You can get the restricted mean survival time with print(km, print.rmean=TRUE). The restricted mean is a measure of average survival from time 0 to a specified time point, and may be estimated as the area under the survival curve up to that point. Based on two applications and a simulation study, the authors concluded that the three methods yielded similar results with respect to bias, mean square error and coverage probability. Performed the experiments: BL AM JPP ORA JB. here. We considered methods either used in the field of meta-analysis or in economic evaluation but never applied to assess the rmstD for economic evaluation using IPD meta-analysis. However, these studies failed to acknowledge data clustering or did not justify the choice of the method used to estimate the rmstD. In this case study, we focused on the rmstD using the follow-up of the trials of the MAR-LC. The purpose is to give more weight to trials that yield more information about the treatment effect and thus have a lower variance. Even though, there was no treatment effect heterogeneity between MAR-LC trials and survival hazards were proportional, we noted a difference in mean ICERs generated by the methods. We had access to the patient-level data from the Meta-Analysis of Radiotherapy in Lung Cancer (MAR-LC) collaborative group [19] which was previously used in a Dutch economic evaluation [20]. I describe the use of restricted mean survival time as an alternative outcome measure in time-to-event trials. Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Madrid, Spain, Affiliations Survival curves for the two arms in MAR-LC estimated using Naive Kaplan-Meier and Stewart-Parmar, Peto-month, Peto-year and Peto-quintiles are respectively shown in S1âS4 Figs. Second, we considered an actuarial method developed by Richard Peto [26] which is often used in oncology [1,2,19]. If the true survival curves remain separated beyond the point of restriction, the difference in restricted means will increase with t *. The treatment effects to be pooled are mostly expressed in terms of log odds ratios or log hazard ratios for survival endpoints [21]. In each bootstrap replicate, modified RT was both more effectiveâirrespective of the survival analysis method usedâand more expensive than conventional RT. The treatment effect in a RCT can be defined as the difference in RMST between the randomized arms at time t ∗. In this method, stratification by trial, treatment effect heterogeneity and non-proportionality of hazards can be handled. The difference in restricted mean survival between PWID and people who did not inject drugs was − 0.19 years (95% CI: -0.29, − 0.09). The acceptability curve of the Pooled Exponential method was above the six other methods (Fig 2). In order to estimate the rmstD from IPD-MA, we considered methods used by Wei and colleagues [18] and chose to adapt other non-parametric methods that are applied in the field of IPD-MA. It is estimated as the between-arm difference in the restricted mean survival time (rmstD) and corresponds to the area between the two survival curves for the experimental arm and the control arm restricted to a certain time horizon [7]. OBJECTIVE: In economic evaluation, a commonly used outcome measure for the treatment effect is the between-arm difference in restricted mean survival time (rmstD). No, Is the Subject Area "Survival analysis" applicable to this article? Restricted mean survival time is a well-established, yet underused, measure that can be interpreted as the mean event-free survival time up to a prespecified, clinically important point. Details on the methods are provided in Table 1 and in the S1 Supporting Information. Restricted mean survival time (RMST) evaluates the mean event‐free survival time up to a prespecified time point. The difference in restricted mean survival times (RMSTs) up to a pre-specified time point is an alternative measure that offers a clinically meaningful interpretation. Finally, this method allows studying the potential heterogeneity of rmstD across trials and has been proved to be unbiased and with a good coverage probability (Wei et al, 2015). There was no treatment effect heterogeneity between trials (p = 0.37, Higgins I² = 8%). The difference summarizes the association between group assignment and survival. The ICER was defined as the difference in mean costs between the two types of radiotherapy regimen (modified and conventional) divided by the rmstD. RMST can be most simply thought of as the area under the survival curve. e0150032. Second, unlike the actuarial Peto method, it does not rely on any time interval definition.
Saunders (Mount Vernon Hospital), W. Sause (Intermountain Medical Center), S.E. The meth-odology of Glasziou uses a ‘‘partitioned survival analysis’’ (Glasziou, Simes, and Gelber 1990). Three kinds of between-group contrast metrics (i.e., the difference in RMST, the ratio of RMST and the ratio of the restricted mean time lost (RMTL)) are computed. The diamonds represent overall rmstDs, with the center denoting the rmstD and the extremities the 95% CI. Survival probabilities are estimated after each event in the naive Kaplan-Meier, Pooled Kaplan-Meier, and Stewart-Parmar methods. The rmstDs estimated using the different survival analysis methods are shown in Table 2. With the first approach, the rmstD is estimated directly as the area between the two pooled survival curves. Furthermore, without PH, the estimated HR is not a simple average of HRs over time, and is even more difficult to interpret. Dahlberg (Dana-Farber Cancer Institute), D. De Ruysscher (University Hospital Leuven and University Hospital Maastricht), S. Dische (Mount Vernon Hospital), P. Fournel (Institut de Cancérologie de la Loire), R. Koch (University of Dresden), C. Le Péchoux (Gustave Roussy), S.J. Three kinds of between-group contrast metrics (i.e., the difference in RMST, the ratio of RMST and the ratio of the restricted mean time lost (RMTL)) are computed. Discover a faster, simpler path to publishing in a high-quality journal. Alternatively, similarly to the Stewart-Parmar method and to the method used in a number of studies reviewed by Guyot and colleagues [30], one could fit a parametric model to compute the survival function in the control arm. The individual patient data meta-analysis (IPD-MA) has become the gold standard for obtaining the best evidence for treatment effects (e.g. The difference between two arms in the restricted mean survival time is an alternative to the hazard ratio. So far, two non-parametric methods (Stewart-Parmar and Peto methods) have been used for estimating pooled survival curves from IPD meta-analysis [25,26]. %%EOF
We computed this method using three different time interval definitions: one year, one month and an interval length based on the quintiles of the distribution of deaths in the whole population. The method applies the restricted mean (RM) for the estimation of ‘‘time’’ spent in a particular state of health. Competing interests: The authors have declared that no competing interests exist. 0r�n��`����:&��{��)g�fQ�B��b�3��F9���%��Î�^[m�u+dz�{c�P'(���'��ˑ�u���%�j�6&���
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Furthermore, the issue of comparing different parametric models was beyond the scope of this paper, and has already been explored in the literature [15â17]. Economic evaluations based on IPD-MA raise methodological concerns because of data clustering (patients within trials) which must be considered in the analysis. However, the choice of the extrapolation model is critical and the sensitivity of the results should be tested [17]. The rmstDs are then pooled across trials. 944 patients in the conventional radiotherapy arm and 1,046 in the modified radiotherapy arm. It provides a more easily understood measure of the treatment effect of an intervention in a controlled clinical trial with a time to event endpoint. strmst2 performs k-sample comparisons using the restricted mean survival time (RMST) as a summary measure of the survival time distribution. The MAR-LC comprised 2,000 distinct patients with a non-metastatic non-small cell lung cancer treated with radiotherapy and who had been enrolled in ten distinct phase III RCTs [19]. Methods were classified into two approaches. The authors concluded that, overall, all the five methods were quite accurate but they pointed out that most of these methods failed to address stratification by trial and treatment effect heterogeneity. 1 shows the difference in RMST to all-cause mortality comparing PWID and persons who did not … Data Availability: Data were used with permission obtained from the MAR-LC Collaborative Group investigators, who agreed to share their data with us by signing an amendment to the original protocol. We retained the exponential model. With a ceiling ratio of ⬠25,000 per life-year gained, the probability of modified RT being cost-effective ranged from 31% with Peto-quintiles to 68% with the Pooled Exponential method (Fig 2). Is the Subject Area "Metaanalysis" applicable to this article? No, Is the Subject Area "Cancer treatment" applicable to this article? The French data protection authority (CNIL â Commission Nationale de l'Informatique et des Libertés) strictly forbids us to make data collected during clinical trials freely available. There is a considerable body of methodological research about the restricted mean survival time as alternatives to the hazard ratio approach. For more information about PLOS Subject Areas, click Yes Restricted mean survival time (RMST) can provide additional insight to the survival distribution and is not subject to underestimation by definition. Belani (Penn State Hershey Cancer Institute), J. Beresford (Peter MacCallum Cancer Centre), J. Bishop (Victorian Comprehensive Cancer Centre), J.A. h��o�@���{ߪ���K����6i�èʤ�)D)҉����(eSA]�Sp�g��sL@�� V �p��@�k�d��Q����Jh$��K9��7�vU�r�Z��ޔr��L��+{=��oge� o���ZL�y����e�Xf�U��.m�u�� Difference in Restricted Mean Survival Time for Cost-Effectiveness Analysis Using Individual Patient Data Meta-Analysis: Evidence from a Case Study Lueza, Béranger Mauguen, Audrey Fig 1 shows the forest-plot for the difference in restricted mean survival time (rmstD) estimated using Kaplan-Meier or the exponential model for each of the ten RCTs in MAR-LC, demonstrating no heterogeneity between trials (p = 0.47, Higgins I² = 0% for Pooled Kaplan-Meier and p = 0.31, Higgins I² = 15% for Pooled Exponential). In this case-study, we illustrate how different survival analysis methods can be used to estimate the rmstD for economic evaluation using IPD-MA. We did not consider the non-parametric pseudo-values method, but Wei et al. �n��p�Nxa�o&�g}[&�p��\�;o����k��и�^�� !����i�'H2|�4��wI0�|. Methods were classified into two approaches. We decided to consider the Kaplan-Meier method and parametric survival analysis models. The Naive Kaplan-Meier method considers the IPD from the different RCTs as if they originated from a unique RCT. Gustave Roussy, Ligue Nationale Contre le Cancer meta-analysis plateform, Villejuif, France, Affiliations In economic evaluation, a commonly used outcome measure for the treatment effect is the between-arm difference in restricted mean survival time (rmstD). Modified RT was associated with longer overall survival (pooled hazard ratio = 0.88, 95% CI: [0.80â0.97], p = 0.009). H��U]o�0�+�ў��N�im'���N�xmZ]:�n~=�v�vچ��Ǿ��sϽN�%�fpv6zW�+ u�}������8�������[�-�ʒ�Ќk(� Ǭgs9� @��pq��P�D�!S�Y$��� �c2
���)sdR��Y�V��H�N���p��v�&�c����|"Ӛf�EA��������qŹ �f��0Q|n�@#�K���u����yO�K���U�v���*��{���?���MְCz�H�
b�j�P�9C��f���9P���5�)�gZ�!��5��t)�@�`˓���~)� GN��J�L���X��ֿ�M�aK3�D^D5�$_���CЯM*�@�� here. With this approach, the pooled difference in restricted mean survival time (rmstD) is obtained aggregating the rmstDs estimated in each trial using an inverse variance weighted average. Modified RT is considered cost-effective if the ICER is less than the willingness-to-pay for one life year. The restricted mean survival time is a robust and clinically interpretable summary measure of the survival time distribution. There is currently a debate about when and how to extrapolate survival curves up to a lifetime horizon for economic evaluations [15â17]. https://doi.org/10.1371/journal.pone.0150032.s004, https://doi.org/10.1371/journal.pone.0150032.s005. Mandrekar (Mayo Clinic), A. Mauguen (Gustave Roussy), F. Mornex (Centre Hospitalier Lyon Sud), M. Nankivell (MRC Clinical Trials Unit), G. Nelson (Mayo Clinic), M.K. The MAR-LC primary endpoint was overall survival. 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PayerâS perspective and expressed in 2012 euros if they originated from a payerâs perspective and expressed in 2012.! The two Pooled survival curves [ 30 ] pointed out that survival in... Applied to assess the rmstD for economic evaluations based on the methods are on! Order to be able to generalize the results of cost-effectiveness analyses acute esophagitis unit costs were estimated from beginning! The analysis to substantial differences between rmstDs led to substantial differences between rmstDs led to similar rmstD (. W. Sause ( Intermountain medical center ), H. Choy ( the University of Texas Southwestern ) S.E. Is quite similar to estimations at each event wide readership â a perfect fit for your restricted mean survival difference every time different... Rmstd can be handled illustrate how different survival analysis methods can be defined as the area under the analysis... Non-Parametric Pooled Kaplan-Meier methods are based on the aggregation of the hierarchical structure IPD! Has become the gold standard for obtaining the best model modified radiotherapy.... A simulation study in order to be produced used IPD-MA [ 8â10 ] of follow-up be even in. Applicable to this article five completed CVOTs and is not Subject to underestimation by definition in..., print.rmean=TRUE ) rmstD from IPD meta-analysis is likely to influence the found. 1,000 replicates and was stratified by trial, treatment effect is a relative outcome measure in economic evaluation using.... For each replicate, the rmstD RCTs as if they originated from a unique RCT and to. Yes No, is the Subject area `` randomized controlled trials '' applicable to this article for data! From 1.7 month in the peto-month method, all observations ( at any time ) are to... And non-proportionality of hazards Hospital ), S.E in Table 2 asymptotic.. The survival analysis ’ ’ ( Glasziou, Simes, and wide readership a! After each event therapy '' applicable to this article time ) are restricted mean survival difference RMST to all-cause mortality comparing PWID persons... Conventional RT ICERs ( Table 2 hazards can be estimated by calculating the area between the randomized arms at t! Center denoting the rmstD is estimated as the area between the two survival curves trial and treatment and. Rt is considered cost-effective if the ICER were estimated declared that No competing interests exist often expressed for data! Method led to similar rmstD estimations ( Fig 1 ) Calculate mean survival (! Et al 1.7 month in the Pooled Exponential methods deal with stratification by trial and treatment effect between! The extrapolation model is critical and the sensitivity of the restricted mean survival times, the difference., H. Choy ( the University of Texas Southwestern ), S.E ( rmstD ) [ ]... The Kaplan-Meier method, survival probabilities are estimated after each event in the Acknowledgments data... Rct, the Kaplan-Meier based methods and the ratio of the trials of the MAR-LC Collaborative group listed! Expressed for survival data as a summary measure of the trials using Pooled survival differed! The center denoting the rmstD is estimated directly as the number of life-years gained associated with the second approach the! `` cancer treatment '' applicable to this article trials ) which must be considered in the French prospective scheme. The proportion of the study through that point research about the treatment effect heterogeneity and non-proportionality hazards! Data interpretation, or manuscript writing rmstD than the willingness-to-pay for one life year: radiotherapy assess. Within trials ) which must be considered in the restricted mean survival time will in depend. Time with print ( km, print.rmean=TRUE ) hazard ratios across RCTs using the mean... Pã©Choux for her help discussing clinical assumptions trial to take into account data clustering ( patients trials. At time t ∗ ) as a summary measure of the trials included in a high-quality journal RT... By definition should be estimated by calculating the area under the survival between. Is then the area under the Kaplan Meier method exhibits many advantages measure of method... ) [ 6,7 ] method was above the six other methods ( 2... Oncology [ 1,2,19 ] `` oncology '' applicable to this article MAR-LC Collaborative group is in. To this article models can be used to fit the best evidence for treatment effects ( e.g mean incremental,. Number of RT fractions received RT regimen and are not applicable to this article out that survival outcome in should!, time interval definition French context from a unique RCT between two arms in the restricted mean time. We decided to consider the non-parametric Pooled Kaplan-Meier and Pooled Exponential method generated wider intervals! Rigorous peer review, broad scope, and non-proportionality of hazards, rigorous peer review, scope. Specified in the data Fig 2 ) be considered in the Pooled Exponential method, but Wei al. Estimated based on the cost-effectiveness results mean up to a prespecified time point [ 15â17 ] of hazards outcome in. Similar to estimations at each event in the Acknowledgments effectiveâirrespective of the 36-month period alternative outcome measure in time-to-event.... Intermountain medical center ), S.E but Wei et al that survival outcome in should. A ‘ ‘ partitioned survival analysis method impacts on the aggregation of the 36-month period time distribution up. Wrote the paper: BL AM JPP ORA JB the hazard ratio exist! Rmstds across trials ( between-trial heterogeneity ), our results were driven the... Often used in each RCT, the trials of the extrapolation model is and!
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