scholarly journals Revisiting the use of remission criteria for rheumatoid arthritis by excluding patient global assessment: an individual meta-analysis of 5792 patients

2020 ◽  
pp. annrheumdis-2020-217171 ◽  
Author(s):  
Ricardo J O Ferreira ◽  
Paco M J Welsing ◽  
Johannes W G Jacobs ◽  
Laure Gossec ◽  
Mwidimi Ndosi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Functional Outcome ◽  
Global Assessment ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Health Assessment ◽  
Patient Data ◽  
Patient Global Assessment ◽  
Remission Criteria ◽  
The Impact

ObjectivesTo determine the impact of excluding patient global assessment (PGA) from the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean remission criteria, on prediction of radiographic and functional outcome of rheumatoid arthritis (RA).MethodsMeta-analyses using individual patient data from randomised controlled trials testing the efficacy of biological agents on radiographic and functional outcomes at ≥2 years. Remission states were defined by 4 variants of the ACR/EULAR Boolean definition: (i) tender and swollen 28-joint counts (TJC28/SJC28), C reactive protein (CRP, mg/dL) and PGA (0–10=worst) all ≤1 (4V-remission); (ii) the same, except PGA >1 (4V-near-remission); (iii) 3V-remission (i and ii combined; similar to 4V, but without PGA); (iv) non-remission (TJC28 >1 and/or SJC28 >1 and/or CRP >1). The most stringent class achieved at 6 or 12 months was considered. Good radiographic (GRO) and functional outcome (GFO) were defined as no worsening (ie, change in modified total Sharp score (ΔmTSS) ≤0.5 units and ≤0.0 Health Assessment Questionnaire–Disability Index points, respectively, during the second year). The pooled probabilities of GRO and GFO for the different definitions of remission were estimated and compared.ResultsIndividual patient data (n=5792) from 11 trials were analysed. 4V-remission was achieved by 23% of patients and 4V-near-remission by 19%. The probability of GRO in the 4V-near-remission group was numerically, but non-significantly, lower than that in the 4V-remission (78 vs 81%) and significantly higher than that for non-remission (72%; difference=6%, 95% CI 2% to 10%). Applying 3V-remission could have prevented therapy escalation in 19% of all participants, at the cost of an additional 6.1%, 4.0% and 0.7% of patients having ΔmTSS >0.0, >0.5 and >5 units over 2 years, respectively. The probability of GFO (assessed in 8 trials) in 4V-near-remission (67%, 95% CI 63% to 71%) was significantly lower than in 4V-remission (78%, 74% to 81%) and similar to non-remission (69%, 66% to 72%).Conclusion4V-near-remission and 3V-remission have similar validity as the original 4V-remission definition in predicting GRO, despite expected worse prediction of GFO, while potentially reducing the risk of overtreatment. This supports further exploration of 3V-remission as the target for immunosuppressive therapy complemented by patient-oriented targets.

scholarly journals When does the use of individual patient data in network meta-analysis make a difference? A simulation study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Steve Kanters ◽  
Mohammad Ehsanul Karim ◽  
Kristian Thorlund ◽  
Aslam Anis ◽  
Nick Bansback
Keyword(s):  
Simulation Study ◽  
Treatment Effect ◽  
Mean Squared Error ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Model Performance ◽  
Patient Data ◽  
Meta Regression ◽  
Treatment Comparisons ◽  
The Impact

Abstract Background The use of individual patient data (IPD) in network meta-analyses (NMA) is rapidly growing. This study aimed to determine, through simulations, the impact of select factors on the validity and precision of NMA estimates when combining IPD and aggregate data (AgD) relative to using AgD only. Methods Three analysis strategies were compared via simulations: 1) AgD NMA without adjustments (AgD-NMA); 2) AgD NMA with meta-regression (AgD-NMA-MR); and 3) IPD-AgD NMA with meta-regression (IPD-NMA). We compared 108 parameter permutations: number of network nodes (3, 5 or 10); proportion of treatment comparisons informed by IPD (low, medium or high); equal size trials (2-armed with 200 patients per arm) or larger IPD trials (500 patients per arm); sparse or well-populated networks; and type of effect-modification (none, constant across treatment comparisons, or exchangeable). Data were generated over 200 simulations for each combination of parameters, each using linear regression with Normal distributions. To assess model performance and estimate validity, the mean squared error (MSE) and bias of treatment-effect and covariate estimates were collected. Standard errors (SE) and percentiles were used to compare estimate precision. Results Overall, IPD-NMA performed best in terms of validity and precision. The median MSE was lower in the IPD-NMA in 88 of 108 scenarios (similar results otherwise). On average, the IPD-NMA median MSE was 0.54 times the median using AgD-NMA-MR. Similarly, the SEs of the IPD-NMA treatment-effect estimates were 1/5 the size of AgD-NMA-MR SEs. The magnitude of superior validity and precision of using IPD-NMA varied across scenarios and was associated with the amount of IPD. Using IPD in small or sparse networks consistently led to improved validity and precision; however, in large/dense networks IPD tended to have negligible impact if too few IPD were included. Similar results also apply to the meta-regression coefficient estimates. Conclusions Our simulation study suggests that the use of IPD in NMA will considerably improve the validity and precision of estimates of treatment effect and regression coefficients in the most NMA IPD data-scenarios. However, IPD may not add meaningful validity and precision to NMAs of large and dense treatment networks when negligible IPD are used.

Melphalan and Prednisone (MP) Versus Melphalan, Prednisone and Thalidomide (MPT) as Initial Therapy for Previously Untreated Elderly and/or Transplant Ineligible Patients with Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 615-615 ◽  
Author(s):  
Prashant Kapoor ◽  
S. Vincent Rajkumar ◽  
Angela Dispenzieri ◽  
Martha Q. Lacy ◽  
David Dingli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Elderly Patients ◽  
Randomized Controlled Trials ◽  
Research Funding ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Patient Data ◽  
Controlled Trials ◽  
Randomized Controlled ◽  
The Impact

Abstract Abstract 615 Background: Trials comparing efficacy of standard melphalan prednisone (MP) therapy with MP plus thalidomide (T) in the transplant ineligible, elderly patients with multiple myeloma have provided conflicting evidence. While there is greater agreement with regard to superior response rates (RR) with the addition of T to MP in elderly patients, the impact on progression free survival (PFS) and overall survival (OS) is less clear with some trials showing an improvement in PFS and/or OS with MPT and others demonstrating no difference in outcomes. We performed a systematic review to integrate the existing outcome data related to the efficacy of MP vs. MPT using a meta-analytic approach. Methods: A comprehensive search of electronic database through July 31st, 2009 was performed for publications, abstracts and presentations to identify randomized controlled trials (RCTs) comparing MP with MPT. A meta-analysis was performed by pooling results on clinical endpoints of RR, PFS and OS reported in all the identified RCTs under a random effects model. We did not have access to individual patient data from these trials. Results: Overall, five prospective RCTs (3 published articles and 2 abstracts) comparing MP with MPT regimen and comprising a total of 1571 patients were identified. For the endpoints of OS and PFS, data were extractable only from 4 RCTs (abstract by Gulbrandsen et al. was excluded). The Bregg and Egger funnel plot for OS demonstrated a symmetric distribution (P = 0.6) indicating no significant publication bias. The test of heterogeneity among all RCTs was statistically significant in the estimate of RR (tau2=0.21; chi2=16.33; p=0.003 (df=4); I2 = 75.5%), but not significant for the estimates of PFS (tau2=0.01; chi2=4.61; p=0.2 (df=3); I2 = 34.9%), and OS (tau2=0.02; chi2=5.53; p=0.14 (df=3); I2 = 45.8%). As expected, the pooled odds ratio of responding to treatment with MP versus MPT was 0.307 (P<0.001) indicating that MP was worse than MPT in achieving at least a partial response. The pooled hazard ratios (HR) for PFS and OS were 1.59 (p<0.001) and 1.34 (p=0.006), respectively (see table for forest plots) in favor of MPT. Conclusion: Our meta-analysis implies that in previously untreated, transplant ineligible elderly patients with multiple myeloma, the addition of thalidomide to melphalan-prednisone demonstrates improved RR, PFS and OS compared with the use of melphalan-prednisone alone. Although the results from a comprehensive individual patient data pooled analysis would give a more precise estimate, our analysis suggests that MPT is superior to MP in terms of response and survival. Disclosures: Dispenzieri: Celgene: Research Funding. Gertz:Celgene: Honoraria. Kumar:celgene, genzyme, millennium, novartis, bayer: Research Funding; genzyme: Membership on an entity's Board of Directors or advisory committees.

Testing different thresholds for patient global assessment in defining remission for rheumatoid arthritis: are the current ACR/EULAR Boolean criteria optimal?

2020 ◽  
Vol 79 (4) ◽  
pp. 445-452 ◽  
Author(s):  
Paul Studenic ◽  
David Felson ◽  
Maarten de Wit ◽  
Farideh Alasti ◽  
Tanja A Stamm ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Global Assessment ◽  
Activity Index ◽  
Recursive Partitioning ◽  
Regression Tree ◽  
Disease Activity Index ◽  
Patient Global Assessment ◽  
Classification And Regression Tree ◽  
Operating Characteristics ◽  
The Impact

ObjectivesThis study aimed to evaluate different patient global assessment (PGA) cut-offs required in the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean remission definition for their utility in rheumatoid arthritis (RA).MethodsWe used data from six randomised controlled trials in early and established RA. We increased the threshold for the 0–10 score for PGA gradually from 1 to 3 in steps of 0.5 (Boolean1.5 to Boolean3.0) and omitted PGA completely (BooleanX) at 6 and 12 months. Agreement with the index-based (Simplified Disease Activity Index (SDAI)) remission definition was analysed using kappa, recursive partitioning (classification and regression tree (CART)) and receiver operating characteristics. The impact of achieving each definition on functional and radiographic outcomes after 1 year was explored.ResultsData from 1680 patients with early RA and 920 patients with established RA were included. The proportion of patients achieving Boolean remission increased with higher thresholds for PGA from 12.4% to 19.7% in early and 5.9% to 12.3% in established RA at 6 months. Best agreement with SDAI remission occurred at PGA cut-offs of 1.5 and 2.0, while agreement decreased with higher PGA (CART: optimal agreement at PGA≤1.6 cm; sensitivity of PGA≤1.5 95%). Changing PGA thresholds at 6 months did not affect radiographic progression at 12 months (mean ꙙsmTSS for Boolean, 1.5, 2.0, 2.5, 3.0, BooleanX: 0.35±5.4, 0.38±5.14, 0.41±5.1, 0.37±4.9, 0.34±4.9, 0.27±4.7). However, the proportion attaining HAQ≤0.5 was 90.2%, 87.9%, 85.2%, 81.1%, 80.7% and 73.1% for the respective Boolean definitions.ConclusionIncreasing the PGA cut-off to 1.5 cm would provide high consistency between Boolean with the index-based remission; the integer cut-off of 2.0 cm performed similarly.

Recombinant Human Erythropoiesis Stimulating Agents in Cancer Patients: Individual Patient Data Meta-Analysis on Behalf of the EPO IPD Meta-Analysis Collaborative Group

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4675-4675 ◽  
Author(s):  
Julia Bohlius ◽  
Corinne Brillant ◽  
Michael Clarke ◽  
Sabine Kluge ◽  
Maryann Napoli ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Patient Data ◽  
Red Blood Cell Transfusion ◽  
Collaborative Group ◽  
Study Phase ◽  
Erythropoiesis Stimulating Agents ◽  
Meta Analyses ◽  
The Impact

Abstract Background: Erythropoiesis stimulating agents (ESAs) consistently have been shown to decrease transfusions in anemic oncology patients. However, whether they increase mortality in cancer patients is under debate. Results from individual studies conflict, and results from literature based meta-analyses are inconclusive. We conducted a meta-analysis based on individual patient data (IPD) from all available randomized controlled trials (RCTs). Meta-analyses with individual patient data offer several advantages over study-level analysis, including the ability to gain statistical power and increase validity using time-to-event analyses, to adjust for prognostic variables that may have confounded the original treatment comparisons and to investigate subgroups in which treatment may be either more or less effective or harmful. Methods: An international collaboration conducted an individual patent data meta-analysis of ESA effects on mortality in cancer patients. With guidance from an independent steering committee of international experts in hematology, oncology, radiotherapy, epidemiology, medical statistics and a consumer representative, we developed a detailed protocol and statistical analysis plan. Independent RCT investigators and representatives from pharmaceutical companies who submitted data provided additional input through the project’s advisory board. IPD from RCTs of ESA plus red blood cell transfusion (RBCT) (as needed) versus placebo or no ESA plus RBCT (as needed), for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy, were included. Hazard ratios and 95% confidence intervals (CIs) were calculated per study and meta-analyzed with fixed-effects and random-effects models. Primary endpoints were overall survival (during active study phase and for the longest follow-up available) for patients receiving chemotherapy, and for all cancer patients regardless of anticancer treatment. Stratified multivariable Cox-regression analyses were conducted to assess the impact of baseline imbalances and to identify potential effect modifiers. Duplicate main statistical analyses were conducted independently at two academic statistical departments. Results: Data on 13933 patients enrolled in 53 studies were included in the analysis. Data were provided by the companies Amgen Inc., Johnson & Johnson Pharmaceutical Research & Development, L.L.C., and F. Hoffmann-La Roche Ltd.; and by five independent investigators. Results are currently undergoing internal verification and final evaluation and will be presented at the meeting. Conclusion: Final conclusions will be presented at the meeting. Future analyses using IPD will be conducted to estimate the risks (clots, tumor progression) and potential benefits (transfusion needs and quality of life/fatigue) from other outcomes.

scholarly journals Comparative effectiveness of biological medicines in rheumatoid arthritis: systematic review and network meta-analysis including aggregate results from reanalysed individual patient data

BMJ ◽  
2020 ◽  
pp. m2288 ◽  
Author(s):  
Kirsten Janke ◽  
Katharina Biester ◽  
Dietmar Krause ◽  
Bernd Richter ◽  
Christoph Schürmann ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Comparative Effectiveness ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Patient Data ◽  
The Other ◽  
Serious Adverse Events ◽  
Low Disease Activity ◽  
Clinical Study Reports

Abstract Objective To assess the comparative effectiveness of biological medicines in rheumatoid arthritis in sufficiently similar patient populations, based on the current definitions of key outcomes. Design Systematic review and network meta-analysis including aggregate results from reanalysed individual patient data. Data sources Clinical study reports and aggregate results from reanalyses of individual patient data on key outcomes for rheumatoid arthritis provided by study sponsors for studies conducted up to 2017, and several databases and registries from inception up to February 2017. Eligibility criteria for selecting studies Randomised controlled trials investigating patient relevant outcomes in adults with rheumatoid arthritis treated with biological medicines in combination with methotrexate after methotrexate failure for at least 24 weeks. Results 45 eligible trials were identified. Combining data from clinical study reports and aggregate results from reanalyses of individual patient data allowed extensive analyses yielding sufficiently similar populations and homogeneous study results for network meta-analyses, including up to 35 studies on eight biological medicines combined with methotrexate. These analyses showed few statistically significant differences between the combination treatments. For example, anakinra showed less benefit than almost all the other seven biological medicines regarding clinical remission or low disease activity (clinical disease activity index ≤2.8 or ≤10, respectively) and certolizumab pegol showed more harm than the other seven biological medicines regarding serious adverse events or infections. Some outcomes had very wide 95% confidence intervals, potentially implying unidentified differences between the eight biological medicines, but wide 95% confidence intervals were less prominent for low disease activity, serious adverse events, and infections. Owing to a lack of head-to-head trials, results were mainly based on indirect comparisons with a limited number of studies, and recently approved Janus kinase inhibitors could not be included. Conclusions For patients with rheumatoid arthritis after methotrexate failure, only minor differences in benefits and harms were seen between biological medicines in combination with methotrexate. However, the analysis was hampered by a lack of long term direct comparisons. The substantial information gain achieved by the reanalysis of individual patient data calls for the routine availability of individual patient data.

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