECOURSE trial of trifluridine/tipiracil in metastatic colorectal cancer

PurposeA Quality-adjusted Time WIthout Symptoms of disease or Toxicity (QTWiST) analysis was carried out to assess quality-adjusted survival time in the RECOURSE trial of trifluridine/tipiracil versus placebo in pretreated metastatic colorectal cancer (mCRC).MethodsDuration of overall survival in the RECOURSE trial (n=798 patients) was partitioned into three discrete health states: toxicity (TOX), time without symptoms or toxicity (TWIST) and relapse (REL). TOX was defined as time spent with grade 3 or 4 treatment-related adverse events (AEs) after randomisation and before progression or censoring. AEs were limited to those related to trifluridine/tipiracil and known to affect quality of life (QoL) (ie, nausea, vomiting, diarrhoea, fatigue/asthaenia, anorexia and febrile neutropaenia). The estimated mean duration of each state, weighted by a utility coefficient representing QoL, was combined into a global QTWiST score.ResultsIn the RECOURSE trial, overall survival was 7.1 months with trifluridine/tipiracil versus 5.3 months with placebo. Patients receiving trifluridine/tipiracil spent longer in each health state than placebo recipients. Using assumed utility coefficients of 1 for TWIST and 0.5 for TOX and REL, the QTWiST was 5.48 months for the trifluridine/tipiracil group and 3.98 months for the placebo group, a difference of 1.5 (95% CI 1.49 to 1.52) months in favour of trifluridine/tipiracil. A sensitivity analysis using large variations in utility coefficients for TOX and REL produced a range of only approximately 0.5 months from minimum to maximum QTWiST.ConclusionsQuality-adjusted survival, as measured by QTWiST, shows clinically meaningful improvements in patients treated with trifluridine/tipiracil versus placebo in pretreated mCRC.

Quality-adjusted survival comparison between androgen deprivation with radiation therapy versus radiation therapy alone for locally advanced prostate cancer: Decision analysis from RTOG 85-31 trial.

265 Background: Radiation Therapy Oncology Group (RTOG) trial 85-31 has shown that addition of androgen deprivation therapy to radiation therapy (RT+ADT) for patients with locally advanced prostate cancer benefits local control and progression-free survival compared to RT alone. However, the survival gain may be diluted with increased toxicity of hormone manipulation. There is a need to develop new decision analysis methods to incorporate survival time and quality of life (QoL) adjusting for various health states and persistent complications. Methods: We previously developed “quality-adjusted survival analysis using duration” (QASAD) and “quality-adjusted survival analysis using probability” (QASAP) to estimate quality-adjusted survival time. The QASAD uses the median duration in each state to weight the utilities, while the QASAP uses the proportional probability of being in each state for weighting. The survival and complication rates of RTOG 85-31 were reconstructed based on published Kaplan-Meier survival curves, and the utility values for states were obtained from the literature. Probabilistic sensitivity analysis was applied using Monte Carlo simulation with 1000 simulated samples. Results: QASAD and QASAP showed that the quality-adjusted life year (QALY) values in RT+ADT were generally higher than those in RT. In probabilistic sensitivity analysis, QASAD resulted in 4.93 (95% bootstrapped confidence interval [CI] = 4.12 to 5.71) for RT and 5.60 (95% CI = 4.30 to 6.48) for RT+ADT. QASAP resulted in 4.85 (95% CI = 4.16 to 5.39) for RT and 4.96 (95% CI = 3.73 to 5.78) for RT+ADT. Conclusions: The decision analyses showed that RT+ADT provided slightly better quality-adjusted survival outcome after treatment than RT alone. The QASAD and QASAP methods may help the decision of optimal treatment balancing between survival gain and unfavorable quality of life. [Table: see text]

Q-TWiST analysis of panitumumab plus FOLFOX4 versus FOLFOX4 alone in patients with previously untreated wild-type RAS metastatic colorectal cancer

Introduction:Panitumumab plus infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) significantly improved overall survival versus FOLFOX4 alone in patients with previously untreated wild-type RAS metastatic colorectal cancer (mCRC). We applied a quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis to provide an integrated measure of clinical benefit, with the objective of comparing quality-adjusted survival between the two arms. We acknowledge that there are limitations associated with Q-TWIST methodology for crossover trials.Methods:For each treatment arm, the truncated mean times spent in the toxicity (TOX: grade 3 or 4 adverse events), time without symptoms of disease or toxicity (TWiST), and relapse (REL: after disease progression) states were estimated by the product-limit method, and adjusted using utility weights derived from patient-reported EuroQol 5-dimension measures. Sensitivity analyses were performed in which utility weights (varying from 0 to 1) were applied to time in the TOX and REL health states.Results:Quality-adjusted overall survival time was statistically significantly longer with panitumumab plus FOLFOX4 (20.5 months) than with FOLFOX4 alone (18.2 months) (P = 0.025).Conclusion:In patients with previously untreated wild-type RAS mCRC, panitumumab plus FOLFOX4 significantly improved quality-adjusted survival compared with FOLFOX4 alone.

Q-TWiST analysis to estimate overall benefit for patients with metastatic renal cell carcinoma treated in a phase III trial of sunitinib vs interferon-α

Background:In a randomised phase III trial of treatment-naive patients with metastatic renal cell carcinoma, sunitinib showed significant improvement in progression-free survival (PFS) compared with interferon (IFN)-α. We assessed between-treatment differences in overall benefit using a quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (TWiST; Gelber and Goldhirsch) analysis.Methods:In this analysis, in which only grade 3/4 treatment-related toxicities were included, overall survival was partitioned into three health states: toxicity (time with toxicity after randomisation and before progression), time without symptoms of disease progression or toxicity, and time from progression until death. Between-treatment differences in the mean duration of each state were calculated. A threshold utility analysis was used to assess quality-adjusted TWiST (Q-TWiST) outcomes.Results:Q-TWiST scores showed that quality-adjusted survival time was greater with sunitinib than with IFN-α, even though certain grade 3/4 toxicities occurred more frequently with sunitinib. For both treatments, the mean number of days with toxicity was small compared with PFS. This effect was more pronounced with sunitinib in which time spent without progression or toxicity was 151 days greater than with IFN-α.Conclusion:Patients randomised to sunitinib had longer clinical benefit, defined as Q-TWiST scores, than patients randomised to IFN-α.

Quality-of-Life-Adjusted Survival Analysis of Concurrent Chemo Radiotherapy for Locally Advanced (Nonmetastatic) Nasopharyngeal Cancer

To assess whether the benefits of adding cisplatin (CDDP) concurrent with radiotherapy, followed by adjuvant CDDP and fluorouracil, justifies the toxicity cost for nasopharyngeal cancer (NPC) using the quality-adjusted time without symptoms or toxicity (Q-TWiST) approach. One hundred seven patients treated with radiotherapy (RT) and 111 with concurrent chemotherapy and radiotherapy (CRT) were analyzed. The overall survival was divided into three health states: time on active treatment only, during which any subjective nonhematologic toxic event of grade > = 3 was reported; time without symptoms of disease relapse; or treatment and time following first disease RELapse. The relative advantage of CRT and RT was examined by conducting the analysis cumulatively at restriction times 3, 6, 24, 36, 48 months. At 48 months, the improvement in disease-free survival was 14.4% for CRT, whereas that for overall survival was 18.9%. The differences in Q-TWiST were -0.4, -0.7, 0.1, 1.6, and 3.6 months at 3, 6, 24, 36, and 48 months, respectively, with positive differences favoring CRT. At 24 months, the difference in Q-TWiST began to favor CRT. At 36 months, CRT may be the preferred option from the patient's viewpoint if the time spent in the REL state is valued to be <0.83, with the value of perfect health being 1. Finally, Q-TWiST accumulated within 48 months indicated a significant advantage in quality-adjusted survival time for CRT (p = 0.020). Irrespective of how patients valued periods of toxicity and delayed disease progression, concurrent chemotherapy and radiotherapy offered NPC patients significantly more quality-adjusted survival than radiotherapy alone in the long term.

Regression analysis of mean quality‐adjusted survival time based on pseudo‐observations

Regression models for the mean quality-adjusted survival time are specified from hazard functions of transitions between two states and the mean quality-adjusted survival time may be a complex function of covariates. We discuss a regression model for the mean quality-adjusted survival (QAS) time based on pseudo-observations, which has the advantage of directly modeling the effect of covariates in the QAS time. Both Monte Carlo simulations and a real data set are studied.

Estimation of the mean quality-adjusted survival using a multistate model for the sojourn times

In clinical trials, it may be of interest taking into account physical and emotional well-being in addition to survival when comparing treatments. Quality-adjusted survival time has the advantage of incorporating information about both survival time and quality-of-life. In this paper, we discuss the estimation of the expected value of the quality-adjusted survival, based on multistate models for the sojourn times in health states. Semiparametric and parametric (with exponential distribution) approaches are considered. A simulation study is presented to evaluate the performance of the proposed estimator and the jackknife resampling method is used to compute bias and variance of the estimator.

Intraperitoneal cisplatin and paclitaxel versus intravenous carboplatin and paclitaxel chemotherapy for Stage III ovarian cancer: A cost-effectiveness analysis

Objective. To evaluate the cost-effectiveness of intraperitoneal cisplatin and paclitaxel chemotherapy as front-line treatment for patients with Stage III epithelial ovarian cancer following optimal primary cytoreductive surgery. Methods. Based on Gynecologic Oncology Group protocols #172 and #158, a decision analysis model was created to compare two treatment strategies for patients with optimal residual disease Stage III ovarian cancer: (1) inpatient intravenous paclitaxel (24 h) and intraperitoneal cisplatin plus outpatient intraperitoneal paclitaxel chemotherapy (IP/IV), and (2) outpatient intravenous paclitaxel (3 h) and carboplatin chemotherapy (IV/IV). The cost-effectiveness of each strategy was evaluated from the perspective of society. Results. Cost-effectiveness analysis revealed that the strategy of IP/IV chemotherapy had an overall cost per patient of $39,861 and effectiveness of 5.16 QALYs compared to $18,822 and 4.59 QALYs for IV/IV chemotherapy. The IP/IV chemotherapy strategy was associated with an additional 0.56 QALYs at an incremental cost of $21,039. The incremental C/E ratio for IP/IV chemotherapy was $37,454/QALY. Inpatient treatment accounted for 43.2% of the cost of IP/IV chemotherapy. Sensitivity analysis testing confirmed the robustness of the model. Conclusions. In this model, IP/IV chemotherapy was associated with a modest extension in quality-adjusted survival time but was also more costly than IV/IV chemotherapy. On balance, the IP/IV strategy can be considered a good healthcare value. However, these data also suggest that efforts to reduce the cost of IP/IV chemotherapy, such as through development of an ambulatory regimen with equivalent therapeutic efficacy but an improved toxicity profile, would improve the overall value of this adjuvant treatment program.

Semi‐parametric regression models for cost‐effectiveness analysis: improving the efficiency of estimation from censored data

In a cost-effectiveness analysis using clinical trial data, estimates of the between-treatment difference in mean cost and mean effectiveness are needed. Several methods for handling censored data have been suggested. One of them is inverse-probability weighting, and has the advantage that it can also be applied to estimate the parameters from a linear regression of the mean. Such regression models can potentially estimate the treatment contrast more precisely, since some of the residual variance can be explained by baseline covariates. The drawback, however, is that inverse-probability weighting may not be efficient. Using existing results on semi-parametric efficiency, this paper derives the semi-parametric efficient parameter estimates for regression of mean cost, mean quality-adjusted survival time and mean survival time. The performance of these estimates is evaluated through a simulation study. Applying both the new estimators and the inverse-probability weighted estimators to the results of the EVALUATE trial showed that the new estimators achieved a halving of the variance of the estimated treatment contrast for cost. Some practical suggestions for choosing an estimator are offered.

Economic Evaluation of Rivastigmine in Patients with Parkinson??s Disease Dementia

The positive results of a randomised clinical trial of rivastigmine in patients with dementia associated with Parkinson's disease have been published recently. Patient-level healthcare utilisation data were also collected, and this report is the economic evaluation based on these data. To determine the cost effectiveness of rivastigmine 3-12 mg/day in patients in whom mild to moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson's disease. A cost-effectiveness analysis was performed by applying Canadian and UK cost weights (year 2004 values) to healthcare utilisation data collected prospectively during a randomised, double-blind, multinational, 24-week trial of rivastigmine 3-12 mg/day (n = 362) versus placebo (n = 179). Patients were > or =50 years of age, had a Mini-Mental State Examination (MMSE) score of between 20 and 24 and had contact with a responsible caregiver at least 3 days a week.Quality-adjusted survival time, transformed from MMSE scores, was the measure of effectiveness. Caregiver costs included paid and unpaid time, and direct costs included concomitant medications, outpatient care, hospitalisations, long-term care and study medications. Analysis was conducted from a societal perspective with a time horizon of 24 weeks. Consistent with the improvement in clinical outcomes, there was an observed increase in quality-adjusted survival time in the rivastigmine arm of 2.81 quality-adjusted life-days (two-sided p-value 0.13 [90% CI -0.243, 5.86]). Using Canadian price weights, there was an observed increase in cost in the rivastigmine arm of Can 55.76 dollars(two-sided p-value 0.98 [90% CI -3431, 3543]), with a resulting incremental cost-effectiveness ratio of Can 7429 dollars per QALY. Using UK price weights, there was an observed decrease in cost in the rivastigmine arm of pound 26.18 (two-sided p-value 0.99 [90% CI -2407, 2355]). Although no between-treatment differences in cost were seen, the small sample size, highly variable cost distributions and short time horizon prevent us from making strong conclusions with regard to the effect of rivastigmine on total costs and, by inference, on cost effectiveness.

Development and validation of a model to project the long-term benefit and cost of alternative lipid-lowering strategies in patients with hypercholesterolaemia

Patients not currently reaching their lipid goals, even with the use of statins, are at elevated coronary heart disease (CHD) risk. Ezetimibe, when coadministered with a patient's current statin, has been shown to effectively reduce cholesterol in patients with hypercholesterolaemia. In order to help healthcare decision makers assess the cost effectiveness of this treatment strategy, a model is needed to compare ezetimibe coadministration versus alternative statin titration strategies among patients who have failed to reach their lipid goal with their current statin dose. A flexible decision-analytic model that projects the long-term benefit and cost of alternative lipid-lowering strategies is described. Using a Markov process, the model allows movement from one health state to another based on the predicted risk of CHD events (fatal and nonfatal) and the risk of death from non-CHD causes. Each health state can be assigned a quality-of-life weight and an expected cost in order to determine the total survival time, quality-adjusted survival time and cost associated with the alternative treatment strategies. The accuracy of the model in projecting the percentage of patients who experience fatal and nonfatal CHD events was assessed by using individual baseline patient characteristics from two long-term outcomes trials: the Air Force Coronary Atherosclerosis Prevention Study, a primary prevention trial, and the Scandinavian Simvastatin Survival Study, a secondary prevention trial. Compared with event rates in the two outcome trials, the model appears to underestimate both the absolute risk of nonfatal CHD events and its reduction due to lipid lowering. But the model appears to provide reasonable estimates of the absolute reduction in fatal CHD events following lipid treatment. The model will allow one to assess the cost effectiveness of alternative treatment strategies for hypercholesterolaemia including statin titration and the coadministration of ezetimibe in patients who have failed to reach their lipid goal with a statin. Because the benefit of reducing nonfatal CHD events may be underestimated, the model may overestimate the cost-effectiveness ratio of ezetimibe coadministration.

Regression methods for cost-effectiveness analysis with censored data

A system of seemingly unrelated regression equations is proposed for prognostic factor adjustment and subgroup analysis when comparing two groups in a cost-effectiveness analysis with censored data. Because of the induced dependent censoring on costs and quality-adjusted survival, inverse probability weighting is employed for parameter estimation. The method is illustrated with data from two recent examples using both survival time and quality-adjusted survival time as the measures of effectiveness.