Implementing Multilevel Network Meta-Regression for Time-To-Event Outcomes: A Case Study in Relapsed Refractory Multiple Myeloma.

OBJECTIVES: Multilevel network meta-regression (ML-NMR) leverages individual patient data (IPD) and aggregate data from a network of randomized controlled trials (RCTs) to assess the comparative efficacy of multiple treatments, while adjusting for between-study differences. We provide an overview of ML-NMR for time-to-event outcomes and apply it to an illustrative case study, including example R code. METHODS: The case study evaluated the comparative efficacy of idecabtagene vicleucel (ide-cel), selinexor+dexamethasone (Sd), belantamab mafodotin (BM), and conventional care (CC) for patients with triple-class exposed relapsed/refractory multiple myeloma in terms of overall survival. Single-arm clinical trials and real-world data were naively combined to create an aggregate data artificial RCT (aRCT) (MAMMOTH-CC versus DREAMM-2-BM versus STORM-2-Sd) and an IPD aRCT (KarMMa-ide-cel versus KarMMa-RW-CC). With some assumptions, we incorporated continuous covariates with skewed distributions, reported as median and range. The ML-NMR models adjusted for number of prior lines, triple-class refractory status, and age and were compared using the leave-one-out information criterion. We summarized predicted hazard ratios and survival (95% credible intervals) in the IPD aRCT population. RESULTS: The Weibull ML-NMR model had the lowest leave-one-out information criterion. Ide-cel was more efficacious than Sd, BM, and CC in terms of overall survival. Effect modifiers had minimal impact on the model, and only triple-class refractory was a prognostic factor. CONCLUSIONS: We demonstrate an application of ML-NMR for time-to-event outcomes and introduce code that can be used to aid implementation. Given its benefits, we encourage practitioners to utilize ML-NMR when population adjustment is necessary for comparisons of multiple treatments.

Unanchored Population-Adjusted Indirect Comparison Methods for Time-to-Event Outcomes Using Inverse Odds Weighting, Regression Adjustment, and Doubly Robust Methods With Either Individual Patient or Aggregate Data.

OBJECTIVES: Several methods for unanchored population-adjusted indirect comparisons (PAICs) are available. Exploring alternative adjustment methods, depending on the available individual patient data (IPD) and the aggregate data (AD) in the external study, may help minimize bias in unanchored indirect comparisons. However, methods for time-to-event outcomes are not well understood. This study provides an overview and comparison of methods using a case study to increase familiarity. A recent method is applied to marginalize conditional hazard ratios, which allows for the comparisons of methods, and a doubly robust method is proposed. METHODS: The following PAIC methods were compared through a case study in third-line small cell lung cancer, comparing nivolumab with standard of care based on a single-arm phase II trial (CheckMate 032) and real-world study (Flatiron) in terms of overall survival: IPD-IPD analyses using inverse odds weighting, regression adjustment, and a doubly robust method; IPD-AD analyses using matching-adjusted indirect comparison, simulated treatment comparison, and a doubly robust method. RESULTS: Nivolumab extended survival versus standard of care with hazard ratios ranging from 0.63 (95% CI 0.44-0.90) in naive comparisons (identical estimates for IPD-IPD and IPD-AD analyses) to 0.69 (95% CI 0.44-0.98) in the IPD-IPD analyses using regression adjustment. Regression-based and doubly robust estimates yielded slightly wider confidence intervals versus the propensity score-based analyses. CONCLUSIONS: The proposed doubly robust approach for time-to-event outcomes may help to minimize bias due to model misspecification. However, all methods for unanchored PAIC rely on the strong assumption that all prognostic covariates have been included.

A Comparison of Alternative Network Meta-Analysis Methods in the Presence of Nonproportional Hazards: A Case Study in First-Line Advanced or Metastatic Renal Cell Carcinoma.

OBJECTIVES: Network meta-analysis (NMA) of time-to-event outcomes based on constant hazard ratios can result in biased findings when the proportional hazards (PHs) assumption does not hold in a subset of trials. We aimed to summarize the published non-PH NMA methods for time-to-event outcomes, demonstrate their application, and compare their results. METHODS: The following non-PH NMA methods were compared through an illustrative case study in oncology of 4 randomized controlled trials in terms of progression-free survival and overall survival: (1) 1-step or (2) 2-step multivariate NMAs based on traditional survival distributions or fractional polynomials, (3) NMAs with restricted cubic splines for baseline hazard, and (4) restricted mean survival NMA. RESULTS: For progression-free survival, the PH assumption did not hold across trials and non-PH NMA methods better reflected the relative treatment effects over time. The most flexible models (fractional polynomials and restricted cubic splines) fit better to the data than the other approaches. Estimated hazard ratios obtained with different non-PH NMA methods were similar at 5 years of follow-up but differed thereafter in the extrapolations. Although there was no strong evidence of PH violation for overall survival, non-PH NMA methods captured this uncertainty in the relative treatment effects over time. CONCLUSIONS: When the PH assumption is questionable in a subset of the randomized controlled trials, we recommend assessing alternative non-PH NMA methods to estimate relative treatment effects for time-to-event outcomes. We propose a transparent and explicit stepwise model selection process considering model fit, external constraints, and clinical validity. Given inherent uncertainty, sensitivity analyses are suggested.

Structured expert elicitation to inform long-term survival extrapolations using alternative parametric distributions: a case study of CAR T therapy for relapsed/ refractory multiple myeloma.

BACKGROUND: Our aim was to extend traditional parametric models used to extrapolate survival in cost-effectiveness analyses (CEAs) by integrating individual-level patient data (IPD) from a clinical trial with estimates from experts regarding long-term survival. This was illustrated using a case study evaluating survival of patients with triple-class exposed relapsed/refractory multiple myeloma treated with the chimeric antigen receptor (CAR) T cell therapy idecabtagene vicleucel (ide-cel, bb2121) in KarMMa (a phase 2, single-arm trial). METHODS: The distribution of patients expected to be alive at 3, 5, and 10 years given the observed survival from KarMMa (13.3 months of follow-up) was elicited from 6 experts using the SHeffield ELicitation Framework. Quantities of interest were elicited from each expert individually, which informed the consensus elicitation including all experts. Estimates for each time point were assumed to follow a truncated normal distribution. These distributions were incorporated into survival models, which constrained the expected survival based on standard survival distributions informed by IPD from KarMMa. RESULTS: Models for ide-cel that combined KarMMa data with expert opinion were more consistent in terms of survival as well as mean survival at 10 years (survival point estimates under different parametric models were 29-33% at 3 years, 5-17% at 5 years, and 0-6% at 10 years) versus models with KarMMa data alone (11-39% at 3 years, 0-25% at 5 years, and 0-11% at 10 years). CONCLUSION: This case study demonstrates a transparent approach to integrate IPD from trials with expert opinion using traditional parametric distributions to ensure long-term survival extrapolations are clinically plausible.

Indirect treatment comparison of idecabtagene vicleucel versus conventional care in triple-class exposed multiple myeloma.

Aim: To compare the efficacy of idecabtagene vicleucel (ide-cel, bb2121) versus conventional care (CC) in triple-class exposed relapsed and refractory multiple myeloma (RRMM) patients. Patients & methods: A matching-adjusted indirect comparison was conducted using individual patient-level data from the pivotal, phase II, single-arm KarMMa trial (NCT03361748) and aggregate-level data from MAMMOTH, the largest independent observational study of CC in heavily pretreated RRMM patients. Results: Ide-cel improved overall response rate (odds ratio: 5.30; 95% CI: 2.96-9.51), progression-free survival (hazard ratio: 0.50; 95% CI: 0.36-0.70) and overall survival (hazard ratio: 0.37; 95% CI: 0.25-0.56) versus CC. Conclusion: These results suggest ide-cel offers improvements in clinical outcomes relative to CC in this heavily pretreated RRMM population.

Cost-effectiveness analysis of cemiplimab vs pembrolizumab for treatment of advanced cutaneous squamous cell carcinoma.

BACKGROUND: Most cutaneous squamous cell carcinomas (CSCCs) can be treated with surgical excision or radiation; however, approximately 1% of patients develop advanced disease. In 2018, the FDA approved cemiplimab-rwlc as the first programmed cell death-1 (PD-1) monoclonal antibody for the treatment of patients with metastatic CSCC or locally advanced CSCC who are not candidates for curative surgery or curative radiation. In June 2020, pembrolizumab, another PD-1 monoclonal antibody, was approved for the treatment of patients with recurrent or metastatic CSCC who are not candidates for curative surgery or radiation. We previously reported on the cost-effectiveness of cemiplimab vs historical standard of care for the treatment of advanced CSCC from a US perspective. OBJECTIVE: To estimate the cost-effectiveness of cemiplimab vs pembrolizumab for patients with advanced CSCC in the United States. METHODS: A "partitioned survival" framework was used to assess the cost-effectiveness of cemiplimab vs pembrolizumab. Clinical inputs were based on the most recent data cut of the phase 2 trials for cemiplimab (EMPOWER-CSCC-1; NCT02760498) and pembrolizumab (KEYNOTE-629). Progression-free survival and overall survival were extrapolated using parametric models until all patients had progressed or died. Health state utilities were derived from data collected in the EMPOWER-CSCC-1 trial. Costs included drug acquisition, drug administration, disease management, terminal care, and adverse events and were based on published 2020 US list prices. To assess model uncertainty, 1-way sensitivity and probabilistic sensitivity analyses (PSA) were conducted, alongside scenario analyses evaluating key modeling assumptions. RESULTS: In the base case, cemiplimab resulted in an incremental gain of 3.44 life-years (discounted) and incremental cost-effectiveness ratio (ICER) of $130,329 per quality-adjusted life-year (QALY) vs pembrolizumab. At a willingness-to-pay threshold of $150,000/QALY, PSA indicated a 71% probability that cemiplimab is cost-effective when compared with pembrolizumab. Scenario analysis resulted in ICERs ranging from $115,909 to $187,374. CONCLUSIONS: Findings suggest that cemiplimab is a cost-effective treatment for patients with advanced CSCC, compared with pembrolizumab. These results should be interpreted cautiously in the absence of head-to-head trials; however, in the absence of such data, these results can be used to inform health care decisions over resource allocation. DISCLOSURES: This study was supported by Regeneron Pharmaceuticals, Inc., and Sanofi. Paul, Cope, Keeping, Mojebi, and Ayers are employees of PRECISIONheor, which received funding to produce this work. Chen, Kuznik, and Xu are employees and stockholders of Regeneron Pharmaceuticals, Inc. Sasane is an employee and stockholder of Sanofi, Inc. Konidaris, Atsou, and Guyot are employees of Sanofi, Inc. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication.

Matching adjusted indirect comparisons of efficacy outcomes for idecabtagene vicleucel (ide-cel, bb2121) versus selinexor + dexamethasone and belantamab mafodotin in relapsed and refractory multiple myeloma.

Idecabtagene vicleucel (ide-cel, bb2121), a chimeric antigen receptor (CAR) T cell therapy, has been investigated in patients with relapsed and refractory multiple myeloma (RRMM) who have received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody in the single-arm phase 2 KarMMa clinical trial. Two therapies with distinct mechanisms of action - selinexor plus dexamethasone (Sd) and belantamab mafodotin (BM) - are currently approved in the United States for heavily pretreated patients, including those who are triple-class refractory. To compare ide-cel versus Sd and ide-cel versus BM, matching-adjusted indirect comparisons were performed. Ide-cel extended progression-free survival (PFS) and overall survival (OS) versus both Sd and BM (hazard ratio (HR); 95% confidence interval (CI)). PFS: ide-cel versus Sd, 0.46; 0.28-0.75; ide-cel versus BM, 0.45; 0.27-0.77. OS: ide-cel versus Sd, 0.23; 0.13-0.42; ide-cel versus BM, 0.35; 0.14-0.87. These results suggest ide-cel offers clinically meaningful improvements over currently approved regimens for patients with heavily pretreated RRMM.

Assessing the Value of Cemiplimab for Adults With Advanced Cutaneous Squamous Cell Carcinoma: A Cost-Effectiveness Analysis.

OBJECTIVES: To evaluate the cost-effectiveness of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC) from a payer perspective in the United States. METHODS: A partitioned survival model was developed to assess the cost-effectiveness of cemiplimab versus historical standard of care (SOC). All inputs were identified based on a systematic literature review, supplemented by expert opinion where necessary. Clinical inputs for cemiplimab were based on individual patient data from a cemiplimab phase 2 single-arm trial (NCT27060498). For SOC, analysis was based on a pooled analysis of single-arm clinical trials and retrospective studies evaluating chemotherapy and epidermal growth factor receptor inhibitors (cetuximab, erlotinib, and gefitinib) identified via a systematic literature review (6 of the 27 included studies). Overall survival and progression-free survival were extrapolated over a lifetime horizon. Costs were included for drug acquisition, drug administration, management of adverse events, subsequent therapy, disease management, and terminal care. Unit costs were based on published 2019 US list prices. RESULTS: In the base case, cemiplimab versus SOC resulted in an incremental cost-effectiveness ratio of $99 447 per quality adjusted-life year (QALY), where incremental costs and QALYs were $372 108 and 3.74, respectively. At a willingness-to-pay threshold of $150 000/QALY, the probabilistic sensitivity analysis suggests a 90% probability that cemiplimab is cost-effective compared to SOC. Scenario analyses resulted in incremental cost-effectiveness ratios ranging from $90 590 to $148 738. CONCLUSIONS: Compared with historical SOC, cemiplimab is a cost-effective use of US payer resources for the treatment of advanced CSCC and is expected to provide value for money.

Comparative efficacy of cemiplimab versus other systemic treatments for advanced cutaneous squamous cell carcinoma.

Aim: To estimate the comparative efficacy of cemiplimab, a programmed cell death protein 1 inhibitor, versus EGFR inhibitors, pembrolizumab and platinum-based chemotherapy in terms of overall survival (OS) and progression-free survival. Patients & methods: We performed an indirect treatment comparison of cemiplimab and other available systemic therapies for patients with advanced cutaneous squamous cell carcinoma. Results: Cemiplimab was associated with benefits in OS (hazard ratios range: 0.07-0.52) and progression-free survival (hazard ratios range: 0.30-0.67) versus EGFR inhibitors and pembrolizumab (data from KEYNOTE-629). Cemiplimab was more efficacious versus platinum-based chemotherapy in terms of OS. Conclusion: Cemiplimab may offer improvements in survival for advanced cutaneous squamous cell carcinoma patients compared with existing systemic therapies.

Comparative effectiveness of nivolumab versus standard of care for third-line patients with small-cell lung cancer.

Aim: To estimate the comparative effectiveness of nivolumab versus standard of care (SOC) in terms of overall survival (OS) for small-cell lung cancer patients treated with two prior lines of chemotherapy, in other words, third line in the USA. Materials & methods: Data were from CheckMate 032, a single-arm trial of nivolumab, and real-world electronic patient records. Comparisons of OS were conducted using three different methods to adjust for differences (regression, weighting and doubly robust) between the populations. Results: Nivolumab was associated with longer survival compared with SOC (hazard ratio for OS: 0.58-0.70) across all methods for adjustment. Conclusion: Nivolumab was more efficacious in terms of OS as third-line treatment for small-cell lung cancer compared with current SOC in the USA.

Critical Appraisal of Published Indirect Comparisons and Network Meta-Analyses of Competing Interventions for Multiple Myeloma.

OBJECTIVES: In the field of relapsed or refractory multiple myeloma (RRMM), between-trial or indirect comparisons are required to estimate relative treatment effects between competing interventions based on the available evidence. Two approaches are frequently used in RRMM: network meta-analysis (NMA) and unanchored matching-adjusted indirect comparison (MAIC). The objective of the current study was to evaluate the relevance and credibility of published NMA and unanchored MAIC studies aiming to estimate the comparative efficacy of treatment options for RRMM. METHODS: Twelve relevant studies were identified in the published literature (n = 7) and from health technology assessment agencies (n = 5). Data from trials were extracted to identify between-trial differences that may have biased results. Credibility of the performed analyses and relevance of the research questions were critically appraised using the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) checklist and feedback based on consultations with clinical experts. RESULTS: The identified studies concerned NMAs of randomized controlled trials (RCTs; n = 7), unanchored MAICs (n = 4), or both types of analyses (n = 1). According to clinical expert consultation, the majority of the identified NMAs did not consider differences in prior therapies or treatment duration across the RCTs included in the analyses, thereby compromising the relevance. CONCLUSION: Based on the results and feedback from clinicians, the majority of NMAs did not consider prior treatment history or treatment duration, which resulted in nonrelevant comparisons. Furthermore, it may have compromised the credibility of the estimates owing to differences in effect-modifiers between the different trials. Pairwise comparisons by means of unanchored MAICs require clear justification given the reliance on non-randomized comparisons.

Multivariate network meta-analysis of survival function parameters.

BACKGROUND: Network meta-analysis (NMA) of survival data with a multidimensional treatment effect has been introduced as an alternative to NMA based on the proportional hazards assumption. However, these flexible models have some limitations, such as the use of an approximate likelihood based on discrete hazards, rather than a likelihood for individual event times. The aim of this article is to overcome the limitations and present an alternative implementation of these flexible NMA models for time-to-event outcomes with a two-step approach. METHODS: First, for each arm of every randomised controlled trial (RCT) connected in the network of evidence, reconstructed patient data are fit to alternative survival distributions, including the exponential, Weibull, Gompertz, log-normal, and log-logistic. Next, for each distribution, its scale and shape parameters are included in a multivariate NMA to obtain time-varying estimates of relative treatment effects between competing interventions. RESULTS: An illustrative analysis is presented for a network of RCTs evaluating multiple interventions for advanced melanoma regarding overall survival. Alternative survival distributions were compared based on model fit criteria. Based on the log-logistic distribution, the difference in shape and scale parameters for each treatment versus dacarbazine (DTIC) was identified and the corresponding log hazard and survival curves were presented. CONCLUSIONS: The presented two-step NMA approach provides an evidence synthesis framework for time-to-event outcomes grounded in standard practice of parametric survival analysis. The method allows for a more transparent and efficient model selection process.

Comparative effectiveness of nivolumab versus clinical practice for advanced gastric or gastroesophageal junction cancer.

Aim: To determine the effectiveness of nivolumab compared with routine clinical practice (RCP) for patients with gastric or gastroesophageal cancer refractory to, or intolerant of, two or more previous regimens, using real-world electronic patient records from a US population, a single-arm trial (CheckMate 032) and a randomized controlled trial in an Asian setting (ATTRACTION-2). Materials & methods: A simulated treatment comparison was conducted to predict overall survival for patients treated with nivolumab compared with RCP in the USA. Results: Results of the indirect simulated treatment comparison suggest that nivolumab is associated with a 50% reduction in the risk of all-cause mortality relative to RCP (Hazard ratio: 0.50; 95% CI: 0.36, 0.68). Conclusion: The survival benefit of nivolumab may extend more generally to the USA.

Integrating expert opinion with clinical trial data to extrapolate long-term survival: a case study of CAR-T therapy for children and young adults with relapsed or refractory acute lymphoblastic leukemia.

BACKGROUND: Long-term clinical outcomes are necessary to assess the cost-effectiveness of new treatments over a lifetime horizon. Without long-term clinical trial data, current practice to extrapolate survival beyond the trial period involves fitting alternative parametric models to the observed survival. Choosing the most appropriate model is based on how well each model fits to the observed data. Supplementing trial data with feedback from experts may improve the plausibility of survival extrapolations. We demonstrate the feasibility of formally integrating long-term survival estimates from experts with empirical clinical trial data to provide more credible extrapolated survival curves. METHODS: The case study involved relapsed or refractory B-cell pediatric and young adult acute lymphoblastic leukemia (r/r pALL) regarding long-term survival for tisagenlecleucel (chimeric antigen receptor T-cell [CAR-T]) with evidence from the phase II ELIANA trial. Seven pediatric oncologists and hematologists experienced with CAR-T therapies were recruited. Relevant evidence regarding r/r pALL and tisagenlecleucel provided a common basis for expert judgments. Survival rates and related uncertainty at 2, 3, 4, and 5 years were elicited from experts using a web-based application adapted from Sheffield Elicitation Framework. Estimates from each expert were combined with observed data using time-to-event parametric models that accounted for experts' uncertainty, producing an overall distribution of survival over time. These results were validated based on longer term follow-up (median duration 24.2 months) from ELIANA following the elicitation. RESULTS: Extrapolated survival curves based on ELIANA trial without expert information were highly uncertain, differing substantially depending on the model choice. Survival estimates between 2 to 5 years from individual experts varied with a fair amount of uncertainty. However, incorporating expert estimates improved the precision in the extrapolated survival curves. Predictions from a Gompertz model, which experts believed was most appropriate, suggested that more than half of the ELIANA patients treated with tisagenlecleucel will survive up to 5 years. Expert estimates at 24 months were validated by longer follow-up. CONCLUSIONS: This study provides an example of how expert opinion can be elicited and synthesized with observed survival data using a transparent and formal procedure, capturing expert uncertainty, and ensuring projected long-term survival is clinically plausible.

Indirect comparison of nivolumab ± ipilimumab (CheckMate 032) versus other treatments for recurrent small-cell lung cancer.

Aim: To estimate the comparative efficacy of nivolumab ± ipilimumab versus alternative treatments for small-cell lung cancer after at least one prior line of chemotherapy. Materials & methods: A systematic literature review identified six randomized controlled trials (RCTs) that could be connected in a network. The Kaplan-Meier survival curves from these RCTs were synthesized using network meta-analysis models. Aggregate-level matching was used to connect CheckMate 032 to the RCTs. Results: CheckMate 032 was connected to the network by Amrubicin Clinical Trial-1. Nivolumab ± ipilimumab had a more durable tumor response and more favorable long-term survival versus topotecan via intravenous and versus amrubicin. Conclusion: Compared with chemotherapies for recurrent small-cell lung cancer, nivolumab ± ipilimumab improves response duration, which may translate to long-term survival benefits.

Thirty Years of Evidence on the Efficacy of Drug Treatments for Chronic Heart Failure With Reduced Ejection Fraction: A Network Meta-Analysis.

BACKGROUND: Treatments that reduce mortality and morbidity in patients with heart failure with reduced ejection fraction, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), ß-blockers (BB), mineralocorticoid receptor antagonists (MRA), and angiotensin receptor-neprilysin inhibitors (ARNI), have not been studied in a head-to-head fashion. This network meta-analysis aimed to compare the efficacy of these drugs and their combinations regarding all-cause mortality in patients with heart failure with reduced ejection fraction. METHODS AND RESULTS: A systematic literature review identified 57 randomized controlled trials published between 1987 and 2015, which were compared in terms of study and patient characteristics, baseline risk, outcome definitions, and the observed treatment effects. Despite differences identified in terms of study duration, New York Heart Association class, ejection fraction, and use of background digoxin, a network meta-analysis was considered feasible and all trials were analyzed simultaneously. The random-effects network meta-analysis suggested that the combination of ACEI+BB+MRA was associated with a 56% reduction in mortality versus placebo (hazard ratio 0.44, 95% credible interval 0.26-0.66); ARNI+BB+MRA was associated with the greatest reduction in all-cause mortality versus placebo (hazard ratio 0.37, 95% credible interval 0.19-0.65). A sensitivity analysis that did not account for background therapy suggested that ARNI monotherapy is more efficacious than ACEI or ARB monotherapy. CONCLUSIONS: The network meta-analysis showed that treatment with ACEI, ARB, BB, MRA, and ARNI and their combinations were better than the treatment with placebo in reducing all-cause mortality, with the exception of ARB monotherapy and ARB plus ACEI. The combination of ARNI+BB+MRA resulted in the greatest mortality reduction.

Critical appraisal of network meta-analyses evaluating the efficacy and safety of new oral anticoagulants in atrial fibrillation stroke prevention trials.

OBJECTIVES: To critically appraise published network meta-analyses (NMAs) evaluating the efficacy or safety of the new oral anticogulants (NOACs) dabigatran, rivaroxaban, and apixaban for the prevention of stroke in patients with nonvalvular atrial fibrillation (AF). METHODS: A systematic literature review was performed to identify the relevant NMAs using MEDLINE, EMBASE, Cochrane Library, Database of Abstracts of Reviews of Effects, and Health Technology Assessment. The synthesis studies were evaluated using the "Questionnaire to assess the relevance and credibility of the NMA." RESULTS: Eleven NMAs evaluating NOACs among adults with nonvalvular AF were identified. Most NMAs included three large phase III randomized controlled trials, comparing NOACs to adjusted-dose warfarin (Randomized Evaluation of Long-Term Anticoagulation Therapy [RE-LY], Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ROCKET-AF], and Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]). The main differences identified related to potential treatment effect modifiers regarding the mean time spent in therapeutic range (TTR) in the warfarin arm, the risk of stroke or systemic embolism across the trials (mean CHADS2 score: C = congestive heart failure, H = hypertension, A = older than age 75 years, D = diabetes mellitus, S2 = prior stroke or history of transient ischemic attack) or primary versus secondary prevention, and type of populations used in the analysis. Kansal et al. [Kansal AR, Sharma M, Bradley-Kennedy C, et al. Dabigatran versus rivaroxaban for the prevention of stroke and systemic embolism in atrial fibrillation in Canada: comparative efficacy and cost-effectiveness. Thromb Haemost 2012;108:672-82] appropriately adjusted the ROCKET-AF TTR to match the RE-LY population on the basis of individual patient data. Meta-regressions are not expected to minimize confounding bias given limited data, whereas subgroup analyses had some impact on the point estimates for the treatment comparisons. CONCLUSIONS: Results of the synthesis studies were generally comparable and suggested that the NOACs had similar efficacy, although some differences were identified depending on the outcome. The extent to which differences in the distribution of TTR, CHADS2 score, or primary versus secondary prevention biased the results remains unclear.

A process for assessing the feasibility of a network meta-analysis: a case study of everolimus in combination with hormonal therapy versus chemotherapy for advanced breast cancer.

BACKGROUND: The aim of this study is to outline a general process for assessing the feasibility of performing a valid network meta-analysis (NMA) of randomized controlled trials (RCTs) to synthesize direct and indirect evidence for alternative treatments for a specific disease population. METHODS: Several steps to assess the feasibility of an NMA are proposed based on existing recommendations. Next, a case study is used to illustrate this NMA feasibility assessment process in order to compare everolimus in combination with hormonal therapy to alternative chemotherapies in terms of progression-free survival for women with advanced breast cancer. RESULTS: A general process for assessing the feasibility of an NMA is outlined that incorporates explicit steps to visualize the heterogeneity in terms of treatment and outcome characteristics (Part A) as well as the study and patient characteristics (Part B). Additionally, steps are performed to illustrate differences within and across different types of direct comparisons in terms of baseline risk (Part C) and observed treatment effects (Part D) since there is a risk that the treatment effect modifiers identified may not explain the observed heterogeneity or inconsistency in the results due to unexpected, unreported or unmeasured differences. Depending on the data available, alternative approaches are suggested: list assumptions, perform a meta-regression analysis, subgroup analysis, sensitivity analyses, or summarize why an NMA is not feasible. CONCLUSIONS: The process outlined to assess the feasibility of an NMA provides a stepwise framework that will help to ensure that the underlying assumptions are systematically explored and that the risks (and benefits) of pooling and indirectly comparing treatment effects from RCTs for a particular research question are transparent.

Quantitative summaries of treatment effect estimates obtained with network meta-analysis of survival curves to inform decision-making.

BACKGROUND: Increasingly, network meta-analysis (NMA) of published survival data are based on parametric survival curves as opposed to reported hazard ratios to avoid relying on the proportional hazards assumption. If a Bayesian framework is used for the NMA, rank probabilities associated with the alternative treatments can be obtained, which directly support decision-making. In the context of survival analysis multiple treatment effect measures are available to inform the rank probabilities. METHODS: A fractional polynomial NMA of overall survival in advanced melanoma was performed as an illustrative example. Rank probabilities were calculated and presented for the following effect measures: 1) median survival; 2) expected survival; 3) mean survival at the follow-up time point of the trial with the shortest follow-up; 4) hazard or hazard ratio over time; 5) cumulative hazard or survival proportions over time; and 6) mean survival at subsequent time points. The advantages and disadvantages of the alternative measures were discussed. RESULTS: Since hazard and survival estimates may vary over time for the compared interventions, calculations of rank probabilities for an NMA of survival curves may depend on the effect measure. With methods 1-3 rank probabilities do not vary over time, which are easier to understand and communicate than rank probabilities that vary over time as obtained with methods 4-6. However, rank probabilities based on methods 4-6 provide useful information regarding the relative treatment effects over time. CONCLUSIONS: Different approaches to summarize results of a NMA of survival curves with rank probabilities have pros and cons. Rank probabilities of treatment effects over time provide a more transparent and informative approach to help guide decision-making than single rank probabilities based on collapsed measures, such as median survival or expected survival. Rank probabilities based on survival proportions are the most intuitive and straightforward to communicate, but alternatives based on the hazard function or mean survival over time may also be useful.