UNASSIGNED: We aimed to perform a meta-analysis of randomized trials comparing long-term outcomes of patients undergoing transcatheter aortic valve replacement (TAVR) vs surgical aortic valve replacement (SAVR) for severe aortic stenosis. The short-term efficacy and safety of TAVR are proven, but long-term outcomes are unclear.
UNASSIGNED: We included randomized controlled trials comparing TAVR vs SAVR at the longest available follow-up. The primary end point was death or disabling stroke. Secondary end points were all-cause mortality, cardiac mortality, stroke, pacemaker implantation, valve thrombosis, valve gradients, and moderate-to-severe paravalvular leaks. The study is registered with PROSPERO (CRD42023481856).
UNASSIGNED: Seven trials (N = 7785 patients) were included. Weighted mean trial follow-up was 5.76 ± 0.073 years. Overall, no significant difference in death or disabling stroke was observed with TAVR vs SAVR (HR, 1.02; 95% CI, 0.93-1.11; P = .70). Mortality risks were similar. TAVR resulted in higher pacemaker implantation and moderate-to-severe paravalvular leaks compared to SAVR. Results were consistent across different surgical risk profiles. As compared to SAVR, self-expanding TAVR had lower death or stroke risk (P interaction = .06), valve thrombosis (P interaction = .06), and valve gradients (P interaction < .01) but higher pacemaker implantation rates than balloon-expandable TAVR (P interaction < .01).
UNASSIGNED: In severe aortic stenosis, the long-term mortality or disabling stroke risk of TAVR is similar to SAVR, but with higher risk of pacemaker implantation, especially with self-expanding valves. As compared with SAVR, the relative reduction in death or stroke risk and valve thrombosis was greater with self-expanding than with balloon-expandable valves.

UNASSIGNED: Noninferiority trials are increasingly common in cardiovascular medicine, but their reporting and interpretation are challenging, particularly when an absolute risk difference is used as noninferiority margin.
UNASSIGNED: This study aimed to investigate the effect of using absolute rather than relative noninferiority margins in cardiovascular trials.
UNASSIGNED: We reviewed noninferiority trials presented at major cardiovascular conferences from 2015 to 2022 and published within the same period. Based on the actual versus anticipated event rates in the control group, we recalculated the absolute noninferiority margin and re-assessed the trial results. The primary outcome of interest was the proportion of trials with a different interpretation after recalculation. Additionally, we analyzed the conclusion statements of these trials to determine if cautionary notes for the interpretation of study results were included.
UNASSIGNED: We analyzed a total of 768 trials, of which 88 had a noninferiority design and 66 used an absolute noninferiority margin. Of 48 comparisons from 45 trials qualifying for the analysis, 11 (22.9%) had divergent results after recalculation of the absolute noninferiority margin based on the observed rather than anticipated event rate. Ten trials originally claiming noninferiority, did not meet it after the margin recalculation. All of them did not include statements suggesting cautionary interpretation of the study results in the conclusion section. Compared with the other trials, these displayed a larger median difference between anticipated and recalculated noninferiority margins (44.7% [IQR: 38.6%-56.7%] vs 15.3% [IQR: -1.5% to 28.9%]; P < 0.001).
UNASSIGNED: Recalculating noninferiority margins based on actual event rates, rather than anticipated ones, led to different outcomes in approximately 1 out of 4 cardiovascular trials, with most divergent trials lacking cautionary interpretation. These findings emphasize the importance of using or supplementing the relative noninferiority margin, particularly in studies with significant deviations between observed and expected event rates. This underscores the critical need for enhanced methodological and reporting standards in noninferiority trials, especially those employing absolute margins.

In \"Explanatory and Pragmatic Attitudes in Therapeutic Trials\", Schwatrz and Lelouch describe two approaches to the design of trials, \"… the first \"explanatory\", the second \"pragmatic\". They explained \"… the biologist may be interested to know whether the drugs differ in their effects … the explanatory approach\". Biologically endpoints might determine whether it was better to give androgen deprivation therapy (ADT) before or after external beam radiation (EBRT) (i.e., does the sequence of treatments matter). Alternatively, if the arms focus on a clinical endpoint, this is considered … \"the pragmatic approach\". An example of a clinically relevant endpoint is overall survival (OS). A real-world example of this are the two randomized controlled trials (RCTs) evaluating the role of prophylactic whole pelvic radiotherapy (WPRT) conducted by the Radiation Therapy Oncology Group (RTOG). RTOG 9413 evaluated possible interactions between the sequence of drugs and volume irradiated, while RTOG/NRG 0924 focuses on OS. There appears to be a common pattern of \"what not to do\", or \"design errors\" made by a number of investigators, that I call the \"three sins\". I posit that the prospects for a well-designed pragmatic RCT are likely to be high if these \"three sins\" are avoided/minimized. The \"three sins\" alluded to are: 1. You can\'t prove something doesn\'t work by treating people who don\'t need the treatment. 2. You can\'t prove something does not work if the treatment is not done properly. 3. You can\'t prove something does not work with an underpowered study.

BACKGROUND: Randomized controlled trials are the gold standard for determining treatment efficacy in medicine. To deter harmful practices such as p-hacking and hypothesizing after the results are known, any analysis of subgroups and secondary outcomes must be documented and pre-specified. However, they can still introduce bias (and routinely do) if they are not treated with the same consideration as the primary analysis.
METHODS: We describe several sources of bias that affect subgroup and secondary outcome analyses using published randomized trials and causal directed acyclic graphs (DAGs).
RESULTS: We use the RECOVERY and START trials to elucidate sources of bias in analyses of subgroups and secondary outcomes. Chance imbalance can occur if the distribution of prognostic variables is not sought for any given subgroup analysis as for the main analysis. This differential distribution of prognostic variables can also occur in analyses of secondary outcomes. Selection bias can occur if the subgroup variable is causally related to staying in the trial. Given loss to follow up is not normally addressed in subgroups, attrition bias can pass unnoticed in these cases. In every case, the solution is to take the same considerations for these analyses as we do for primary analyses.
CONCLUSIONS: Approval of treatments and clinical decisions can occur based on results from subgroup or secondary outcome analyses. Thus, it is important to give them the same treatment as primary analyses to avoid preventable biases.

BACKGROUND: To evaluate if comprehensive geriatric assessment (CGA)-guided care improves health-related quality of life (HRQL) in older adults with cancer compared to usual care.
METHODS: Relevant randomized controlled trials (RCTs) were identified through biomedical databases. Meta-analyses using DerSimonian-Laird model summarized the difference in the mean change of HRQL scores from baseline across various time points, with evidence certainty assessed by the GRADE tool. Logistic regression via generalized estimating equations analyzed predictors of HRQL improvement.
RESULTS: Potential improvement in the global HRQL score by CGA-guided care at 3 months (Cohen\'s d 0.27, 95 % CI -0.03-0.58, moderate certainty), could not be excluded. Larger RCTs or those mandating CGA before initiating anti-cancer treatment were predictors of improved HRQL.
CONCLUSIONS: The effects of CGA-guided care on HRQL were variable. Larger RCTs and those mandating pre-treatment CGA tended to report improved HRQL.

Randomized trials can take more explanatory or more pragmatic approaches. Pragmatic studies, conducted closer to real-world conditions, assess treatment effectiveness while considering factors like protocol adherence. In these studies, intention-to-treat (ITT) analysis is fundamental, comparing outcomes regardless of the actual treatment received. Explanatory trials, conducted closer to optimal conditions, evaluate treatment efficacy, commonly with a per protocol (PP) analysis, which includes only outcomes from adherent participants. ITT and PP are strategies used in the conception, design, conduct (protocol execution), analysis, and interpretation of trials. Each serves distinct objectives. While both can be valid, when bias is controlled, and complementary, each has its own limitations. By excluding nonadherent participants, PP analyses can lose the benefits of randomization, resulting in group differences in factors (influencing adherence and outcomes) that were present at baseline. Additionally, clinical and social factors affecting adherence can also operate during follow-up, that is, after randomization. Therefore, incomplete adherence may introduce postrandomization confounding. Conversely, ITT analysis, including all participants regardless of adherence, may dilute treatment effects. Moreover, varying adherence levels could limit the applicability of ITT findings in settings with diverse adherence patterns. Both ITT and PP analyses can be affected by selection bias due to differential losses and nonresponse (ie, missing data) during follow-up. Combining high-quality and comprehensive data with advanced statistical methods, known as g-methods, like inverse probability weighting, may help address postrandomization confounding in PP analysis as well as selection bias in both ITT and PP analyses.

The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data (SISAQOL) initiative was established in 2016 to assess the quality and standardization of patient-reported outcomes (PRO) data analysis in randomized controlled trials (RCTs) on advanced breast cancer. The initiative identified deficiencies in PRO data reporting, including nonstandardized methods for handling missing data. This study evaluated the reporting of health-related quality of life (HRQOL) in Japanese cancer RCTs to provide insights into the state of PRO reporting in Japan. The study reviewed PubMed articles published from 2010 to 2018. Eligible studies included Japanese cancer RCTs with ≥50 adult patients (≥50% were Japanese) with solid tumors receiving anticancer treatments. The evaluation criteria included clarity of the HRQOL hypotheses, multiplicity testing, primary analysis methods, and reporting of clinically meaningful differences. Twenty-seven HRQOL trials were identified. Only 15% provided a clear HRQOL hypothesis, and 63% examined multiple HRQOL domains without adjusting for multiplicity. Model-based methods were the most common statistical methods for the primary HRQOL analysis. Only 22% of the trials explicitly reported clinically meaningful differences in HRQOL. Baseline assessments were reported in most trials, but only 26% reported comparisons between the treatment groups. HRQOL analysis was based on the intention-to-treat population in 19% of the trials, and 74% reported compliance at follow-up; however, 41% did not specify how missing values were handled. Although the rates of reporting clinical hypotheses and clinically meaningful differences were relatively low, the current state of HRQOL evaluation in the Japanese cancer RCT appears comparable to that of previous studies.

Equity and health equity are fundamental pillars in fostering a just and inclusive society. While equity underscores fairness in resource allocation and opportunity, health equity aims to eradicate avoidable health disparities among social groups. The concept of harms in interventions-undesirable consequences associated with the use of interventions-often varies across populations due to biological and social factors, necessitating a nuanced understanding. An equity lens reveals disparities in harm distribution, urging researchers and policymakers to address these differences in their decision-making processes. Furthermore, interventions, even well-intentioned ones, can inadvertently exacerbate disparities, emphasizing the need for comprehensive harm assessment. Integrating equity considerations in research practices and trial methodologies, through study design or through practices such as inclusive participant recruitment, is pivotal in advancing health equity. By prioritizing interventions that address disparities and ensuring inclusivity in research, we can foster a more equitable healthcare system.

OBJECTIVE: There is uncertainty about the optimum dose of omega-3 fatty acids for anxiety symptoms. We aimed to find the dose-dependent effect of omega-3 supplementation on anxiety symptoms.
METHODS: We systematically reviewed PubMed, Scopus, and Web of Science until December 2022 to find randomized trials that assessed the effects of omega-3 fatty acids supplementation on anxiety symptoms in adults. Investigators performed the literature search and screened the titles/abstracts and full-texts and between-reviewer agreement was assessed as Cohen\'s kappa coefficient. We conducted a random-effects dose-response meta-analysis to estimate standardized mean differences (SMD) and 95% confidence intervals (CIs) and assessed the certainty of evidence using the GRADE framework.
RESULTS: A total of 23 trials with 2189 participants were included. Each 1 gram per day supplementation with omega-3 fatty acids resulted in a moderate decrease in anxiety symptoms (SMD: -0.70, 95%CI: -1.17, -0.22; GRADE = low). The non-linear dose-response analysis indicated the greatest improvement at 2 g/d (SMD: -0.93, 95%CI: -1.85, -0.01), and that supplementation in a dose lower than 2 g/d did not affect anxiety symptoms. Omega-3 fatty acids did not increase adverse events (odds ratio: 1.20, 95%CI: 0.89, 1.61; GRADE = moderate).
CONCLUSIONS: The present dose-response meta-analysis suggested evidence of very low certainty that supplementation with omega-3 fatty acids may significantly improve anxiety symptoms, with the greatest improvements at 2 g/d. More trials with better methodological quality are needed to reach more robust evidence.
BACKGROUND: PROSPERO (CRD42022309636).

OBJECTIVE: To summarize current evidence of high-dose influenza vaccine (HD-IV) vs standard-dose (SD-IV) regarding severe clinical outcomes.
METHODS: A prespecified meta-analysis was conducted to assess relative vaccine effectiveness (rVE) of HD-IV vs SD-IV in reducing the rates of (1) pneumonia and influenza (P&I) hospitalization, (2) all hospitalizations, and (3) all-cause death in adults ≥ 65 years in randomized controlled trials. Pooled effect sizes were estimated using fixed-effects models with the inverse variance method.
RESULTS: Five randomized trials were included encompassing 105,685 individuals. HD-IV vs SD-IV reduced P&I hospitalizations (rVE: 23.5 %, [95 %CI: 12.3 to 33.2]). HD-IV vs SD-IV also reduced rate of all-cause hospitalizations (rVE: 7.3 %, [95 %CI: 4.5 to 10.0]). No significant differences were observed in death rates (rVE = 1.6 % ([95 %CI: -2.0 to 5.0]) in HD-IV vs SD-IV. Sensitivity analyses omitting trials with participants sharing the same comorbidity, trials with ≥ 100 events, and random-effects models provided comparable estimates for all outcomes.
CONCLUSIONS: HD-IV reduced the incidence of P&I and all-cause hospitalization vs SD-IV in adults ≥ 65 years in randomized trials, through no significant difference was observed in all-cause death rates. These findings, supported by evidence from several randomized studies, can benefit from replication in a fully powered, individually randomized trial.