Restricted Mean Survival Time Analysis Research Articles

Ramucirumab plus paclitaxel as switch maintenance versus continuation of oxaliplatin-based chemotherapy in patients (pts) with advanced HER2-negative gastric or gastroesophageal junction (GEJ) cancer: The ARMANI phase III trial.

LBA4002 Background: In pts with HER2-negative advanced gastric/GEJ cancer and PD-L1 low/absent expression, platinum/fluoropyrimidine doublets are a standard first-line therapy. In this patient population, the outcomes are unsatisfactory and second-line therapy is given in only 40% of clinical trial patients. Switch consolidation maintenance may prolong the benefit of the initial strategy and delay clinical deterioration. Despite ramucirumab failing to prolong both progression-free survival (PFS) and overall survival (OS) in the first-line setting, paclitaxel plus ramucirumab is a standard second-line therapy and warrants investigation as a post-induction strategy. Methods: Pts with HER2-negative advanced gastric/GEJ cancer without disease progression after 3 months of initial oxaliplatin-based chemotherapy, stratified by site of origin (GEJ vs gastric), prior gastrectomy and peritoneal disease, were randomized 1:1 to ramucirumab 8 mg/Kg on days 1,15 plus paclitaxel 80 mg/sqm on days 1,8,15 every 28 days (arm A) vs CAPOX/FOLFOX at the same doses used in the last induction cycle, for additional 3 mos followed by fluoropyrimidine monotherapy maintenance (arm B). The primary endpoint was PFS, OS was a key secondary endpoint; quality of life, safety, and biomarkers were evaluated. A sample size of 280 pts achieved a 90% power to detect as significant at a 5% level (2-sided log-rank test) a median PFS increase from 4 to 6 mos (target HR=0.67). HRs were estimated by Cox models adjusting for stratification factors. Restricted Mean Survival Time (RMST) analysis was conducted in case of violation of proportional hazards assumption. Results: From Jan 2017 to Oct 2023, 280 patients were randomly assigned (144 arm A/136 arm B). Baseline characteristics were: male sex 67/61%, median age 64/66 years, PS 0 74/65%, GEJ 26/26%, prior gastrectomy 28/23%, peritoneal metastases 53/42%. At a median follow-up of 43.7 months (IQR 22.0-57.9), median PFS was 6.6 vs. 3.5 mos in Arm A vs. B (HR=0.63, 95%CI 0.49-0.81; P<0.001). 24-mos RMST analysis showed a statistically significant 2.4-mos average increment (p=0.002). Median OS was 12.6 vs. 10.4 mos in Arm A vs. B (HR=0.75, 95%CI 0.58-0.97; P=0.030). The frequency of grade ≥3 adverse events was 40.4% vs. 20.7% in arms A vs. B, respectively, mainly neutropenia 25.5/9.6%; febrile neutropenia 2.1/0%; hypertension 6.4/0%; venous thromboembolism 2.1/0%; peripheral neuropathy 5.7/6.7%. No treatment-related deaths were reported. Conclusions: Switch maintenance with paclitaxel plus ramucirumab after 3 months of oxaliplatin-based doublets may be a new strategy in patients with HER2-negative metastatic gastric/GEJ cancer who are non-eligible for initial immune checkpoint inhibitor-based regimens according to specific guidelines and regulatory approvals. Clinical trial information: NCT02934464 .

Difficult-to-treat inflammatory bowel disease: Effectiveness and safety of 4th and 5th lines of treatment.

Many patients with inflammatory bowel disease (IBD) have signs or symptoms of active disease despite multiple treatment attempts. This emerging concept is defined as difficult-to-treat IBD. The objective of this study was to investigate for the first time the treatment persistence, efficacy and safety of biologics or small molecules used in 4th or 5th line therapy. We reviewed all consecutive patients with IBD treated at the Nancy University Hospital between July 2022 and April 2023 with the 4th or 5th line treatment for at least three months. The primary outcome was to assess the persistence rate of 4th and 5th line therapy. We enrolled 82 patients with IBD (4th line: 44; 5th line: 38). On Kaplan-Meier analysis, the duration of risankizumab, ustekinumab or vedolizumab therapy did not differ significantly (p>0.05) as 4th and 5th line treatment. The restricted mean survival time analysis showed that the persistence rate of risankizumab was the highest as 4th line therapy (risankizumab vs. vedolizumab: 36.0 and 29.4weeks, respectively, p=0.008; risankizumab vs. ustekinumab: 36.0 and 32.8weeks, respectively, p=0.035). In multivariate regression, Crohn's disease diagnosis (Odd ratio 4.6; 95% confidence interval 1.7-12.4) was significantly associated with treatment persistence. In this first real-world setting, risankizumab could have a longer persistence rate as 4th line treatment for IBD than other agents. Persistence of biological agents was greater in Crohn's disease than in ulcerative colitis. More studies are needed to compare treatment efficacy in patients with difficult-to-treat IBD.

Invasive Treatment Strategy in Adults With Frailty and Non–ST-Segment Elevation Myocardial Infarction

The MOSCA-FRAIL randomized clinical trial compared invasive and conservative treatment strategies in patients with frailty with non-ST-segment elevation myocardial infarction (NSTEMI). It showed no differences in the number of days alive and out of the hospital at 1 year. To assess the outcomes of the MOSCA-FRAIL trial during extended follow-up. The MOSCA-FRAIL randomized clinical trial was conducted at 13 hospitals in Spain between July 7, 2017, and January 9, 2021, and included 167 adults (aged ≥70 years) with frailty (Clinical Frailty Scale score ≥4) and NSTEMI. In this preplanned secondary analysis, follow-up was extended to January 31, 2023. Data analysis was performed from April 5 to 29, 2023, using the intention-to-treat principle. Patients were randomized to a routine invasive (coronary angiography and revascularization if feasible [n = 84]) or a conservative (medical treatment with coronary angiography only if recurrent ischemia [n = 83]) strategy. The primary end point was the difference in restricted mean survival time (RMST). Secondary end points included readmissions for any cause, considering recurrent readmissions. Among the 167 patients included in the analysis, the mean (SD) age was 86 (5) years; 79 (47.3%) were men and 88 (52.7%) were women. A total of 93 deaths and 367 readmissions accrued. The RMST for all-cause death over the entire follow-up was 3.13 (95% CI, 2.72-3.60) years in the invasive and 3.06 (95% CI, 2.84-3.32) years in the conservative treatment groups. The RMST analysis showed inconclusive differences in survival time (invasive minus conservative difference, 28 [95% CI, -188 to 230] days). Patients under invasive treatment tended to have shorter survival in the first year (-28 [95% CI, -63 to 7] days), which improved after the first year (192 [95% CI, 90-230] days). Kaplan-Meier mortality curves intersected, displaying higher mortality to 1 year in the invasive group that shifted to a late benefit (landmark analysis hazard ratio, 0.58 [95% CI, 0.33-0.99]; P = .045). Early harm was more evident in the subgroup with a Clinical Frailty Scale score greater than 4. No differences were found for the secondary end points. In this extended follow-up of a randomized clinical trial of patients with frailty and NSTEMI, an invasive treatment strategy did not improve outcomes at a median follow-up of 1113 (IQR, 443-1441) days. However, a differential distribution of deaths was observed, with early harm followed by later benefit. The phenomenon of depletion of susceptible patients may be responsible for this behavior. ClinicalTrials.gov Identifier: NCT03208153.

P752 Difficult-to-treat inflammatory bowel disease: effectiveness and safety of 4th and 5th lines

Abstract Background Many patients with inflammatory bowel disease (IBD) have signs or symptoms of active disease despite multiple treatment attempts. This emerging concept is defined difficult-to-treat IBD. The objective of this study was to investigate for the first time treatment persistence, efficacy and safety of biologics or small molecules used in 4th or 5th line therapy. Methods We reviewed all consecutive patients with IBD treated at Nancy University Hospital between July 2022 and April 2023 with the 4th or 5th line treatment for at least three months. The primary outcome was to assess the persistence rate of 4th and 5th line therapy. Results We enrolled 82 patients with IBD (4th line: 44; 5th line: 38). On Kaplan-Meier analysis the duration of risankizumab, ustekinumab or vedolizumab therapy did not differ significantly (p>0.05) as 4th and 5th line treatment. The restricted mean survival time analysis showed that persistence rate of risankizumab was the highest as 4th line therapy (risankizumab vs. vedolizumab: 36.0 and 29.4 weeks respectively, p=0.008; risankizumab vs. ustekinumab: 36.0 and 32.8 weeks respectively, p=0.035). In multivariate regression, Crohn’s disease diagnosis (Odd ratio 4.6; 95% confidence interval 1.7-12.4) was significantly associated with treatment persistence. Conclusion In this first real-world setting, risankizumab could have longer persistence rate as 4th line treatment for IBD than other agents. Persistence of biological agents was greater in Crohn’s disease than in ulcerative colitis. More studies are needed to compare treatment efficacy in patients with difficult-to-treat IBD.

Matching-Adjusted Indirect Comparisons of Brexucabtagene Autoleucel with Alternative Standard Therapies for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in Adult Patients.

Brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, is approved for relapsed/refractory B-cell precursor acute lymphoblastic leukemia in adults aged 18+/26+ years in the US/European Union (EU), based on efficacy results from the single-arm ZUMA-3 trial. This study aimed to estimate the relative treatment effects of brexu-cel versus inotuzumab ozogamicin (InO), blinatumomab (blina), and chemotherapies using unanchored matching-adjusted indirect comparison (MAIC) methods. Individual patient data from ZUMA-3 and published aggregate level data from two randomized controlled trials, INO-VATE (InO versus chemotherapy) and TOWER (blina versus chemotherapy), were used. Patient-level data from ZUMA-3 were weighted to match the mean of the following prognostic variables at baseline, which were pre-specified based on clinical input, for each comparator population: primary refractory disease, duration of first remission < 12months, prior stem-cell transplantation, age, performance status, salvage status, bone marrow blast, complex karyotype, and Philadelphia chromosome status. The base case analysis was conducted using the modified intention-to-treat population (i.e., received brexu-cel) from ZUMA-3. Relative treatment effects for overall survival (OS) and event-free survival (EFS) were expressed as hazard ratios (HR) and differences in restricted mean survival time (RMST) with 95% confidence intervals (CI). The base case MAIC results suggested brexu-cel improved OS and EFS compared to blina (OS HR 0.46 [95% CI 0.28, 0.75]; EFS HR 0.37 [95% CI 0.25, 0.56]) and pooled INO-VATE/TOWER chemotherapy (OS HR 0.32 [95% CI 0.18, 0.56]; EFS HR 0.27 [0.18, 0.40]). Brexu-cel also improved OS compared to InO (HR 0.45 [95% CI 0.24, 0.85]). The point estimate for EFS favored brexu-cel over Ino but the difference was not statistically significant (HR 0.67 [95% CI 0.41, 1.10]). Findings were consistent between the HR and RMST analyses. Despite limitations, these MAIC results suggest that brexu-cel may improve OS and EFS versus currently used therapies in this population.

Interatrial Block Association With Adverse Cardiovascular Outcomes in Patients Without a History of Atrial Fibrillation

BackgroundInteratrial block (IAB) is associated with thromboembolism and atrial arrhythmias. However, prior studies included small patient cohorts so it remains unclear whether IAB predicts adverse outcomes particularly in context of atrial fibrillation (AF)/atrial flutter (AFL). ObjectivesThis study sought to determine whether IAB portends increased stroke risk in a large cohort in the presence or absence of AFAF/AFL. MethodsWe performed a 5-center retrospective analysis of 4,837,989 electrocardiograms (ECGs) from 1,228,291 patients. IAB was defined as P-wave duration ≥120 ms in leads II, III, or aVF. Measurements were extracted as .XML files. After excluding patients with prior AF/AFL, 1,825,958 ECGs from 458,994 patients remained. Outcomes were analyzed using restricted mean survival time analysis and restricted mean time lost. ResultsThere were 86,317 patients with IAB and 355,032 patients without IAB. IAB prevalence in the cohort was 19.6% and was most common in Black (26.1%), White (20.9%), and Hispanic (18.5%) patients and least prevalent in Native Americans (9.2%). IAB was independently associated with increased stroke probability (restricted mean time lost ratio coefficient [RMTLRC]: 1.43; 95% CI: 1.35-1.51; tau = 1,895), mortality (RMTLRC: 1.14; 95% CI: 1.07-1.21; tau = 1,924), heart failure (RMTLRC: 1.94; 95% CI: 1.83-2.04; tau = 1,921), systemic thromboembolism (RMTLRC: 1.62; 95% CI: 1.53-1.71; tau = 1,897), and incident AF/AFL (RMTLRC: 1.16; 95% CI: 1.10-1.22; tau = 1,888). IAB was not associated with stroke in patients with pre-existing AF/AFL. ConclusionsIAB is independently associated with stroke in patients with no history of AF/AFL even after adjustment for incident AF/AFL and CHA2DS2-VASc score. Patients are at increased risk of stroke even when AF/AFL is not identified.

Inequalities in the impact of having a chronic disease on entering permanent paid employment: a registry-based 10-year follow-up study

BackgroundThis study aimed to investigate among unemployed persons (1) the impact of having a chronic disease on entering paid employment and obtaining a permanent contract and (2) whether these associations...

Prognosis of Patients With Heart Failure Receiving Autologous Myoblast Patches - Comparison of Single-Arm Trial Data to Registry Data.

Clinical studies in regenerative medicine remain insufficient in Japan due to ethical concerns regarding the control group and a lack of statistical methodology to evaluate efficacy in a small treatment group. This study evaluated the efficacy of autologous myoblast patch (AMP) treatment for heart failure using restricted mean survival time (RMST) analysis by comparing data from a small single-arm trial to epidemiological data from a registry.Methods and Results: The clinical trial arm included 55 patients with advanced ischemic cardiomyopathy who received an AMP between 2010 and 2020. The registry-based control group comprised 937 participants with severely impaired left ventricular function who were hospitalized for heart failure during the study period. Due to the limited number of patients, RMST analysis was used to compare survival between the 2 groups. Cox regression analyses revealed non-significant differences in survival between the groups at 3, 3.5, and 4 years. In contrast, RMST analyses revealed significant differences in survival at 3 years (P=0.008) and 3.5 (P=0.024) years, but not at 4 years. This small single-arm trial using RMST analyses was able to detect the efficacy of AMP transplantation for advanced heart failure (compared with a registry-based control group), with better survival until 3.5 years. This approach may be useful for efficacy analyses in regenerative medicine, where traditional clinical trials are difficult.

Effect of Routine Invasive vs Conservative Strategy in Older Adults With Frailty and Non–ST-Segment Elevation Acute Myocardial Infarction

To our knowledge, no randomized clinical trial has compared the invasive and conservative strategies in frail, older patients with non-ST-segment elevation acute myocardial infarction (NSTEMI). To compare outcomes of invasive and conservative strategies in frail, older patients with NSTEMI at 1 year. This multicenter randomized clinical trial was conducted at 13 Spanish hospitals between July 7, 2017, and January 9, 2021, and included 167 older adult (≥70 years) patients with frailty (Clinical Frailty Scale score ≥4) and NSTEMI. Data analysis was performed from April 2022 to June 2022. Patients were randomized to routine invasive (coronary angiography and revascularization if feasible; n = 84) or conservative (medical treatment with coronary angiography for recurrent ischemia; n = 83) strategy. The primary end point was the number of days alive and out of the hospital (DAOH) from discharge to 1 year. The coprimary end point was the composite of cardiac death, reinfarction, or postdischarge revascularization. The study was prematurely stopped due to the COVID-19 pandemic when 95% of the calculated sample size had been enrolled. Among the 167 patients included, the mean (SD) age was 86 (5) years, and mean (SD) Clinical Frailty Scale score was 5 (1). While not statistically different, DAOH were about 1 month (28 days; 95% CI, -7 to 62) greater for patients managed conservatively (312 days; 95% CI, 289 to 335) vs patients managed invasively (284 days; 95% CI, 255 to 311; P = .12). A sensitivity analysis stratified by sex did not show differences. In addition, we found no differences in all-cause mortality (hazard ratio, 1.45; 95% CI, 0.74-2.85; P = .28). There was a 28-day shorter survival in the invasive vs conservatively managed group (95% CI, -63 to 7 days; restricted mean survival time analysis). Noncardiac reasons accounted for 56% of the readmissions. There were no differences in the number of readmissions or days spent in the hospital after discharge between groups. Neither were there differences in the coprimary end point of ischemic cardiac events (subdistribution hazard ratio, 0.92; 95% CI, 0.54-1.57; P = .78). In this randomized clinical trial of NSTEMI in frail older patients, there was no benefit to a routine invasive strategy in DAOH during the first year. Based on these findings, a policy of medical management and watchful observation is recommended for older patients with frailty and NSTEMI. ClinicalTrials.gov Identifier: NCT03208153.

Central obesity as assessed by conicity index and a-body shape index associates with cardiovascular risk factors and mortality in kidney failure patients.

Anthropometric indices of central obesity, waist circumference (WC), conicity index (CI), and a-body shape index (ABSI), are prognostic indicators of cardiovascular (CV) risk. The association of CI and ABSI with other CV risk indices, markers of nutritional status and inflammation, and clinical outcomes in chronic kidney disease (CKD) stage 5 (CKD5) patients was investigated. In a cross-sectional study with longitudinal follow up of 203 clinically stable patients with CKD5 (median age 56 years; 68% males, 17% diabetics, 22% with CV disease, and 39% malnourished), we investigated CI and ABSI and their associations with atherogenic index of plasma (AIP), Framingham CV risk score (FRS), Agatston scoring of coronary artery calcium (CAC) and aortic valve calcium (AVC), handgrip strength (HGS), high sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6). CV events (CVE) and all-cause mortality during up to 10-years follow up were analyzed by multivariate survival analysis of restricted mean survival time (RMST). Chronic kidney disease patients with middle and highest CI and ABSI tertiles (indicating greater abdominal fat deposition), compared to those with the lowest CI and ABSI tertiles, tended to be older, more often men and diabetic, had significantly higher levels of hsCRP, IL-6, AIP, FRS, CAC and AVC scores. CI and ABSI were positively correlated with CAC, FRS, AIP, hsCRP and IL-6. Both CI and ABSI were negatively correlated with HGS. In age-weighted survival analysis, higher CI and ABSI were associated with higher risk of CVE (Wald test = 4.92, p = 0.027; Wald test = 4.95, p = 0.026, respectively) and all-cause mortality (Wald test = 5.24, p = 0.022; Wald test = 5.19, p = 0.023, respectively). In RMST analysis, low vs. high and middle tertiles of CI and ABSI associated with prolonged CVE-free time and death-free time, and these differences between groups increased over time. Abdominal fat deposit indices, CI and ABSI, predicted CV outcomes and all-cause mortality, and were significantly associated with the inflammatory status in CKD patients.

Unfractionated heparin versus nafamostat mesylate for anticoagulation during continuous kidney replacement therapy: an observational study

BackgroundUnfractionated heparin sodium and nafamostat mesylate have long been used as anticoagulants in continuous kidney replacement therapy (CKRT) where citrate is unavailable. This study aimed to determine whether heparin or nafamostat mesylate used during CKRT was associated with a longer filter life.MethodsIn this single-centre observational study, we included adult patients who required CKRT and used heparin or nafamostat mesylate for their first CKRT in the intensive care unit from September 1, 2013, to December 31, 2020. The primary outcome was filter life (from the start to the end of using the first filter). We used propensity score matching to adjust for the imbalance in patients’ characteristics and laboratory data at the start of CKRT and compared the outcomes between the two groups. We also performed restricted mean survival time analysis to compare the filter survival times.ResultsWe included 286 patients, 157 patients on heparin and 129 patients on nafamostat mesylate. After propensity score matching, the mean filter life with heparin was 1.58 days (N = 91, Standard deviation [SD], 1.52) and with nafamostat mesylate was 1.06 days (N = 91, SD, 0.94, p = 0.006). Multivariable regression analysis adjusted for confounding factors supported that heparin was associated with a longer filter life compared with nafamostat mesylate (regression coefficient, days, 0.52 [95% CI, 0.15, 0.89]). The between group difference of the restricted mean filter survival time in the matched cohort was 0.29 (95% CI, 0.07–0.50, p = 0.008).ConclusionCompared to nafamostat mesylate, heparin was associated with one-third to one-half a day longer filter life.Trial registrationNot applicable.

Does Surgical Resection Significantly Prolong the Long-Term Survival of Patients with Oligometastatic Pancreatic Ductal Adenocarcinoma? A Cross-Sectional Study Based on 18 Registries.

Pancreatic ductal adenocarcinoma (PDAC) is a type of lethal gastrointestinal malignancy. It is mainly discovered at, and diagnosed with, an advanced stage of metastasis. As the only potentially curative treatment for PDAC, surgical resection has an uncertain impact on the survival of these patients. As such, we aimed to investigate if patients with metastatic PDAC (mPDAC) benefit from surgery. Patients with pancreatic cancer in 18 registries of the Surveillance, Epidemiology, and End Results database between 2000 and 2018 were reviewed retrospectively. According to the American Joint Committee on Cancer (AJCC), the eighth edition staging system was utilized. Propensity score matching was applied to strengthen the comparability of the study. The impact of surgery on survival was evaluated by restricted mean survival time (RMST) and Kaplan-Meier analysis. A total of 210 well-matched mPDAC patients were included in the study. The 1 year, 3 year, and 5 year overall survival (OS) of patients undergoing surgery was 34.3%, 15.2%, and 11.0%, respectively. The 1 year, 3 year, and 5 year cancer-specific survival (CSS) of these patients was 36.1%, 19.7%, and 14.2%, respectively. RMST analysis revealed that mPDAC patients with surgery had better OS and CSS than those without (OS: 9.49 months vs. 6.45 months, p &lt; 0.01; CSS: 9.76 months vs. 6.54 months, p &lt; 0.01). Nevertheless, subgroup analysis demonstrated that such statistical significance especially existed in oligometastatic PDAC patients, which refers to those metastases that were limited in number and concentrated to a single organ in this study. Additionally, surgery was identified as a significant predictor for the long-term prognosis of patients (OS: [HR, hazard ratio] = 0.48, 95% CI: 0.36-0.65, p &lt; 0.001; CSS: HR = 0.45, 95% CI: 0.33-0.63, p &lt; 0.001). Lastly, a nomogram was established to predict whether an individual was suitable for surgical treatment in this study. Surgical resection significantly prolonged the long-term prognosis of oligometastatic PDAC patients. Such insights might broaden the management of patients with mPDAC to a large extent. However, a prospective clinical trial should be conducted before a recommendation of surgery in these patients.

Restricted Mean Survival Time Analysis to Estimate SGLT2i–Associated Heterogeneous Treatment Effects on Primary and Secondary Prevention of Cardiorenal Outcomes in Patients With Type 2 Diabetes in Taiwan

Increasing numbers of post hoc analyses have applied restricted mean survival time (RMST) analysis on the aggregated-level data from clinical trials to report treatment effects, but studies that use individual-level claims data are needed to determine the feasibility of RMST analysis for quantifying treatment effects among patients with type 2 diabetes in routine clinical settings. To apply RMST analysis for assessing sodium-glucose cotransporter-2 inhibitor (SGLT2i)-associated cardiovascular (CV) events and estimating heterogenous treatment effects (HTEs) on CV and kidney outcomes in routine clinical settings. This comparative effectiveness study of Taiwan's National Health Insurance Research Database examined 21 144 propensity score (PS)-matched pairs of patients with type 2 diabetes with SGLT2i and dipeptidyl peptidase-4 inhibitor (DPP4i) treatment for assessing CV outcomes, and 19 951 PS-matched pairs of patients with type 2 diabetes with SGLT2i and DPP4i treatment for assessing kidney outcomes. Patients were followed until December 31, 2018. Statistical analysis was performed from August 2021 to April 2022. Newly stable SGLT2i or DPP4i use in 2017. Study outcomes were CV events including hospitalization for heart failure (HHF), 3-point major adverse CV events (3P-MACE: nonfatal myocardial infarction [MI], nonfatal stroke, and CV death), 4-point MACE (4P-MACE: HHF and 3P-MACE), and all-cause death, and chronic kidney disease (CKD). RMST and Cox modeling analyses were applied to estimate treatment effects on study outcomes. After PS matching, the baseline patient characteristics were comparable between 21 144 patients with stable SGLT2i use (eg, mean [SD] age: 58.3 [10.7] years; 11 990 [56.7%] male) and 21 144 patients with stable DPP4i use (eg, mean [SD] age: 58.1 [11.6] years; 12 163 [57.5%] male) for assessing CV outcomes, and those were also comparable between 19 951 patients with stable SGLT2i use (eg, mean [SD] age: 58.1 [10.7] years; 11 231 [56.2%] male) and 19 951 patients with stable DPP4i use (eg, mean [SD] age: 57.9 [11.5] years; 11 340 [56.8%] male) for assessing kidney outcome. The 2-year difference in RMST between patients with SGLT2i use and patients with DPP4i use was 4.99 (95% CI, 3.56-6.42) days for HHF, 4.12 (95% CI, 2.72-5.52) days for 3P-MACE, 7.72 (95% CI, 5.83-9.61) days for 4P-MACE, 1.26 (95% CI, 0.47-2.04) days for MI, 2.70 (95% CI, 1.57-3.82) days for stroke, 0.69 (95% CI, 0.28-1.11) days for CV death, 6.05 (95% CI, 4.89-7.20) days for all-cause death, and 14.75 (95% CI, 12.99-16.52) days for CKD. Directions of hazard ratios from Cox modeling analyses were consistent with RMST estimates. No association was found between study treatment and the negative control outcome (dental visits for tooth care). Consistent results across sensitivity analyses using high-dimensional PS-matched and PS-weighting approaches supported the validity of primary analysis results. Largest difference in RMST of SGLT2i vs DPP4i use for HHF and CKD was found among patients with established heart failure (30.80 [95% CI, 5.08-56.51] days) and retinopathy (40.43 [95% CI, 31.74-49.13] days), respectively. In this comparative effectiveness study, RMST analysis was feasible for translating treatment effects into more clinical intuitive estimates and valuable for quantifying HTEs among diverse patients in routine clinical settings.

Percutaneous coronary intervention versus repeat surgical revascularization in patients with prior coronary artery bypass grafting: A systematic review and meta-analysis

ObjectivesRepeat coronary artery bypass grafting (RCABG) and percutaneous coronary intervention (PCI) are both used for the treatment of symptomatic patients with coronary artery disease and prior CABG, but the optimal treatment strategy remains unknown. We sought to perform a systematic review and meta-analysis to compare operative and follow-up outcomes following RCABG versus PCI in patients with prior CABG. MethodsMedline and Embase were searched for studies comparing RCABG versus PCI. The primary outcome was follow-up mortality, and secondary outcomes were follow-up repeat revascularization, operative mortality, periprocedural stroke, and myocardial infarction. Time-to-event outcomes were summarized as incidence rate ratios, whereas operative outcomes were summarized as odds ratios. A random effect meta-analysis was performed. Individual patient survival data was extracted from available survival curves and reconstructed using restricted mean survival time. ResultsAmong 2982 articles, 7 studies (9945 patients) were included. In the aggregated data meta-analysis, there was no difference in follow-up survival between RCABG and PCI (incidence rate ratio, 1.02; 95% CI, 0.83-1.25); however, restricted mean survival time analysis of individual data showed a survival benefit for RCABG over PCI (0.7 years; 95% CI, 0.23-1.19 years; P = .004). PCI was found to have a higher incidence rate of follow-up need for repeat revascularization (incidence rate ratio, 1.61; 95% CI, 1.16-2.23), but lower odds for operative mortality and stroke. No difference in the odds for myocardial infarction was found. ConclusionsIn patients with prior CABG, PCI is associated with better operative outcomes, but RCABG is associated with better survival and freedom from repeat revascularization at follow-up.

Regorafenib versus Cabozantinib as a Second-Line Treatment for Advanced Hepatocellular Carcinoma: An Anchored Matching-Adjusted Indirect Comparison of Efficacy and Safety

Introduction: The tyrosine kinase inhibitors regorafenib and cabozantinib remain the mainstay in second-line treatment of advanced hepatocellular carcinoma (HCC). There is currently no clear evidence of superiority in efficacy or safety to guide choice between the two treatments. Methods: We conducted an anchored matching-adjusted indirect comparison using individual patient data from the RESORCE trial of regorafenib and published aggregate data from the CELESTIAL trial of cabozantinib. Second-line HCC patients with prior sorafenib exposure of ≥3 months were included in the analyses. Hazard ratios (HRs) and restricted mean survival time (RMST) were estimated to quantify differences in overall survival (OS) and progression-free survival (PFS). Safety outcomes compared were rates of grade 3 or 4 adverse events (AEs), occurring in >10% of patients, and discontinuation or dose reduction due to treatment-related AEs. Results: After matching adjustment for differences in baseline patient characteristics, regorafenib showed a favorable OS (HR, 0.80; 95% CI: 0.54, 1.20) and ∼3-month-longer RMST over cabozantinib (RMST difference, 2.76 months; 95% CI: −1.03, 6.54), although not statistically significant. For PFS, there was no numerical difference in HR (HR, 1.00; 95% CI: 0.68, 1.49) and no clinically meaningful difference based on RMST analyses (RMST difference, −0.59 months; 95% CI: −1.83, 0.65). Regorafenib showed a significantly lower incidence of discontinuation (risk difference, −9.2%; 95% CI: −17.7%, −0.6%) and dose reductions (−15.2%; 95% CI: −29.0%, −1.5%) due to treatment-related AEs (any grade). Regorafenib was also associated with a lower incidence (not statistically significant) of grade 3 or 4 diarrhea (risk difference, −7.1%; 95% CI: −14.7%, 0.4%) and fatigue (−6.3%; 95% CI: −14.6%, 2.0%). Conclusion: This indirect treatment comparison suggests, relative to cabozantinib, that regorafenib could be associated with favorable OS (not statistically significant), lower rates of dose reductions and discontinuation due to treatment-related AEs, and lower rates of severe diarrhea and fatigue.

Risk of Hepatocellular Carcinoma With Tenofovir vs Entecavir Treatment for Chronic Hepatitis B Virus

Conventional meta-analyses with aggregated study-level data have yielded conflicting results for the comparative effectiveness of tenofovir disoproxil fumarate vs entecavir in reducing hepatocellular carcinoma (HCC) risk among patients with chronic hepatitis B virus. Within-study heterogeneity, between-study heterogeneity, and the inability of conventional meta-analyses to capture time-to-event data were associated with these results. To perform a reconstructed individual patient data meta-analysis of high-quality propensity score-matched studies to provide robust estimates for comparative HCC risk between groups receiving tenofovir or entecavir. Medline and Embase databases were searched from inception to October 6, 2021. The initial search yielded 3435 articles. Fourteen studies that used propensity score matching to balance baseline characteristics were included in the final analysis. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was followed. Individual patient data were reconstructed from Kaplan-Meier curves. Risk of HCC was evaluated using random-effects hazard ratios (HRs) via a shared-frailty model and a Cox proportional hazards model stratified by study group. Restricted mean survival time (RMST) analysis was conducted to account for varying estimated treatment effect across time. The comparative risk of HCC with tenofovir vs entecavir treatment. From analysis of 14 studes with 24 269 patients (10 534 receiving tenofovir and 13 735 receiving entecavir; mean age, 49.86 [95% CI, 48.35-51.36] years; 65.05% [95% CI, 58.60%-71.00%] men), tenofovir was associated with decreased HCC incidence compared with entecavir (stratified Cox HR, 0.85 [95% CI, 0.76-0.94] at 5 years; P = .002). However, there was no significant difference in subanalysis of clinical cohort studies (stratified Cox HR, 0.92 [95% CI, 0.80-1.06] at 5 years; P = .24). Among administrative database studies, proportionality was violated, and HRs could not be obtained via Cox proporational hazards-based models. The mean time to HCC development in RMST analysis was 2.8 (95% CI, 1.8-3.7) weeks longer (P < .001) for tenofovir vs entecavir at 5 years. The RMST analyses for other subgroups revealed either insignificant or minimal differences (<3 weeks) in the mean time to HCC at 5 years. In this meta-analysis, there was no clinically meaningful difference in the risk of HCC between patients who received entecavir and patients who received tenofovir. There was no difference between tenofovir and entecavir among clinical cohort studies, whereas the mean time to HCC development was less than 3 weeks longer for patients who received tenofovir vs those who received entecavir at year 5 among administrative database studies. The choice between tenofovir or entecavir should be decided based on patient convenience and tolerability.

Achievement of Developmental Milestones Recorded in Real Time: A Mobile App-Based Study

To clarify the characteristics of milestone achievement of Japanese infants using data assessed and recorded in real time via a Web-based app by caregivers. Between 2014 and 2019, the achievement of developmental milestones of 16 627 Japanese infants were recorded via the mobile app Papatto Ikuji along with pertinent information including sex, birth date, anthropometric measurements, and information on feeding. The milestones consisted of 20 items belonging to 4 domains: personal-social, fine motor-adaptative, language, and gross motor. The distribution of age at milestone achievement was compared with 4 conventional normative data. Subgroup analyses according to sex, season of birth, and feeding methods were performed with restricted mean survival time analysis. Age distributions of milestone achievement were generally similar in the app-based and conventional data. The exception was "Smile responsively," for which the age at achievement seemed higher in the app-based data. Subgroup analyses showed female-dominant sex differences in the achievement of person-social and language milestones. The results also showed seasonality in achievement of gross motor milestones, with earlier achievement in infants born in winter compared with those born in summer. We describe mobile app-based data on developmental milestone achievements that were recordedin real time. The app-based data were generally comparable with conventional normative data, suggesting that its potential to assess the development of children in real time. This could be used complementarily with the current well-child visits at scheduled time points.

What is the best method for long-term survival analysis?

In the Cox proportional hazards regression model, which is the most commonly used model in survival analysis, the effects of independent variables on survival may not be constant over time and proportionality cannot be achieved, especially when long-term follow-up is required. When this occurs, it would be better to use alternative methods that are more powerful for the evaluation of various effective independent variables, such as milestone survival analysis, restricted mean survival time analysis (RMST), area under the survival curve (AUSC) method, parametric accelerated failure time (AFT), machine learning, nomograms, and offset variable in logistic regression. The aim was to discuss the pros and cons of these methods, especially with respect to long-term follow-up survival studies.

Transthyretin V142I Genetic Variant and Cardiac Remodeling, Injury, and Heart Failure Risk in Black Adults

ObjectivesThis study evaluated the association of transthyretin (TTR) gene variant, in which isoleucine substitutes for valine at position 122 (V142I), with cardiac structure, function, and heart failure (HF) risk among middle-aged Black adults. BackgroundThe valine-to-isoleucine substitution in the TTR protein is prevalent in Black individuals and causes cardiac amyloidosis. MethodsJackson Heart Study participants without HF at baseline who had available data on the TTR V142I variant were included. The association of the TTR V142I variant with baseline echocardiographic parameters and repeated measures of high-sensitivity cardiac troponin-I (hs-cTnI) was assessed using adjusted linear regression models and linear mixed models, respectively. Adjusted Cox models, restricted mean survival time analysis, and Anderson-Gill models were constructed to determine the association of TTR V142I variant with the risk of incident HF, survival free of HF, and total HF hospitalizations. ResultsA total of 119 of 2,960 participants (4%) were heterozygous carriers of the TTR V142I variant. The TTR V142I variant was not associated with measures of cardiac parameters at baseline but was associated with a greater increase in high-sensitivity troponin I (hs-TnI) levels over time. In adjusted Cox models, TTR V142I variant carriers had significantly higher risk of incident HF (HR: 1.80; 95% CI: 1.07-3.05; P = 0.03), lower survival free of HF (mean difference: 4.0 year; 95% CI: 0.6-6.2 years); P = 0.02), and higher risk of overall HF hospitalizations (HR: 2.12; 95% CI: 1.23-3.63; P = 0.007). ConclusionsThe TTR V142I variant in middle-aged Black adults is not associated with adverse cardiac remodeling but was associated with a significantly higher burden of chronic myocardial injury, and greater risk of incident HF and overall HF hospitalizations.

Gemogenovatucel-T (Vigil) maintenance immunotherapy: 3-year survival benefit in homologous recombination proficient (HRP) ovarian cancer

ObjectivePreviously, Vigil demonstrated clinical benefit to prolong relapse free and overall survival in the BRCA wild-type (BRCA-wt), homologous recombination proficient (HRP) patient population. Here we provide long term follow up of 3 years in the HRP patient population enrolled in the Phase 2b VITAL study. MethodsHRP patients treated with Vigil (n = 25) or placebo (n = 20) who were enrolled in the Phase 2b, double-blind, placebo-controlled (VITAL study, NCT02346747) were followed for safety, OS and RFS. OS and RFS from time of randomization (immediately prior to maintenance therapy) and from debulking tissue procurement time points were analyzed by Kaplan-Meier (KM) and restricted mean survival time (RMST) analysis. ResultsOS for Vigil treated patients at 3 years has not yet reached median OS time point (95% CI 41.6 months to not achieved) compared to 26.9 (95% CI 17.4 months to not achieved) in placebo treated patients (HR 0.417 p = 0.020). Three year RFS also showed benefit to Vigil (stratified HR 0.405, p = 0.011) and no long term toxicity to Vigil was observed. Three year OS for Vigil of 70% vs. 40% for placebo from time of randomization was observed (p = 0.019). RMST analysis was also significant for OS (45.7 vs. 32.8 months, p = 0.008) and RFS (p = 0.025). ConclusionIn conclusion, results suggest durable activity of Vigil on RFS and OS and support further evaluation of Vigil in HRP ovarian cancer.