Difference In Restricted Mean Survival Time Research Articles

Conversion of non-inferiority margin from hazard ratio to restricted mean survival time difference using data from multiple historical trials.

The restricted mean survival time measure has gained a lot of interests for designing and analyzing oncology trials with time-to-event endpoints due to its intuitive clinical interpretation and potentially high statistical power. In the non-inferiority trial literature, restricted mean survival time has been used as an alternative measure for reanalyzing a completed trial, which was originally designed and analyzed based on traditional proportional hazard model. However, the reanalysis procedure requires a conversion from the non-inferiority margin measured in hazard ratio to a non-inferiority margin measured by restricted mean survival time difference. An existing conversion method assumes a Weibull distribution for the population survival time of the historical active control group under the proportional hazard assumption using data from a single trial. In this article, we develop a methodology for non-inferiority margin conversion when data from multiple historical active control studies are available, and introduce a Kaplan-Meier estimator-based method for the non-inferiority margin conversion to relax the parametric assumption. We report extensive simulation studies to examine the performances of proposed methods under the Weibull data generative models and a piecewise-exponential data generative model that mimic the tumor recurrence and survival characteristics of advanced colon cancer. This work is motivated to achieve non-inferiority margin conversion, using historical patient-level data from a large colon cancer clinical database, to reanalyze an internationally collaborated non-inferiority study that evaluates 6-month versus 3-month duration of adjuvant chemotherapy in stage III colon cancer patients.

Resident-Driven Dysphagia Screening Protocol for Expedited Antithrombotic Delivery in Acute Ischemic Stroke.

We implemented a multi-disciplinary process improvement intervention at our Comprehensive Stroke Center with speech/language pathologists to expedite oral medication delivery in stroke patients. Following a failed nursing dysphagia screen, trained neurology physicians screened dysphagia further to approve use of oral medications. We analyzed the safety and efficacy of this intervention. We analyzed retrospectively collected data for hospital course, timing of first screen, first oral medication use, and complications (e.g., aspiration pneumonia) in consecutive ischemic stroke patients (9/2019-07/2021). Patients were included if they passed a dysphagia assessment by physicians (Ph), nurses (RN), or speech/language pathologists (SLP). Arrival-to-dysphagia screen and arrival-to-antithrombotic were assessed using restricted mean survival time (RMST). Of the 789 included patients, 673 were passed by RN, 104 by SLP, and 12 by Ph. Compared to patients passed by SLP, those passed by Ph were younger and had less severe deficits (P < .01 for both). Patients were screened more quickly by Ph than RN or SLP (median 38 vs 182 vs 1330-min post-arrival, P = .0001; 299-min RMST difference vs RN [95%CI 22-575, P = .03]; 470-min RMST difference vs SLP [95%CI 175-765, P = .002]). This translated to faster oral antithrombotic use for Ph-passed patients (138-min RMST difference vs RN [95%CI 59-216]; 332-min RMST difference vs SLP [95%CI 253-411]). No patients passed by Ph experienced aspiration pneumonia (0%). We safely conducted a physician-driven dysphagia screening paradigm which led to faster oral antithrombotic delivery without signal of patient harm. Physician availability to complete dysphagia screens in acute stroke patients was a limitation.

Life-Years Lost After Newly Diagnosed Atrial Fibrillation in Patients with Heart Failure

ObjectivePrior work estimated excess death rates associated with atrial fibrillation (AF) in heart failure (HF) with hazard ratios (HR). The aim was to estimate the life-years lost after newly diagnosed AF in HF patients.MethodsAmong patients diagnosed with HF in 2008–2018 in the nationwide Danish Heart Failure Registry, we compared patients with incident AF to referents matched on age, sex, and time since HF. We estimated the marginal hazard ratio (HR) for death and marginal difference in restricted mean survival times (RMST) between AF cases and referents at 10 years after AF diagnosis. We adjusted for sex, age at AF diagnosis, clinical and lifestyle risk factors, and medications.ResultsAmong 4463 AF cases and 17,792 referents (mean age 73.7 years, 29% women), the HR was 1.41 (95% CI 1.38; 1.44) but there was evidence of non-proportional hazards. The difference in RMST was −18.2 months (95% CI −16.8; −19.6) at 10 years after AF diagnosis. There were differences in life-years lost between patients diagnosed with AF >1 year and ≤1 year after HF (−25.7 months, 95% CI −23.7; −27.7 vs −10.4 months, 95% CI −8.2; −12.5, p < 0.001), women and men (−20.3 months, 95% CI −17.7; −21.9 vs −17.2 months, 95% CI −15.5; −19.0, p = 0.05), patients with low, medium, and high CHA2DS2-VASc (10.3 months, 95% CI −4.6; −16.1 vs −18.5 months, 95% CI −16.7; −20.4 vs 22.1, 95% CI −18.8; −22.3, p = 0.002).ConclusionHF patients with incident AF lost on average 1.5 life-years over 10 years after AF. Life-years lost were larger among patients diagnosed with AF >1 year after HF, women, and patients with higher CHA2DS2-VASc.

Combining TMEM Doorway Score and MenaCalc Score Improves the Prediction of Distant Recurrence Risk in HR+/HER2- Breast Cancer Patients.

Simple Summary90% of breast cancer mortality is caused by distant metastasis, a process that involves both dissemination of cancer cells to distant sites as well as their proliferation after arrival. However, prognostic assays currently used in the clinic are based on proliferation and do not measure tumor cell dissemination potential. We previously reported that the density of Tumor Microenvironment of Metastasis (TMEM) doorways (portals for cancer cell intravasation and dissemination) is a prognostic biomarker for the development of distant metastasis in hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) patients. We have shown further that MenaCalc, a mechanistically linked (but independent) biomarker for distant metastasis, is prognostic in some cohorts of triple-negative patients. Here, we develop and compare several digital pathology-based machine vision algorithms to investigate if a combined TMEM-MenaCalc biomarker could provide improved prognostic information over and above that of either biomarker alone.Purpose: to develop several digital pathology-based machine vision algorithms for combining TMEM and MenaCalc scores and determine if a combination of these biomarkers improves the ability to predict development of distant metastasis over and above that of either biomarker alone. Methods: This retrospective study included a subset of 130 patients (65 patients with no recurrence and 65 patients with a recurrence at 5 years) from the Calgary Tamoxifen cohort of breast cancer patients. Patients had confirmed invasive breast cancer and received adjuvant tamoxifen therapy. Of the 130 patients, 86 cases were suitable for analysis in this study. Sequential sections of formalin-fixed paraffin-embedded patient samples were stained for TMEM doorways (immunohistochemistry triple staining) and MenaCalc (immunofluorescence staining). Stained sections were imaged, aligned, and then scored for TMEM doorways and MenaCalc. Different ways of combining TMEM doorway and MenaCalc scores were evaluated and compared to identify the best performing combined marker by using the restricted mean survival time (RMST) difference method. Results: the best performing combined marker gave an RMST difference of 5.27 years (95% CI: 1.71–8.37), compared to 3.56 years (95% CI: 0.95–6.1) for the associated standalone TMEM doorway analysis and 2.94 years (95% CI: 0.25–5.87) for the associated standalone MenaCalc analysis. Conclusions: combining TMEM doorway and MenaCalc scores as a new biomarker improves prognostication over that observed with TMEM doorway or MenaCalc Score alone in this cohort of 86 patients.

Extracorporeal Life-support for Out-of-hospital Cardiac Arrest: A Nationwide Multicenter Study.

Despite potential clinical roles of extracorporeal life support (ECLS) for out-of-hospital cardiac arrest (OHCA) compared to that of conventional cardiopulmonary resuscitation (CCPR), use of ECLS for OHCA is not strongly endorsed by current clinical guidelines. The purpose of this study is to investigate the clinical roles of extracorporeal life support (ECLS) compared with that of conventional cardiopulmonary resuscitation (CCPR) for out-of-hospital cardiac arrest (OHCA) patients. The outcomes of OHCA between 2015 and 2020, enrolled in the Korean Cardiac Arrest Research Consortium (KoCARC), a multicenter OHCA patient registry including 65 participating hospitals throughout the Republic of Korea (ClinicalTrials.gov, number NCT03222999). Differences in clinical features were adjusted by matching the propensity for ECLS. The primary outcome was 30-day neurologically favorable survival with cerebral performance category of 1 or 2. Restricted mean survival time (RMST) was used to compare outcomes between groups. Of 12,006 patients included, ECLS was applied to 272 patients (2.2%). The frequency of neurologically favorable survival was higher in the ECLS group than the CCPR group (RMST difference, 5.5 days [95% CI, 4.1-7.0 days], P < 0.001). In propensity score-matched 271 pairs, the clinical outcome of ECLS and CCPR did not differ to a statistically significant extent (RMST difference, 0.4 days [95% CI -1.6 to 2.5 days], P = 0.67). Subgroup analyses revealed that the clinical roles of ECLS was evident in patients with nonshockable rhythm or CPR time ≥20 min (RMST difference, 2.7 days [95% CI 0.5-4.8 days], P = 0.015), but not in patients without these features (RMST difference, -3.7 days [95% CI -7.6 to 0.2 days], P = 0.07). In this real-world data analysis, ECLS compared to CCPR did not result in better overall clinical outcomes of OHCA. The clinical efficacy of ECLS may be limited to a subgroup of high-risk patients.

Prognostic Impact of High Baseline Stromal Tumor-Infiltrating Lymphocytes in the Absence of Pathologic Complete Response in Early-Stage Triple-Negative Breast Cancer.

Simple SummaryHigh stromal tumor-infiltrating lymphocytes (sTILs) are associated with an improved pathologic complete response (pCR) and survival in triple-negative breast cancer (TNBC). We hypothesized that high baseline sTILs would have a favorable prognostic impact in TNBC patients without a pCR. In this study of 318 early-stage TNBC patients in a prospective clinical trial, event-free survival (EFS) in patients without a pCR was not significantly different between those with high sTILs and those with low sTILs (p = 0.7). Therefore, high baseline sTILs do not confer a benefit in EFS in the absence of a pCR. RNA-seq analysis predicted more CD8+ T cells in the high-sTIL group with favorable EFS compared with the high-sTIL group with unfavorable EFS, suggesting the type of lymphocytes within the TIL fraction may be an important parameter to consider for de-escalation strategies. The implications of our findings in the setting of immune checkpoint inhibitor therapy remain to be investigated.High stromal tumor-infiltrating lymphocytes (sTILs) are associated with an improved pathologic complete response (pCR) and survival in triple-negative breast cancer (TNBC). We hypothesized that high baseline sTILs would have a favorable prognostic impact in TNBC patients without a pCR after neoadjuvant chemotherapy (NACT). In this prospective NACT study, pretreatment biopsies from 318 patients with early-stage TNBC were evaluated for sTILs. Recursive partitioning analysis (RPA) was applied to search for the sTIL cutoff best associated with a pCR. With ≥20% sTILs identified as the optimal cutoff, 33% patients had high sTILs (pCR rate 64%) and 67% had low sTILs (pCR rate 29%). Patients were stratified according to the sTIL cutoff (low vs. high) and response to NACT (pCR vs. residual disease (RD)). The primary endpoint was event-free survival (EFS), with hazard ratios calculated using the Cox proportional hazards regression model and the 3-year restricted mean survival time (RMST) as primary measures. Within the high-sTIL group, EFS was better in patients with a pCR compared with those with RD (HR 0.05; 95% CI 0.01–0.39; p = 0.004). The difference in the 3-year RMST for EFS between the two groups was 5.6 months (95% CI 2.3–8.8; p = 0.001). However, among patients with RD, EFS was not significantly different between those with high sTILs and those with low sTILs (p = 0.7). RNA-seq analysis predicted more CD8+ T cells in the high-sTIL group with favorable EFS compared with the high-sTIL group with unfavorable EFS. This study did not demonstrate that high baseline sTILs confer a benefit in EFS in the absence of a pCR.

Effectiveness and safety of Danmu extract syrup for acute upper respiratory tract infection in children: A real-world, prospective cohort study.

AimTo evaluate the effectiveness and safety of Danmu Extract Syrup for the treatment of acute upper respiratory tract infection (AURI) in children.MethodsIn this prospective cohort study, we enrolled children with AURI in the pediatric outpatient department and emergency department of West China Second Hospital. According to the treatment, they were divided into two groups: Danmu Extract Syrup Group (Danmu Group) and Xiaoer Chiqiao Granule Group (Chiqiao Group). The primary outcome was time to symptom remission, and the secondary outcomes were defervescence time, relief time, admission rate, and adherence. We used restricted mean survival time (RMST) to quantify the treatment effects and test noninferiority for primary outcome. Propensity score matching (PSM) was used to adjust confounding. Subgroup analysis and sensitivity analysis were used to verify the robustness of results.ResultsWe enrolled 1036 children with AURI, including 516 in Danmu Group and 520 in Chiqiao Group. After PSM, no significant difference was observed in the baseline characteristics of the two groups. The primary results showed that the RMST difference was –3 h (95% CI: –15.1 to 9.1) and the upper limit of the 95% CI was less than the noninferiority margin of 11 h. There was no statistical difference in the secondary outcomes except for defervescence between the two groups. The results of safety analysis showed that the incidence of adverse events occurred is 4.1% in Danmu Group, which was lower than the incidence of Chiqiao Group (6.9%).ConclusionThis study indicated that Danmu extract syrup is noninferiority to Chiqiao Granule for AURI in children.

Waiting Time for Second Kidney Transplantation and Mortality.

The median kidney transplant half-life is 10-15 years. Because of the scarcity of donor organs and immunologic sensitization of candidates for retransplantation, there is a need for quantitative information on if and when a second transplantation is no longer associated with a lower risk of mortality compared with waitlisted patients treated by dialysis. Therefore, we investigated the association of time on waiting list with patient survival in patients who received a second transplantation versus remaining on the waiting list. In this retrospective study using target trial emulation, we analyzed data of 2346 patients from the Austrian Dialysis and Transplant Registry and Eurotransplant with a failed first graft, aged over 18 years, and waitlisted for a second kidney transplantation in Austria during the years 1980-2019. The differences in restricted mean survival time and hazard ratios for all-cause mortality comparing the treatment strategies "retransplant" versus "remain waitlisted with maintenance dialysis" are reported for different waiting times after first graft loss. Second kidney transplantation showed a longer restricted mean survival time at 10 years of follow-up compared with remaining on the waiting list (5.8 life months gained; 95% confidence interval, 0.9 to 11.1). This survival difference was diminished in patients with longer waiting time after loss of the first allograft; restricted mean survival time differences at 10 years were 8.0 (95% confidence interval, 1.9 to 14.0) and 0.1 life months gained (95% confidence interval, -14.3 to 15.2) for patients with waiting time for retransplantation of <1 and 8 years, respectively. Second kidney transplant is associated with patient survival compared with remaining waitlisted and treatment by dialysis, but the survival difference diminishes with longer waiting time.

Abstract 13838: Life-Years Lost After Incident Atrial Fibrillation in Heart Failure

Aims: To estimate the life-years lost after newly-diagnosed atrial fibrillation (AF) in heart failure (HF) patients. Methods and Results: Among patients diagnosed with HF in 2008-2018 in the nationwide Danish Heart Failure Registry, we compared patients with incident AF (n=4,463, mean age 73.7 years, 29% women) to AF-free referents matched on age, sex, and time since HF (n=17,792). By using G-computation, we estimated the marginal hazard ratio for death (HR) and difference in restricted mean survival times (RMST) at 10 years after AF diagnosis accounting for sex, age at AF diagnosis, lifestyle factors, clinical characteristics, comorbidities, and medications. The marginal HR was 1.41 (95%CI 1.38 to 1.44). The difference in marginal RMST between HF patients with and without AF was -18.2 months (95%CI -16.8 to -19.6) at 10 years after AF diagnosis. Subgroup analyses showed differences between patients diagnosed with AF &gt;1 year and ≤1 year after HF (marginal difference in RMST at 10 years, -25.7 months, 95%CI -23.7 to -27.7, vs. -10.4 months, 95%CI -8.2 to -12.5), women and men (-20.3 months, 95%CI -17.7 to -21.9, vs. -17.2 months, 95%CI -15.5 to -19.0, p&lt;0.001), patients ≥75 and &lt;75 years old at AF diagnosis (-20.1 months, 95%CI -17.9 to -22.2, vs. -17.8 months, 95%CI -15.6 to -20.0, p&lt;0.001). Conclusion: There is evidence of loss in life expectancy associated with AF in HF, with 1.5 life-years lost over 10 years after AF diagnosis. Life-years lost were significantly larger among patients diagnosed with AF &gt;1 year after HF, women, and older patients.

Overall survival following implementation of clinical pathways for cancer care.

328 Background: Clinical pathways are decision support tools designed to enhance accessibility and ease of use of treatment recommendations. Prior studies that evaluated cancer clinical pathways largely focused on process measures such as concordance with treatment guidelines, but little evidence is available about the effect of clinical pathways on survival. We thus aimed to evaluate the effect of cancer clinical pathways on overall survival. Methods: We used institutional registry data from the JPS Oncology and Infusion Center, which is a Comprehensive Community Cancer Program. Eligible patients were aged ≥18 years, diagnosed with first primary breast, colorectal, or lung cancer between December 2013 and December 2017 with follow-up through June 2020. We used a natural experiment framework, where intervention was implementation of clinical pathways (December 2015). The pre-intervention period was December 2013 – November 2015 and post-intervention period was January 2016 – December 2017. We used marginal structural models with stabilized inverse probability weights for each cancer type to estimate restricted mean survival time (RMST) differences and 95% confidence limits (CL) comparing overall survival between pre- and post-clinical pathways within a 36-month horizon, where weights were based on a minimal sufficient set of covariates (sociodemographics, tumor characteristics, and comorbidities) to reduce confounding bias. Results: Our study population comprised 327 breast, 254 colorectal, and 431 lung cancer patients. Median age ranged between 55 years (breast) and 60 years (lung). The frequency of racial/ethnic minorities ranged between 45% (lung) and 68% (colorectal). The frequency of uninsured patients ranged between 47% (lung) and 58% (colorectal). Adherence to pathways was consistently over 80%. RMST was largely similar between pre- and post-clinical pathways for breast (RMST difference = -0.10 months, 95% CL: -1.9, 1.7), colorectal (RMST difference = -0.48 months, 95% CL: -3.4, 2.5) and lung cancer (RMST difference = 1.1 month, 95% CL: -1.5, 3.7). Conclusions: Our results suggest that implementation of clinical pathways has minimal effect on overall survival within 36 months despite high adherence in a safety-net population, but the estimates are compatible with up to 3.4 month decrease or 3.7 month increase depending on cancer type. Longer follow-up, particularly for breast and colorectal cancer, may provide further insight. Our findings may be useful for informing deliberations about implementing clinical pathways and setting expectations about the effect of clinical pathways on overall survival.

Comparison of invasive treatment strategies in patients with non–ST elevation acute coronary syndrome: A systematic review and meta-analysis

ObjectiveTo compare the mortality associated with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with non–ST elevation acute coronary syndrome (NSTE-ACS). MethodsWe searched publications from PubMed, Embase, Web of Science, and the Cochrane Library from inception until December 23, 2020. All randomized clinical trials (RCTs) and observational studies comparing all-cause mortality after treatment with CABG versus PCI for patients with NSTE-ACS with minimum follow-up of 6 months were included. Restricted mean survival time (RMST) differences from RCTs and adjusted RMST differences from observational studies were computed by reconstructing time-to-event data from published Kaplan–Meier curves. Extracted hazard ratios (HRs) were also assessed as a secondary analysis. ResultsOur systematic review included an individual participant data analysis of 3 RCTs and 8 observational studies. A meta-regression showed a significant association between log-transformed HRs and duration of follow-up (−0.009 [95% confidence interval (CI), −0.002 to −0.016] log-HR per 1-year longer follow-up; P = .037), suggesting a violation of the proportional hazard assumption. Analysis of 6 studies with available RMST data showed a significant inverse association between adjusted RMST differences and cutoff years (slope, −0.028 [95% CI, −0.042 to −0.013] year difference per 1-year longer cutoff; P < .005), suggesting a longer survival benefit in the CABG arm compared with the PCI arm with longer follow-up. ConclusionsThere was a trend toward a benefit of CABG compared with PCI in the longer follow-up in patients with NSTE-ACS. A large, well-designed RCT with longer follow-up is needed to obtain definitive evidence on this topic.

Myosteatosis at diagnosis is adversely associated with 2-year survival in women with estrogen receptor-negative metastatic breast cancer.

To examine the relationship between skeletal muscle (SM) and cancer-specific outcomes for women with estrogen receptor-negative (ER-) metastatic breast cancer (MBC). For this retrospective cohort, females (≥ 18years) with histologically confirmed ER- MBC and computerized tomography (CT) imaging were screened. Demographic, anthropometric, and clinical data were collected uniformly from the electronic medical record. CT images inclusive of the third lumbar region (L3) at diagnosis, 6 and 12months, were used to classify sarcopenia (≤ 41 cm2/m2) and myosteatosis (< 41 or 33 Hounsfield Units, adjusted for body mass index (BMI)) and to evaluate changes in SM and total adipose tissue (TAT) over time. Kaplan-Meier curves, Cox Proportional Hazards (PH), and restricted mean survival time (RMST) estimates were generated to examine the relationship between sarcopenia and myosteatosis and time to tumor progression (TTP), treatment toxicity and 2-year survival, adjusting for covariates. Participants were 58.0 (15.0) years of age, ethnically diverse (55% non-Hispanic white, 31% Black, 11% Hispanic), post-menopausal (73%, n = 111), and classified as overweight (BMI 29.4 (7.6)). At diagnosis, 40% (n = 61) were sarcopenic, 49% had myosteatosis, and 28% (n = 42) had both. While Cox PH modeling and RMST analysis reveal no significant relationship between sarcopenia at diagnosis and 2-year survival (RMST difference - 1.6 (1.4) months, HR 1.35 (0.88-2.08)), these analyses support a significant, adverse association between myosteatosis at diagnosis and 2-year survival (RMST difference - 2.4 (1.5) months, HR 1.72 (1.09-2.72)). Incident sarcopenia was 11% (n = 5/45) and 2.5% (n = 1/40), respectively, while incident myosteatosis was 19% (n = 8/42) and 15% (n = 5/34) at 6 and 12months, respectively. TTP and treatment toxicities did not appear to be related to diagnostic SM or body composition changes over time. Targeted interventions initiated within the first year of diagnosis to preserve or improve SM quality seem warranted for women with ER-MBC.

Counseling Patients (pts) with Higher-Risk Myelodysplastic Syndromes (HR-MDS) Regarding Expected Survival with Azacitidine (aza) Therapy: Are We Using Accurate Estimates?

▪Introduction:Aza is the only drug proven to prolong overall survival (OS) in pts with HR-MDS in the large randomized trial AZA-001 with a median OS of 24·5 months (mos) compared to vs. 15·0 mos for conventional care regimens (CCR) arm, with a hazard ratio of 0·58; p=0·0001 (Fenaux et al, 2009). Two-year OS probability was 51% in aza arm compared to 26% in the CCR arm (p<0·0001). These numbers are often quoted to counsel HR-MDS pts regarding expected benefits with aza therapy. However, increasing real-life and registry data suggest that the OS benefits with aza is much lower than what is suggested by AZA-001 trial. To get a more realistic estimate of OS with aza, we pooled OS data from several reported clinical trials and re-analyzed data from the AZA-001 trial.Methods: We conducted a literature search for published prospective clinical trials that had an aza monotherapy arm at the standard approved dose (75mg/m2/day for 7 days), in which OS results were presented in Kaplan-Meier (KM) methodology. GetData Graph Digitizer Version 2.26 was used to digitize the published KM curves of the aza monotherapy arms in these trials. An algorithm developed by Guyot et al. 2012 was implemented in the R statistical software to recreate individual pt level data based on the information from each KM curve, number of pts at risk, and number of events. Individual pt level data were pooled for pts receiving aza to produce overall KM estimates and estimates of median OS and 1-, 2-, and 3-year OS probabilities. Furthermore, based on the individual level pt data recreated from the AZA-001 trial, the validity of the proportional hazards assumption between the aza and CCR arms was assessed by testing the independence between Schoenfeld residuals and time. The difference (and ratio) of the Restricted Mean Survival Time (RMST) are non-parametric test which are less sensitive to assumptions than the Cox proportional hazards (CPH) ratios, and has been gaining popularity as an estimate of survival benefit in time-to-event endpoints in clinical trials (Uno et al, JCO, 2014). The hazard ratio provided in trials can significantly increase treatment effect estimates than the ratio of RMST, and the hazard ratio may seem large when the absolute effect is small. We calculated the difference (and the ratio) of the RMST in the AZA-001 trial to estimate OS benefit with aza compared to CCR, as an alternative to the hazard ratio reported in the trial, that is less sensitive to violations in the proportional hazards assumption.Results: We have found four published manuscript that fit the research criteria [Table 1]. We first assessed the proportionality of the hazard functions for each treatment arm of AZA-001 trial. While there wassome variability in the CPH model residuals for the log hazard ratio over time, the proportionality assumption is not violated based on the test of the Schoenfeld residuals (Rho = 0.085, p = 0.224). The difference in RMST between aza and CCR arms shows that OS benefit in aza arm was 5.38 months longer than CCR arm on average when pts were followed for 34 months (p < 0.001). The ratio of RMST over 34 months was 0.748, suggesting that hazard of death was reduced with aza by 25% compared to CCR (p < 0.001), in comparison to what was reported in the AZA-001 trial of hazard of death reduction of 42% based on the CPH. When KM curves for the aza arm of each of the four manuscripts were pooled [Figures 1,2], median OS was 19.2 months (95%CI 16.9, 21.8). KM estimates of OS for pooled data at 1-year was 65.4% (95%CI 60.8%, 70.3%), at 2-years 42.4% (95%CI 37.3%, 48.3%), and at 3 years 33.6% (95%CI 27.6%, 40.8%).Summary: Pooled data from clinical trials with aza monotherapy arms support the real-life observation that the median OS of 24.5 months with aza in AZA-001 trial reflects a substantial unexplained over-performance of aza in this landmark trial that is not related to the selective process of enrollment in clinical trials. While individual pts have exceptional responses with aza, such responses are uncommon and a median OS of less than 19 months (based on trial data of selected patients) and 13 to 16 months (based on real-life analyses) might be more realistic estimates for most pts with HR-MDS using aza. These observations provide rationale to strongly consider first-line enrollment into clinical trials or transplantation for HR-MDS pts rather than defaulting to the routine use of “standard-of-care” aza monotherapy, and have important implications for the design of clinical trials. [Display omitted] DisclosuresPodoltsev:CTI biopharma/Baxalta: Consultancy; Ariad: Consultancy; Alexion: Consultancy; Incyte: Consultancy. Ma:Incyte Corp.: Consultancy. Zeidan:AbbVie, Otsuka, Pfizer, Gilead, Celgene, Ariad, Incyte: Consultancy, Honoraria; Takeda: Speakers Bureau; Otsuka: Consultancy.

Effectiveness of angiotensin-neprilysin inhibitor treatment versus renin-angiotensin system blockade in older adults with heart failure in clinical care

ObjectiveTo evaluate the effectiveness of angiotensin receptor-neprilysin inhibitor (ARNI) versus renin-angiotensin system (RAS) blockade alone in older adults with heart failure with reduced ejection fraction (HFrEF).MethodsWe conducted a cohort study...

Association Between First-Line Immune Checkpoint Inhibition and Survival for Medicare-Insured Patients With Advanced Non–Small Cell Lung Cancer

Immunotherapy is now a cornerstone of treatment for advanced non-small cell lung cancer (NSCLC), but its uptake and effectiveness among older patients outside clinical trials remain poorly understood. To understand treatment patterns and evaluate the overall survival associated with checkpoint inhibitor immunotherapy, cytotoxic chemotherapy, and combined chemoimmunotherapy for older patients who have advanced NSCLC and Medicare coverage. This retrospective cohort study included Medicare-insured patients in the US aged 66 to 89 years who initiated first palliative-intent systemic therapy for lung cancer between January 1, 2016, and December 31, 2018. Survival follow-up continued through March 31, 2020. A total of 19 529 patients who had advanced lung cancer and were insured by a Medicare fee-for-service plan were included in the analysis. Regimens included pembrolizumab monotherapy (n = 3079), combined platinum-based drug (ie, cisplatin or carboplatin [hereinafter, platinum]) and pemetrexed disodium (n = 5159), combined platinum and a taxane (ie, paclitaxel, nab-paclitaxel, or docetaxel) (n = 9866), and combined platinum, pemetrexed, and pembrolizumab (n = 1425), as ascertained using Medicare claims from the Centers for Medicare & Medicaid Services. The primary outcome was overall survival, which was measured using the restricted mean survival time (RMST) with propensity score adjustment for clinical and sociodemographic characteristics. Median survival was also reported for comparison with outcomes from registrational trials. A total of 19 529 patients (54% male, 46% female; median age, 73.8 [interquartile range, 69.9-78.4] years) were identified for analysis. The uptake of pembrolizumab-containing regimens in the Medicare population was rapid, increasing from 0.7% of first-line treatments in the second quarter of 2016 to 42.4% in the third quarter of 2018. Patients who were older (≥70 years, 2484 [81%]), were female (1577 [51%]), and/or had higher Risk Stratification Index scores (highest quintile, 922 [30%]) were more likely to receive single-agent pembrolizumab than chemotherapy. After propensity score adjustment, pembrolizumab was associated with survival similar to platinum/pemetrexed (RMST difference, -0.2 [95% CI, -0.5 to 0.2] months) or platinum/taxane (RMST difference, -0.7 [95% CI, -1.0 to -0.4] months). Patients receiving platinum/pemetrexed/pembrolizumab chemoimmunotherapy also had adjusted survival similar to those receiving platinum/pemetrexed chemotherapy (RMST difference, 0.5 [95% CI, 0.1-0.9] months). The unadjusted median survival was 11.4 (95% CI, 10.5-12.3) months among patients receiving single-agent pembrolizumab, approximately 15 months shorter than observed among pembrolizumab-treated participants in the KEYNOTE-024 trial. The unadjusted median survival was 12.9 (95% CI, 11.8-14.0) months among patients receiving platinum/pemetrexed/pembrolizumab chemoimmunotherapy, approximately 10 months shorter than observed among platinum/pemetrexed/pembrolizumab-treated participants in the KEYNOTE-189 trial. Immunotherapy has been incorporated rapidly into treatment for patients with advanced NSCLC. However, survival estimates in the Medicare population are much shorter than those reported in registrational trials. These results provide contemporary estimates of survival for older patients with advanced NSCLC treated in routine practice, facilitating patient-centered decision-making.

Effect of PARP Inhibitors as Maintenance Treatment on Restricted Mean Survival Time in Platinum-Sensitive Recurrent Ovarian Cancer: A Systematic Review and Meta-analysis.

Earlier trials on the efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors in platinum-sensitive relapsed ovarian cancer used the hazard ratio (HR) as an efficacy parameter. The present meta-analysis was focused on improving the robustness and clinical interpretability of the efficacy evaluation of PARP inhibitors using the restricted mean survival time (RMST). A search for relevant studies published up to July 31, 2020, was performed in electronic databases to identify eligible trials comparing PARP inhibitors with placebo. The difference in RMST was used as a PARP inhibitor efficacy parameter. Combined differences in RMST with 95% CIs across studies were calculated using a random-effects model. Four trials (6 articles) were assessed, including 1079 patients treated with PARP inhibitors and 598 with placebo. The combined RMST differences for up to 360 days (PARP inhibitors minus placebo: point estimate and 95% CI) among all patients and the patients of subgroups with BRCA mutations, homologous recombination-deficient (HRD) carcinoma, and BRCA wild-type carcinoma were 87 days (95% CI = 71, 102), 112 days (95% CI = 96, 129), 99 days (95% CI = 80, 119), and 69 days (95% CI = 47, 92), respectively. The combined RMST differences for up to 660 and 720 days were also larger among patients with BRCA mutations than among those with HRD carcinoma. Based on using the RMST difference as an alternative measure to the HR, this meta-analysis suggests that PARP inhibitors are the most effective for patients with BRCA mutations, followed by patients with HRD carcinoma.

Debate: The role of percutaneous coronary intervention for left main disease after EXCEL and NOBEL trials

To compare the mortality associated with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with non–ST elevation acute coronary syndrome (NSTE-ACS).We searched publications from PubMed, Embase, Web of Science, and the Cochrane Library from inception until December 23, 2020. All randomized clinical trials (RCTs) and observational studies comparing all-cause mortality after treatment with CABG versus PCI for patients with NSTE-ACS with minimum follow-up of 6 months were included. Restricted mean survival time (RMST) differences from RCTs and adjusted RMST differences from observational studies were computed by reconstructing time-to-event data from published Kaplan–Meier curves. Extracted hazard ratios (HRs) were also assessed as a secondary analysis.Our systematic review included an individual participant data analysis of 3 RCTs and 8 observational studies. A meta-regression showed a significant association between log-transformed HRs and duration of follow-up (−0.009 [95% confidence interval (CI), −0.002 to −0.016] log-HR per 1-year longer follow-up; P = .037), suggesting a violation of the proportional hazard assumption. Analysis of 6 studies with available RMST data showed a significant inverse association between adjusted RMST differences and cutoff years (slope, −0.028 [95% CI, −0.042 to −0.013] year difference per 1-year longer cutoff; P < .005), suggesting a longer survival benefit in the CABG arm compared with the PCI arm with longer follow-up.There was a trend toward a benefit of CABG compared with PCI in the longer follow-up in patients with NSTE-ACS. A large, well-designed RCT with longer follow-up is needed to obtain definitive evidence on this topic.

Emulation of a Target Trial to Evaluate the Causal Effect of Palliative Care Consultation on the Survival Time of Patients with Hepatocellular Carcinoma.

Simple SummaryHepatocellular carcinoma (HCC) is a common and aggressive liver cancer. As most patients are diagnosed during an incurable stage of the disease, they usually face great suffering during the end-of-life period. Palliative care can improve the patient’s quality of life and alleviate both physical and psychological symptoms. However, the discipline is underutilized due to a common misconception that it will accelerate the patient’s death. We emulated a hypothetical target trial to evaluate the causal effect of palliative care consultation on the survival time of patients diagnosed with HCC from retrospective observational data of a Thai tertiary care center. Although no clear survival benefit or harm was identified, palliative care consultation significantly reduced the use of unnecessary life-sustaining intervention, healthcare costs, and the risk of dying in the hospital among patients with HCC during their end-of-life period.Palliative care has the potential to improve the quality of life of patients with incurable diseases or cancer, such as hepatocellular carcinoma (HCC). A common misconception of palliative care with respect to the patient’s survival remains a significant barrier to the discipline. This study aimed to provide causal evidence for the effect of palliative care consultation on the survival time after diagnosis among HCC patients. An emulation of a target trial was conducted on a retrospective cohort of HCC patients from January 2017 to August 2019. The primary endpoint was the restricted mean survival time (RMST) at 12 months after HCC diagnosis. We used the clone–censor–weight approach to account for potential immortal time bias. In this study, 86 patients with palliative care consultation and 71 patients without palliative care consultation were included. The adjusted RMST difference was −29.7 (95% confidence interval (CI): −81.7, 22.3; p-value = 0.263) days in favor of no palliative care consultation. However, palliative care consultation was associated with an increase in the prescription of symptom control medications, as well as a reduction in life-sustaining interventions and healthcare costs. Our findings suggest that palliative care consultation was associated with neither additional survival benefit nor harm in HCC patients. The misconception that it significantly accelerates the dying process should be disregarded.

Effectiveness of the baby-friendly community initiative on exclusive breastfeeding in Kenya.

The baby‐friendly hospital initiative (BFHI) promotes exclusive breastfeeding (EBF) in hospitals, but this is not accessible in rural settings where mothers give birth at home, hence the need for a community intervention. We tested the effectiveness of the baby‐friendly community initiative (BFCI) on EBF in rural Kenya. This cluster randomized study was conducted in 13 community units in Koibatek sub‐county. Pregnant women aged 15–49 years were recruited and followed up until their children were 6 months old. Mothers in the intervention group received standard maternal, infant and young child nutrition counselling, support from trained community health volunteers, health professionals and community and mother support groups, whereas those in the control group received standard counselling only. Data on breastfeeding practices were collected longitudinally. The probability of EBF up to 6 months of age and the restricted mean survival time difference were estimated. A total of 823 (intervention group n = 351) pregnant women were recruited. Compared with children in the control group, children in the intervention group were more likely to exclusively breastfeed for 6 months (79.2% vs. 54.5%; P < .05). Children in the intervention group were also exclusively breastfed for a longer time, mean difference (95% confidence interval [CI]) 0.62 months (0.38, 0.85; P < .001). The BFCI implemented within the existing health system and including community and mother support groups led to a significant increase in EBF in a rural Kenyan setting. This intervention has the potential to improve EBF rates in similar settings.

Treatment effect of radiofrequency ablation versus liver transplantation and surgical resection for hepatocellular carcinoma within Milan criteria: a population-based study.

Restricted mean survival time (RMST) has been increasingly used to assess the treatment effect. We aimed to evaluate a treatment effect of radiofrequency ablation (RFA) versus liver transplantation (LT) and surgical resection (SR) for hepatocellular carcinoma (HCC) within Milan criteria by using an adjusted RMST. A total of 7,218 HCC patients (RFA, 3,327; LT, 2,332; SR 1,523) within Milan criteria were eligible for this retrospectively study. The RMST using inverse probability of treatment weighting (IPTW) adjustment were applied to estimate the treatment effect between RFA and LT, RFA, and SR groups. The 3-, 5-, and 10-year IPTW-adjusted difference in RMST of OS for LT over RFA were + 4.5, + 12.4, and + 36.3 months, respectively. For SR versus RFA group, the survival benefit was + 2.3, + 6.1, and + 15.8 months at 3, 5, and 10 years, respectively. But the incremental survival benefit of SR over RFA was only half than that of LT over RFA. In the subgroup of solitary tumor ≤ 2 cm, the adjusted RMST of RFA versus SR was comparable with no statistical differences. Beyond that, in comparison with RFA, a notably greater efficacy of LT and SR was consistently across all subgroups with solitary HCC > 2.0 cm, AFP positive or negative, and fibrosis score 0-4 or 5-6. RMST provides a measure of absolute survival benefit at a specific time point. Using IPTW-adjusted RMST, we showed that the incremental survival benefit of SR over RFA was about half than that of LT over RFA. • The restricted mean survival time offers an intuitive, clinically meaningful interpretation to quantify the treatment effect than the hazard ratio. • Liver transplantation and surgical resection provided better overall survival compared to radiofrequency ablation for HCC patients within Milan criteria, but RFA and SR provide equivalent long-term overall survival for solitary HCC ≤ 2 cm. • The incremental survival benefit of surgical resection over radiofrequency ablation was only half than that of liver transplantation over radiofrequency ablation.