Resource use and cost associated with computerized decision support system and usual care in managing patients with atrial fibrillation: analysis of IMPACT-AF randomized trial data.

BACKGROUND: IMPACT-AF is a prospective, randomized, cluster design trial comparing atrial fibrillation (AF) management with a computerized decision support system (CDS) to usual care (control) in the primary care setting of Nova Scotia, Canada. The objective of this analysis was to compare the resource use and costs between CDS and usual care groups. METHODS: Case costing data, 12-month self-administered questionnaires, and monthly diaries from IMPACT-AF were used in this analysis. Descriptive statistics were used to compare costs and resource use between groups. All costs are presented in 2021 Canadian dollars and cover the 12-month period of participation in the study. RESULTS: A total of 1,145 patients enrolled in the trial. Case costing data were available for 466 participants (41.1%), 12-month self-administered questionnaire data for 635 participants (56.0%) and monthly diary data for 223 participants (19.7%). Emergency department visits and hospitalizations comprised the most expensive component of AF care. Across all three datasets, there were no statistically significant differences in costs or resource use between CDS and usual care groups. CONCLUSIONS: Although there were no significant differences in resource use or costs among CDS and usual care groups in the IMPACT-AF trial, this study provides insight into the methodology and practical challenges of collecting economic data alongside a trial. REGISTRATION: Clinicaltrials.gov (registration number: NCT01927367, date of registration: 2013-08-20).

Ipatasertib plus paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: primary results from cohort B of the IPATunity130 randomized phase 3 trial.

PURPOSE: PI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib-paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC). METHODS: Cohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse < 1 year since (neo)adjuvant chemotherapy were ineligible. Patients were randomized 2:1 to ipatasertib (400 mg, days 1-21) or placebo, plus paclitaxel (80 mg/m2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: Overall, 146 patients were randomized to ipatasertib-paclitaxel and 76 to placebo-paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71-1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib-paclitaxel versus placebo-paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib-paclitaxel vs 1% with placebo-paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%). CONCLUSION: Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib-paclitaxel safety profile was consistent with each agent's known adverse effects. Trial registration NCT03337724.

The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study.

Idasanutlin, an MDM2 antagonist, showed clinical activity and a rapid reduction in JAK2 V617F allele burden in patients with polycythemia vera (PV) in a phase 1 study. This open-label phase 2 study evaluated idasanutlin in patients with hydroxyurea (HU)-resistant/-intolerant PV, per the European LeukemiaNet criteria, and phlebotomy dependence; prior ruxolitinib exposure was permitted. Idasanutlin was administered once daily on days 1 through 5 of each 28-day cycle. The primary end point was composite response (hematocrit control and spleen volume reduction > 35%) in patients with splenomegaly and hematocrit control in patients without splenomegaly at week 32. Key secondary end points included safety, complete hematologic response (CHR), patient-reported outcomes, and molecular responses. All patients (n = 27) received idasanutlin; 16 had response assessment (week 32). Among responders with baseline splenomegaly (n = 13), 9 (69%) attained any spleen volume reduction, and 1 achieved composite response. Nine patients (56%) achieved hematocrit control, and 8 patients (50%) achieved CHR. Overall, 43% of evaluable patients (6/14) showed a ≥50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (week 32). Nausea (93%), diarrhea (78%), and vomiting (41%) were the most common adverse events, with grade ≥ 3 nausea or vomiting experienced by 3 patients (11%) and 1 patient (4%), respectively. Reduced JAK2 V617F allele burden occurred early (after 3 cycles), with a median reduction of 76%, and was associated with achieving CHR and hematocrit control. Overall, the idasanutlin dosing regimen showed clinical activity and rapidly reduced JAK2 allele burden in patients with HU-resistant/- intolerant PV but was associated with low-grade gastrointestinal toxicity, leading to poor long-term tolerability. This trial was registered at www.clinincaltrials.gov as #NCT03287245.

Evaluating Progression-Free Survival as a Surrogate Outcome for Health-Related Quality of Life in Oncology: A Systematic Review and Quantitative Analysis.

Importance: Progression-free survival (PFS) has become a commonly used outcome to assess the efficacy of new cancer drugs. However, it is not clear if delay in progression leads to improved quality of life with or without overall survival benefit. Objective: To evaluate the association between PFS and health-related quality of life (HRQoL) in oncology through a systematic review and quantitative analysis of published randomized clinical trials. Eligible trials addressed oral, intravenous, intraperitoneal, or intrapleural chemotherapy or biological treatments, and reported PFS or health-related quality of life. Data Sources: For this systematic review and quantitative analysis of randomized clinical trials of patients with cancer, we searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from January 1, 2000, through May 4, 2016. Study Selection: Paired reviewers independently screened citations, extracted data, and assessed risk of bias of included studies. Data Extraction and Synthesis: We examined the association of difference in median PFS duration (in months) between treatment groups with difference in global, physical, and emotional HRQoL scores between groups (standardized to a range of 0-100, with higher scores representing better HRQoL) using weighted simple regressions. Main Outcome and Measure: The association between PFS duration and HRQoL. Results: Of 35 960 records screened, 52 articles reporting on 38 randomized clinical trials involving 13 979 patients across 12 cancer types using 6 different HRQoL instruments were included. The mean (SD) difference in median PFS between the intervention and the control arms was 1.91 (3.35) months. The mean (SD) differences in change of HRQoL adjusted to per-month values were -0.39 (3.59) for the global domain, 0.26 (5.56) for the physical domain, and 1.08 (3.49) for the emotional domain. The slope of the association between the difference in median PFS and the difference in change for global HRQoL (n = 30 trials) was 0.12 (95% CI, -0.27 to 0.52); for physical HRQoL (n = 20 trials) it was -0.20 (95% CI, -0.62 to 0.23); and for emotional HRQoL (n = 13 trials) it was 0.78 (95% CI, -0.05 to 1.60). Conclusions and Relevance: We failed to find a significant association between PFS and HRQoL in cancer clinical trials. These findings raise questions regarding the assumption that interventions prolonging PFS also improve HRQoL in patients with cancer. Therefore, to ensure that patients are truly obtaining important benefit from cancer therapies, clinical trial investigators should measure HRQoL directly and accurately, ensuring adequate duration and follow-up.

Deficiencies in addressing effect modification in network meta-analyses: a meta-epidemiological survey.

OBJECTIVE: The objectives of this study were to evaluate the current state of reporting and handling of effect modification in network meta-analyses (NMAs) and perform exploratory analyses to identify variables that are potentially associated with incomplete reporting of effect modifiers in NMAs. STUDY DESIGN AND SETTING: We conducted a meta-epidemiological survey using a systematic review of NMAs published in 2013 and identified through MEDLINE and Embase databases. RESULTS: The review identified 77 NMAs. The most common type of effect modifiers identified and explored were patient characteristics (50.7% or 39/77), and the most common adjustment method used was sensitivity analysis (51.7% or 30/58). Over 45% (35/77) of studies did not describe a plan, nearly 40% (30/77) did not report the results of analyses, and approximately 47% (36/77) of studies had incomplete reporting. Exploratory univariate regression analyses yielded a statistically significant association for the variables of journal impact factor, ratio of randomized controlled trials to number of comparisons, and total number of randomized controlled trials. CONCLUSION: Current reporting practices are largely deficient, given that almost half of identified published NMAs do not explore or report effect modification. Journal impact factor and amount of available information in a network were associated with completeness of reporting.

Association between progression-free survival and health-related quality of life in oncology: a systematic review protocol.

INTRODUCTION: There is an increasing number of new oncology drugs being studied, approved and put into clinical practice based on improvement in progression-free survival, when no overall survival benefits exist. In oncology, the association between progression-free survival and health-related quality of life is currently unknown, despite its importance for patients with cancer, and the unverified assumption that longer progression-free survival indicates improved health-related quality of life. Thus far, only 1 study has investigated this association, providing insufficient evidence and inconclusive results. The objective of this study protocol is to provide increased transparency in supporting a systematic summary of the evidence bearing on this association in oncology. METHODS AND ANALYSIS: Using the OVID platform in MEDLINE, Embase and Cochrane databases, we will conduct a systematic review of randomised controlled human trials addressing oncology issues published starting in 2000. A team of reviewers will, in pairs, independently screen and abstract data using standardised, pilot-tested forms. We will employ numerical integration to calculate mean incremental area under the curve between treatment groups in studies for health-related quality of life, along with total related error estimates, and a 95% CI around incremental area. To describe the progression-free survival to health-related quality of life association, we will construct a scatterplot for incremental health-related quality of life versus incremental progression-free survival. To estimate the association, we will use a weighted simple regression approach, comparing mean incremental health-related quality of life with either median incremental progression-free survival time or the progression-free survival HR, in the absence of overall survival benefit. DISCUSSION: Identifying direction and magnitude of association between progression-free survival and health-related quality of life is critically important in interpreting results of oncology trials. Systematic evidence produced from our study will contribute to improvement of patient care and practice of evidence-based medicine in oncology.

Economic and Humanistic Burden of Osteoarthritis: A Systematic Review of Large Sample Studies.

BACKGROUND: Osteoarthritis (OA) consumes a significant amount of healthcare resources, and impairs the health-related quality of life (HRQoL) of patients. Previous reviews have consistently found substantial variations in the costs of OA across studies and countries. The comparability between studies was poor and limited the detection of the true differences between these studies. OBJECTIVE: To review large sample studies on measuring the economic and/or humanistic burden of OA published since May 2006. METHODS: We searched MEDLINE and EMBASE databases using comprehensive search strategies to identify studies reporting economic burden and HRQoL of OA. We included large sample studies if they had a sample size ≥1000 and measured the cost and/or HRQoL of OA. Reviewers worked independently and in duplicate, performing a cross-check between groups to verify agreement. Within- and between-group consolidation was performed to resolve discrepancies, with outstanding discrepancies being resolved by an arbitrator. The Kappa statistic was reported to assess the agreement between the reviewers. All costs were adjusted in their original currency to year 2015 using published inflation rates for the country where the study was conducted, and then converted to 2015 US dollars. RESULTS: A total of 651 articles were screened by title and abstract, 94 were reviewed in full text, and 28 were included in the final review. The Kappa value was 0.794. Twenty studies reported direct costs and nine reported indirect costs. The total annual average direct costs varied from US$1442 to US$21,335, both in USA. The annual average indirect costs ranged from US$238 to US$29,935. Twelve studies measured HRQoL using various instruments. The Short Form 12 version 2 scores ranged from 35.0 to 51.3 for the physical component, and from 43.5 to 55.0 for the mental component. Health utilities varied from 0.30 for severe OA to 0.77 for mild OA. CONCLUSION: Per-patient OA costs are considerable and a patient's quality of life remains poor. Variations in costing methods are a barrier to understanding the true differences in the costs of OA between studies. Standardizing healthcare resource items, the definition of OA-relevant costs, and productivity loss measures would facilitate the comparison.

Economic Evaluation of Bevacizumab for the First-Line Treatment of Newly Diagnosed Glioblastoma Multiforme.

PURPOSE: The Avastin in Glioblastoma trial has shown that patients newly diagnosed with glioblastoma multiforme (GBM) treated with bevacizumab plus radiotherapy and temozolomide versus radiotherapy and temozolomide alone showed improvement in progression-free survival, possibly leading to a new indication for first-line use of bevacizumab in GBM. The cost-utility of this new intervention remains unknown; therefore, we developed a Markov model estimating the incremental cost-utility ratio (ICUR) from a Canadian public payer perspective. METHODS: We incorporated trial data for state transitions and treatment effects from the Avastin in Glioblastoma trial, costs and resource use data from Canadian published studies and databases, and utility parameters from published literature. We addressed uncertainty through one-way deterministic and probabilistic sensitivity analyses, extended the model to lifetime horizon and by another arm to compare first-line versus second-line use of bevacizumab on progression, performed value of information analysis, and performed US costing sensitivity analysis. RESULTS: Adding bevacizumab to radiotherapy and temozolomide resulted in increases of 0.13 quality-adjusted life-years (QALYs) and $80,000 per patient over 2-year time horizon at the base case analysis. The ICUR was $607,966/QALY (95% CI, $305,000/QALY to $2,550,000/QALY), with 0% chance of being cost effective at the $100,000/QALY willingness-to-pay threshold and never going below $450,000/QALY in the one-way sensitivity analysis. The ICUR using the US costing data was $787,519/QALY. The lifetime ICUR was $439,764/QALY (95% CI, $235,000/QALY to $1,520,000/QALY), never going below $350,000/QALY in the sensitivity analysis. Second-line use of bevacizumab on progression is more effective and less expensive than its first-line use. Value of information analysis revealed that future research is unwarranted. CONCLUSION: Bevacizumab has only limited effectiveness and is therefore not likely to be cost effective in treating adult patients with newly diagnosed GBM.