Difference In Restricted Mean Survival Time Research Articles

855PD - Docetaxel for hormone-naïve prostate cancer (PCa): Results from long-term follow-up of non-metastatic (M0) patients in the STAMPEDE randomised trial

855PD - Docetaxel for hormone-naïve prostate cancer (PCa): Results from long-term follow-up of non-metastatic (M0) patients in the STAMPEDE randomised trial

LBA56 - Primary efficacy analysis results from the SORCE trial (RE05): Adjuvant sorafenib for renal cell carcinoma at intermediate or high risk of relapse: An international, randomised double-blind phase III trial led by the MRC CTU at UCL

LBA56 - Primary efficacy analysis results from the SORCE trial (RE05): Adjuvant sorafenib for renal cell carcinoma at intermediate or high risk of relapse: An international, randomised double-blind phase III trial led by the MRC CTU at UCL

Refining the Association Between Body Mass Index and Atrial Fibrillation: G-Formula and Restricted Mean Survival Times.

BackgroundPrevious studies assessing the association between body mass index (BMI) and atrial fibrillation (AF) did not account for time‐varying covariates, which may be affected by previous BMI. We illustrate how the g‐formula can account for time‐varying confounding.Methods and ResultsWe included 4392 participants from the Framingham Heart Study who were AF free at ages 45 to 55 years, and followed them for up to 20 years. We estimated hazard ratios (HRs) comparing time‐varying nonobese versus obese with Cox models. We used the g‐formula to compare nonobese versus obese and 10% annual decrease in BMI (until normal weight is reached) versus natural course. We estimated HRs and differences in restricted mean survival times, the mean difference in time alive and AF free. We adjusted for sex, age, and time‐varying risk factors. Cox models indicated that nonobese participants had a decreased rate of AF versus obese participants (HR, 0.83; 95% CI, 0.72–0.97). G‐formula analyses comparing everyone had they been nonobese versus obese yielded stronger associations (HR, 0.73; 95% CI, 0.58–0.91). The restricted mean survival time was 19.22 years had everyone been nonobese and 19.03 years had everyone been obese (difference, 2.25 months; 95% CI, −0.66 to 5.16). When assessing a 10% annual decrease in BMI, the association was weaker (HR 0.96; 95% CI, 0.86–1.08).ConclusionsDecreased BMI was associated with a lower rate of AF after accounting for time‐varying covariates that depend on previous exposure using the g‐formula, which Cox models cannot accommodate. Absolute measures like the restricted mean survival time difference offer context to relative measures of association.

Chronological Trends in Progression-Free, Overall, and Post-Progression Survival in First-Line Therapy for Advanced NSCLC

BackgroundThere is a debate about the merits of progression-free survival (PFS) versus overall survival (OS) as primary endpoints in NSCLC. It has been postulated that post-progression therapy may influence OS in both arms. To investigate this issue, we analyzed chronological trends in PFS and OS in advanced NSCLC using restricted mean survival times (RMSTs). MethodsWe digitized survival curves from first-line phase III trials published between 1998 and 2015 in 13 leading journals to compute RMSTs for PFS and OS at three truncation landmarks (5, 12, and 18 months). ResultsAmong the 161 trials identified, RMSTs could be computed for both endpoints in 102, 97, and 82 trials for the 5-, 12-, and 18-month truncation landmarks, respectively. Post-progression survival in the control arm, quantified as mean OS minus mean PFS truncated at 18 months, was on average 3.3 months between 1998 and 2003, 4.4 months between 2004 and 2009, and 5.4 months between 2010 and 2015. This increase was due to increasing RMST for OS over time, with no increase in RMST for PFS. The average within-trial difference in RMSTs between experimental and control arm was close to 0 for OS and less than 1 month for PFS. ConclusionsThere is a progressive increase in post-progression survival in NSCLC trials, likely from salvage therapy. These results question both PFS and OS as sensitive endpoints in first-line trials, but suggest that the outlook for patients is improving regardless of within-trial gains.

Adjusted restricted mean survival times in observational studies.

In observational studies with censored data, exposure-outcome associations are commonly measured with adjusted hazard ratios from multivariable Cox proportional hazards models. 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. Several regression-based methods exist to estimate an adjusted difference in RMSTs, but they digress from the model-free method of taking the area under the survival function. We derive the adjusted RMST by integrating an adjusted Kaplan-Meier estimator with inverse probability weighting (IPW). The adjusted difference in RMSTs is the area between the two IPW-adjusted survival functions. In a Monte Carlo-type simulation study, we demonstrate that the proposed estimator performs as well as two regression-based approaches: the ANCOVA-type method of Tian et al and the pseudo-observation method of Andersen et al. We illustrate the methods by reexamining the association between total cholesterol and the 10-year risk of coronary heart disease in the Framingham Heart Study.

Do the ASCO Value Framework and the ESMO Magnitude of Clinical Benefit Scale measure Absolute or Relative clinical benefit?

e18378 Background: It is unclear whether the clinical benefit scores from the ASCO or ESMO valuation frameworks were intended to measure absolute or relative survival benefit. To empirically examine the measurement characteristics of these frameworks, we compared their survival efficacy components (ASCO-CBS and ESMO-PMCBGs) with established measures of absolute (median survival difference and restricted mean survival time (RMST) difference) and relative (HRs) survival benefit. Methods: FDA’s Hematology/Oncology Approvals and Safety Notifications pages were reviewed to identify phase III RCTs cited in oncology drug approvals between January 2006 and December 2017. In our primary analysis, ASCO-CBS and ESMO-PMCBGs were calculated for the included trials using the framework defined endpoint (Fr). Sensitivity analyses were conducted by calculating the scores using 1) Fr + tail-of-curve bonus points (ASCO) or long-term plateau adjustments (ESMO) (defined as Fr + TOC), 2) overall survival (OS) data only, and 3) progression-free survival (PFS) data only. For both primary and sensitivity analyses, Spearman correlation coefficients were calculated to examine the relationships between 1) ASCO-CBS/ESMO-PMCBGs and RMST difference, 2) ASCO-CBS/ESMO-PMCBGs and median survival difference, and 3) ASCO-CBS/ESMO-PMCBGs and HRs. Results: 107 RCTs were included. Compared to measures of absolute survival, ESMO-PMCBG showed low-moderate correlations with RMST difference and moderate-high correlations with median survival difference (Rho = 0.44 and 0.64, respectively). ASCO-CBS showed low-moderate correlations with both measures of absolute benefit (Rho = 0.43 and 0.44 for RMST difference and median survival, respectively). Compared to a relative measure of survival (HRs), ESMO-PMCBG revealed a moderate correlation (Rho = 0.47) while ASCO-CBS showed a higher correlation (Rho = 0.76). Conclusions: Both frameworks do not perform solely as absolute measures of survival benefit. We recommend that the frameworks consider incorporating a direct measure of absolute clinical benefit, such as RMST difference, into the survival efficacy components of their algorithms.

Pembrolizumab alone or with chemotherapy for PD-L1 positive NSCLC: A network meta-analysis of randomized trials.

9087 Background: Pembrolizumab (P) has replaced chemotherapy (C) as first-line treatment for advanced non-small cell lung cancer (NSCLC) with tumor PD-L1 expression > / = 50%. Among PD-L1 unselected patients, P+C is superior to C alone. This network meta-analysis compared P alone with P+C in patients with > / = 50% PD-L1 positive NSCLC. Methods: An indirect network was constructed to compare P and P+C through the control arms of the Keynote 024, 189 and 407 (PD-L1 > / = 50% subgroup) trials. Baseline characteristics and chemotherapy outcomes were examined for heterogeneity. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and toxicities including immune-related adverse events (irAE) were extracted from trial results. Toxicity results were unavailable for the PD-L1 > / = 50% subgroups of KN 189 & 407, so overall study results were used. Survival outcomes are expressed as hazard ratios (HRs) or restricted mean survival time (RMST) ratios, and toxicity and ORR as risk difference (RD). Results: 507 patients were included: 154 on P, 430 on C and 483 on P+C. Patient characteristics across trials were similar in age, sex, performance status and smoking history. All trials had similar chemotherapy outcomes (PFS 6, 4.9, 4.8 mos) suggesting similar populations. Network meta-analysis showed no difference between P+C and C alone in OS (HR 0.85, 95%CI 0.45-1.59, p = 0.60) or PFS (HR 0.73, 95%CI 0.48-1.1, p = 0.13), but P+C was associated with higher ORR (+16.9%, 95%CI 0.7-33%, p = 0.04). RMST analysis suggested fewer early PFS events with P+C (0-6 mo RMST ratio 1.25, RMST difference 1.02 mo, p = 0.002), with the difference disappearing at 1 year (0-12 mo RMST ratio 1.16, p = 0.07). No difference in RMST for OS was found. Overall toxicities, hematologic and grade 3-5 toxicities were higher with P+C compared with P alone (table). Conclusions: Among patients with > / = 50% PD-L1 positive NSCLC, P+C did not improve OS or PFS compared with P alone, but was associated with higher ORR. RMST analysis suggested fewer early progression events using P+C. [Table: see text]

The Use of the Restricted Mean Survival Time as a Treatment Measure in HIV/AIDS Clinical Trial: Reanalysis of the ACTG A5257 Trial.

The restricted mean survival time (RMST) measures have not been used as primary measure of efficacy in HIV/AIDS clinical trials. In this work, we aim to compare analysis based on the difference in RMST (Δ-RMST) measure and 2 other treatment-effect measures in a recent HIV equivalence trial, and to investigate the performance and characteristics of Δ-RMST-based analysis in a simulation study. We reanalyzed a recent HIV equivalence trial (ACTG A5257 trial) with hazard ratio and Δ-RMST, and then compared the results with the original analysis based on risk difference estimated by Kaplan-Meier curves (RDKM). In a simulation study, we investigated the performance and operating characteristics of Δ-RMST-based analysis in the setting of non-proportional hazards (PH) ratio. In the ACTG A5257 trial, analyses based on Δ-RMST globally led to similar conclusions as the published finding based on RDKM. By contrast, analyses based on hazard ratio provided some discordant equivalence conclusions compared both with the initial analyses based on RDKM and the Δ-RMST. Results of simulation study indicate that the violation of the PH assumption has an impact on Δ-RMST-based analysis regarding the probability of declaring equivalence. Although the RMST-based analysis is an alternative measure of efficacy in HIV/AIDS, clinical trials such an analysis can be strongly impacted by departures from the PH assumption.

Individual patient data network meta-analysis using either restricted mean survival time difference or hazard ratios: is there a difference? A case study on locoregionally advanced nasopharyngeal carcinomas

BackgroundThis study aimed at applying the restricted mean survival time difference (rmstD) as an absolute outcome measure in a network meta-analysis and comparing the results with those obtained using hazard ratios (HR) from the individual patient data (IPD) network meta-analysis (NMA) on the role of chemotherapy for nasopharyngeal carcinoma (NPC) recently published by the MAC-NPC collaborative group (Meta-Analysis of Chemotherapy [CT] in NPC).Patients and methodsTwenty trials (5144 patients) comparing radiotherapy (RT) with or without CT in non-metastatic NPC were included. Treatments were grouped in seven categories: RT alone (RT), induction CT followed by RT (IC-RT), RT followed by adjuvant CT (RT-AC), IC followed by RT followed by AC (IC-RT-AC), concomitant chemoradiotherapy (CRT), IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival and locoregional control. The rmstD was estimated at t* = 10 years in each trial. Random-effect frequentist NMA models were applied. P score was used to rank treatments. Heterogeneity and inconsistency were evaluated.ResultsThe three treatments that had the highest effect on OS with rmstD were CRT-AC, IC-CRT, and CRT (respective P scores of 92%, 72%, and 64%) compared to CRT-AC, CRT, and IC-CRT when using HR (respective P scores of 96%, 71%, and 63%). Of the 32 HR and rmstD analyzed, 5 had a different interpretation, 3 with a direction change (different direction of treatment effect) and 2 with a change in significance (same direction but a change in statistical significance). Results for secondary endpoints were overall in agreement.ConclusionThe use of either HR or rmstD impacts the results of NMA. Given the sensitivity of HR to non-proportional hazards, this finding could have implications in terms of meta-analysis methodology.

Abstract P1-13-09: Long-term follow-up of two randomized controlled trials (N-SAS-BC01 trial and CUBC trial) comparing oral tegafur-uracil (UFT) versus classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant therapy in early breast cancer

Abstract Background: Two randomized controlled trials comparing the efficacy of oral tegafur-uracil (UFT) (2 years) with that of classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (6 courses) were conducted in patients with resected early breast cancer. UFT is an oral fluoropyrimidine that combines tegafur, a prodrug of 5-fluorouracil, with uracil in a 1:4 molar ratio. One study was the N-SAS-BC01 trial (Watanabe et al, J Clin Oncol 2009), which was conducted in patients with high-risk node-negative breast cancer (n=733). The other was the CUBC trial (Park et al, Br J Cancer 2009), which was performed in patients with node-positive breast cancer (n=377). We reported the pooled analysis of these two randomized control trials using individual patient data (Ohashi et al, Breast Cancer Res Treat 2010). This pooled analysis showed that UFT was non-inferior to CMF in terms of inhibiting recurrence of estrogen receptor (ER)-positive early breast cancer. In addition, an exploratory subgroup analysis showed that UFT may be more effective in ER-positive patients who were 50 years or older. The present study was conducted to investigate the long-term efficacy of UFT or CMF in patients with early breast cancer. Methods: Long-term follow-up data for disease recurrence and survival were collected. Hazard ratios (HR) were determined using the Cox model stratified by study and adjusted for clinical characteristics, namely age, tumor size, nodal status, histological type, ER, and progesterone receptor (PgR). Survival curves were estimated by the Kaplan-Meier method. Hochberg multiplicity adjustment was applied in the previous pooled analysis, and non-inferiority of UFT versus CMF was shown in terms of relapse-free survival (RFS) in the ER-positive patient group. We investigated the non-inferiority of UFT in the same patient group with updated data. Restricted mean survival time (RMST) was calculated to consider the relative efficacy of UFT. This study is registered with JapicCTI-163321. Results: In total, 1,057 patients were analyzed (CMF, n=528; UFT n=529). The median follow-up time was 11.1 years (12.1 years in the N-SAS-BC 01 trial and 8.3 years in the CUBC trial). Table 1 shows the 10-year RFS and overall survival (OS) in all patients and ER-positive patients. The difference in RMST between arms at 20 years in terms of RFS was -2.7 months in all patients and 3.4 months in ER-positive patients. Table 2 shows the HR for RFS according to ER status and age. UFT (%)CMF (%)UFT to CMF; HR (95% CI)10-year RFSall patients74.477.11.02 (0.81–1.30)ER-positive patients75.075.10.91 (0.66–1.27)10-year OSall patients86.886.90.98 (0.72–1.34)ER-positive patients89.987.90.86 (0.54–1.37) Age <50 yearsAge ≥50 yearsER negative1.76 (0.95–3.26)0.93 (0.58–1.51)ER positive1.29 (0.74–2.23)0.76 (0.50–1.16) Conclusion: This study shows that UFT was shown to be non-inferior to CMF in terms of RFS in ER-positive early breast cancer. This result is similar to that of the previous pooled analysis. Sponsor: Taiho Pharmaceutical Co., LTD Citation Format: Yonemori K, Ohsumi S, Takao S, Tokuda Y, Ito Y, Nakagami K, Takahashi M, Yoshidome K, Nakayama T, Yamaguchi Y, Ohashi Y, Inaji H, Watanabe T. Long-term follow-up of two randomized controlled trials (N-SAS-BC01 trial and CUBC trial) comparing oral tegafur-uracil (UFT) versus classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant therapy in early breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-13-09.

Endovascular Versus Open Repair of Intact Descending Thoracic Aortic Aneurysms

BackgroundFor the management of descending thoracic aortic aneurysms, recent evidence has suggested that outcomes of open surgical repair may surpass thoracic endovascular aortic repair (TEVAR) in as early as 2 years. ObjectivesThe purpose of this study was to evaluate the comparative effectiveness of TEVAR and open surgical repair in the treatment of intact descending thoracic aortic aneurysms. MethodsUsing the Medicare database, a retrospective study using regression discontinuity design and propensity score matching was performed on patients with intact descending thoracic aortic aneurysms who underwent TEVAR or open surgical repair between 1999 and 2010 with follow-up through 2014. Survival was assessed with restricted mean survival time. Perioperative mortality was assessed with logistic regression. Reintervention was evaluated as a secondary outcome. ResultsMatching created comparable groups with 1,235 open surgical repair patients matched to 2,470 TEVAR patients. The odds of perioperative mortality were greater for open surgical repair: high-volume center, odds ratio (OR): 1.97 (95% confidence interval [CI]: 1.53 to 2.61); low-volume center, OR: 3.62 (95% CI: 2.88 to 4.51). The restricted mean survival time difference favored TEVAR at 9 years, −209.2 days (95% CI: −298.7 to −119.7 days; p < 0.001) for open surgical repair. Risk of reintervention was lower for open surgical repair, hazard ratio: 0.40 (95% CI: 0.34 to 0.60; p < 0.001). ConclusionsOpen surgical repair was associated with increased odds of early postoperative mortality but reduced late hazard of death. Despite the late advantage of open repair, mean survival was superior for TEVAR. TEVAR should be considered the first line for repair of intact descending thoracic aortic aneurysms in Medicare beneficiaries.

Effects of Sodium-glucose Cotransporter 2 Inhibitors on Amputation, Bone Fracture, and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus Using an Alternative Measure to the Hazard Ratio.

Empagliflozin and canagliflozin decreased the risk of major adverse cardiovascular events (MACE) compared with placebo in randomized clinical trials which were conducted to evaluate their cardiovascular risks. However, canagliflozin increased the risks of amputation and bone fracture, and the reasons for these observed differences remain unclear. The objective of this study was to evaluate the safety risks, specifically the risks of amputation and bone fracture, associated with sodium-glucose cotransporter 2 (SGLT2) inhibitors by using the difference in restricted mean survival time (RMST), an alternative measure to the hazard ratio. This study included all the randomized clinical trials with cardiovascular events as a primary endpoint, comparing SGLT2 inhibitors with placebo in patients with type 2 diabetesmellitus, theresults of which have been published as of 11 September 2018: EMPA-REG OUTCOME (empagliflozin) and CANVAS Program (canagliflozin). We reevaluated these trials by estimating RMSTs based on the reconstructed individual patient data for each time-to-event outcome from publicly available information. The differences of RMSTs (SGLT2 inhibitors minus placebo: point estimate and 95% confidence interval) for lower-extremity amputations and low-trauma fracture were - 20days (- 30, - 10) and - 15days (- 30, 0), respectively, in CANVAS Program (2190days follow-up). That for lower-limb amputation was 1day (- 6, 8) in EMPA-REG OUTCOME (1440days follow-up). Regarding the MACE, both empagliflozin and canagliflozin statistically significantly decreased the risk compared with placebo. Canagliflozin was shown to increase the risks of amputation and bone fracture compared with placebo when using the difference in RMST.

International Normalized Ratio and Mortality Risk in Acute Heart Failure and Nonvalvular Atrial Fibrillation Patients Receiving Vitamin K Antagonists.

Heart failure patients with nonvalvular atrial fibrillation (NVAF) on treatment with vitamin K antagonists (VKA) often have suboptimal international normalized ratio (INR) values. Our aim was to evaluate the association between INR values at admission due to acute heart failure and mortality risk during follow-up. In this observational study, we retrospectively assessed INR on admission in 1137 consecutive patients with acute heart failure and NVAF who were receiving VKA treatment. INR was categorized into optimal values (INR = 2-3, n = 210), subtherapeutic (INR < 2, n = 660), and supratherapeutic (INR > 3, n = 267). Because INR did not meet the proportional hazards assumption for mortality, restricted mean survival time differences were used to evaluate the association among INR categories and the risk of all-cause mortality. During a median [interquartile range] follow-up of 2.15 years [0.71-4.29], 495 (43.5%) patients died. On multivariable analysis, both patients with subtherapeutic and supratherapeutic INR showed higher risks of all-cause mortality, as evidenced by their restricted mean survival time differences at 5 years' follow-up: -0.50; 95%CI, -0.77 to -0.23 years; P < .001; and -0.40; 95%CI, -0.70 to -0.11 years; P = .007, respectively, compared with INR 2-3. In acute heart failure patients on treatment with VKA for NVAF, INR values out of normal range at admission were independently associated with a higher long-term mortality risk.

Abstract 590: Marital status and survival among breast cancer patients

Abstract Background: Recent evidence suggests improved survival for married breast cancer patients compared with unmarried patients, but unclear is whether this survival benefit extends to socioeconomically disadvantaged women. We aimed to assess the association between marital status and breast cancer survival among socioeconomically disadvantaged breast cancer patients and breast cancer patients from the general population. Methods: We used data from the John Peter Smith (JPS) Oncology Registry, which comprises cancer patients in Tarrant County, TX treated at a safety-net institution, and the Texas Cancer Registry (TCR), a statewide population-based registry. Our eligible population included females aged 18 – 64 years diagnosed with primary breast cancer between January 2008 and June 2013 with follow-up through 2016. We categorized marital status into three groups: single, married, or separated/divorced/widowed. We estimated the 36-month restricted mean survival time, which allows survival comparisons within a specified period. Results: Our study populations comprised 614 JPS and 32,985 TCR patients. The age distribution at diagnosis was similar for both groups (JPS: median=51 years; TCR: median=52 years). JPS patients were more often non-White (JPS=62%; TCR=42%) and uninsured (JPS=56%; TCR=9.6%). A higher frequency of TCR patients were married (TCR=65%; JPS=39%). Survival was shorter for JPS patients (JPS=33.1 months; TCR =34.8 months) after 36-months (Table 1). Married women had longer survival than unmarried women in both populations. Conclusion: Our results suggest similar magnitudes of improved survival for married women with breast cancer compared with unmarried women in both populations, but socioeconomically disadvantaged patients have consistently lower survival estimates across marital subgroups compared with patients from the general population. Our findings warrant further studies that explore mechanisms of how marital status influences breast cancer survival in different populations. Table 1. Restricted mean survival time (RMST) after breast cancer diagnosis based on marital statusDisadvantaged Cancer PatientsaCancer Patients from General PopulationbRMSTc (months)Difference in RMST (95% CLd) (months)RMST (months)Difference in RMST (95% CL) (months)Separated/Divorced/Widowed32.2-0.89 (-2.8, 1.0)34.10.01 (-0.23, 0.25)Married33.80.56 (-0.96, 2.1)35.10.54 (0.36, 0.71)Single33.00 (Reference)34.10 (Reference)aCancer patients from JPS Oncology RegistrybCancer patients in the Texas Cancer RegistrycBased on 36-month restricted mean survivaldCL: Confidence limits Citation Format: Yan Lu, Bradford E. Jackson, Bassam Ghabach, Rohit P. Ojha. Marital status and survival among breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 590.

Razón internacional normalizada y mortalidad de los pacientes con insuficiencia cardiaca y fibrilación auricular tratados con antagonistas de la vitamina K

Introduction and objectivesHeart failure patients with nonvalvular atrial fibrillation (NVAF) on treatment with vitamin K antagonists (VKA) often have suboptimal international normalized ratio (INR) values. Our aim was to evaluate the association between INR values at admission due to acute heart failure and mortality risk during follow-up. MethodsIn this observational study, we retrospectively assessed INR on admission in 1137 consecutive patients with acute heart failure and NVAF who were receiving VKA treatment. INR was categorized into optimal values (INR = 2-3, n = 210), subtherapeutic (INR < 2, n = 660), and supratherapeutic (INR > 3, n = 267). Because INR did not meet the proportional hazards assumption for mortality, restricted mean survival time differences were used to evaluate the association among INR categories and the risk of all-cause mortality. ResultsDuring a median [interquartile range] follow-up of 2.15 years [0.71-4.29], 495 (43.5%) patients died. On multivariable analysis, both patients with subtherapeutic and supratherapeutic INR showed higher risks of all-cause mortality, as evidenced by their restricted mean survival time differences at 5 years’ follow-up: –0.50; 95%CI, –0.77 to –0.23 years; P < .001; and –0.40; 95%CI, –0.70 to –0.11 years; P = .007, respectively, compared with INR 2-3. ConclusionsIn acute heart failure patients on treatment with VKA for NVAF, INR values out of normal range at admission were independently associated with a higher long-term mortality risk.

Surgery for pulmonary metastases from colorectal cancer: survival and prognostic factors

This study aimed to describe overall survival following pulmonary metastasectomy for colorectal cancer (CRC) in Sweden, and to assess the discrimination of a recently proposed risk prediction model. Individual-level data of 756 patients who underwent resection of pulmonary metastases from CRC between 2009 and 2015 were obtained from ThoR, a Swedish national quality register for thoracic surgery. We classified patients into three risk categories according to the number of preoperative risk factors [age, disease-free interval (DFI), presence of extrathoracic lesions, number of pulmonary metastases] established in a prior study. We estimated the hazard ratios (HRs) and 95% confidence interval (CI) by Cox regression and the restricted mean survival time difference as group contrast measures. During a median follow-up time of 2.9 years, 35% (268/756) patients died. At 5 years, overall survival was 56% (95% CI: 51-60%). In a Cox regression model with risk category as the only independent variable, the HR for all-cause mortality was 1.94 (95% CI: 1.38-2.72, P<0.001) and 4.35 (95% CI: 2.49-7.62, P<0.001) in the moderate- (n=558) and high-risk categories (n=32), respectively, versus the low-risk category (n=166). At 5 years, the differences in restricted mean survival time were 6 months (P<0.001) and 1.5 years (P<0.001) in the moderate- and high-risk categories, respectively, versus the low-risk category. Five-year survival after surgery for pulmonary metastases from CRC in Sweden was similar or higher compared with contemporary reports. A prognostic model, initially developed in Japanese patients, had excellent discrimination in an external validation cohort of Swedish patients.

Adjuvant gemcitabine plus docetaxel followed by doxorubicin versus observation for uterus-limited, high-grade leiomyosarcoma: A phase III GOG study.

5505 Background: We conducted a phase III trial to determine whether adjuvant chemotherapy with gemcitabine-docetaxel followed by doxorubicin improves survival compared to observation in women with resected, uterus-confined, high grade LMS. Methods: Women with uterus-confined high grade LMS, confirmed disease-free by post-resection imaging, were randomly assigned to treatment with gemcitabine-docetaxel x 4 cycles, followed by doxorubicin x 4 cycles (CHEMO) or to observation (OBS). All were followed by CT or MR imaging every 4 mos for 3 yrs, then every 6 mos for 2 yrs for recurrence. The primary endpoint was overall survival. Results: The study was opened with international collaboration. 38 of the target accrual of 216 patients (pts) were enrolled, after which the study was closed for National Cancer Institute-defined accrual futility. 20 pts were assigned to CHEMO and 18 to OBS. 3 pts assigned to CHEMO never received treatment. Among the 17 pts treated with at least one cycle of CHEMO grade 3 or 4 toxicities were observed in 47%; among 18 pts assigned to OBS, 1 had grade 3 hypertension. There were 6 deaths, (5 - CHEMO, 1-OBS), all due to disease. Over 48 mos, the restricted mean survival time (RMST) for OS in the CHEMO arm was estimated to be 34.3 mos (95% CI: 25.3 mos – 43.3 mos); RMST for OS in the OBS arm was estimated to be 46.4 mos (95% CI: 43.6 mos – 49.1 mos). There were 8 recurrences in each arm. Over 24 mos, the RMST for RFS in the CHEMO arm was estimated to be 18.1 mos (95% CI: 14.2 mos – 22.0 mos) and the RMST for RFS in the OBS arm was estimated to be 14.6 mos (95% CI: 10.3 mos – 19.0 mos). The difference in RMST comparing the CHEMO arm to the OBS arm was estimated as 3.4 mos (95% CI: -2.4 mos – 9.3 mos). Neither survival outcome comparison is considered statistically robust due to the small sample size and low number of events. Conclusions: Despite international collaboration to answer the critical question of the role of adjuvant chemotherapy in early-stage uterine LMS, this study was closed for accrual futility. While sample size and number of events preclude robust statistical comparison, observed OS and RFS data do not suggest superior outcomes for patients treated with adjuvant chemotherapy. Clinical trial information: NCT01533207.

Power and sample-size analysis for the Royston–Parmar combined test in clinical trials with a time-to-event outcome

Randomized controlled trials with a time-to-event outcome are usually designed and analyzed assuming proportional hazards (PH) of the treatment effect. The sample-size calculation is based on a log-rank test or the nearly identical Cox test, henceforth called the Cox/log-rank test. Nonproportional hazards (non-PH) has become more common in trials and is recognized as a potential threat to interpreting the trial treatment effect and the power of the log-rank test—hence to the success of the trial. To address the issue, in 2016, Royston and Parmar ( BMC Medical Research Methodology 16: 16) proposed a “combined test” of the global null hypothesis of identical survival curves in each trial arm. The Cox/log-rank test is combined with a new test derived from the maximal standardized difference in restricted mean survival time (RMST) between the trial arms. The test statistic is based on evaluations of the between-arm difference in RMST over several preselected time points. The combined test involves the minimum p-value across the Cox/log-rank and RMST-based tests, appropriately standardized to have the correct distribution under the global null hypothesis. In this article, I introduce a new command, power_ct, that uses simulation to implement power and sample-size calculations for the combined test. power_ct supports designs with PH or non-PH of the treatment effect. I provide examples in which the power of the combined test is compared with that of the Cox/log-rank test under PH and non-PH scenarios. I conclude by offering guidance for sample-size calculations in time-to-event trials to allow for possible non-PH.

Assessment of Cardiovascular Risk With Glucagon-Like Peptide 1 Receptor Agonists in Patients With Type 2 Diabetes Using an Alternative Measure to the Hazard Ratio.

Randomized clinical trials with the aim of evaluating the cardiovascular risks associated with glucagon-like peptide 1 (GLP-1) receptor agonists, lixisenatide, liraglutide, semaglutide, and exenatide, have been conducted. They showed different results among the agents, but the reason has not been explained. To evaluate the cardiovascular risks associated with GLP-1 receptor agonists by using an alternative measure to the hazard ratio. We used the difference in restricted mean survival time (RMST) as a measure of cardiovascular risks. Four randomized clinical trials with cardiovascular events as a primary endpoint, ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), and EXSCEL (exenatide), were reevaluated by estimating the RMSTs for each of the agents and placebo based on the reconstructed individual patient data for each time-to-event outcome from publicly available information. The differences of RMSTs (GLP-1 receptor agonist minus placebo: point estimate and 95% CI) for primary composite endpoint of cardiovascular events were 0 days [-14, 14] in ELIXA (1080 days follow-up), 20 days [6, 34] in LEADER (1620 days follow-up), 8 days [1, 15] in SUSTAIN-6 (672 days follow-up), and 11 days [-3, 26] in EXSCEL (1825 days follow-up). As for the risk of other cardiovascular outcomes, there were no substantial differences between GLP-1 receptor agonists and placebo. Liraglutide and semaglutide decrease the risk of major adverse cardiovascular events compared with placebo when using the difference in RMST. The previously reported result that GLP-1 receptor agonists do not increase the risk of cardiovascular outcomes compared with placebo is also confirmed.

Efficacy and Safety of Oseltamivir in Children: Systematic Review and Individual Patient Data Meta-analysis of Randomized Controlled Trials.

Oseltamivir has been used to treat children with influenza for nearly 2 decades, with treatment currently approved for infants aged ≥2 weeks. However, efficacy and safety remain controversial. Newer randomized, placebo-controlled trials (RCTs), not included in previous meta-analyses, can add to the evidence base. We conducted a systematic review to identify RCTs of oseltamivir therapy in children. We obtained individual patient data and examined protocol-defined outcomes. We then conducted a 2-stage, random-effects meta-analysis to determine the efficacy of treatment in reducing the duration of illness, estimated using differences in restricted mean survival time (RMST) by treatment group. We also examined complications and safety. We identified 5 trials that included 2561 patients in the intention-to-treat (ITT) and 1598 in the intention-to-treat infected (ITTI) populations. Overall, oseltamivir treatment significantly reduced the duration of illness in the ITTI population (RMST difference, -17.6 hours; 95% confidence interval [CI], -34.7 to -0.62 hours). In trials that enrolled patients without asthma, the difference was larger (-29.9 hours; 95% CI, -53.9 to -5.8 hours). Risk of otitis media was 34% lower in the ITTI population. Vomiting was the only adverse event with a significantly higher risk in the treatment group. Despite substantial heterogeneity in pediatric trials, we found that treatment with oseltamivir significantly reduced the duration of illness in those with influenza and lowered the risk of developing otitis media. Alternative endpoints may be required to evaluate the efficacy of oseltamivir in pediatric patients with asthma.