Impact of Finerenone-Induced Albuminuria Reduction on Chronic Kidney Disease Outcomes in Type 2 Diabetes : A Mediation Analysis.

BACKGROUND: In patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), finerenone, a nonsteroidal mineralocorticoid receptor antagonist, reduces cardiovascular and kidney failure outcomes. Finerenone also lowers the urine albumin-to-creatinine ratio (UACR). Whether finerenone-induced change in UACR mediates cardiovascular and kidney failure outcomes is unknown. OBJECTIVE: To quantify the proportion of kidney and cardiovascular risk reductions seen over a 4-year period mediated by a change in kidney injury, as measured by the change in log UACR between baseline and month 4. DESIGN: Post hoc mediation analysis using pooled data from 2 phase 3, double-blind trials of finerenone. (ClinicalTrials.gov: NCT02540993 and NCT02545049). SETTING: Several clinical sites in 48 countries. PATIENTS: 12 512 patients with CKD and T2D. INTERVENTION: Finerenone and placebo (1:1). MEASUREMENTS: Separate mediation analyses were done for the composite kidney (kidney failure, sustained ≥57% decrease in estimated glomerular filtration rate from baseline [approximately a doubling of serum creatinine], or kidney disease death) and cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) outcomes. RESULTS: At baseline, median UACR was 514 mg/g. A 30% or greater reduction in UACR was seen in 3338 (53.2%) patients in the finerenone group and 1684 (27.0%) patients in the placebo group. Reduction in UACR (analyzed as a continuous variable) mediated 84% and 37% of the treatment effect on the kidney and cardiovascular outcomes, respectively. When change in UACR was analyzed as a binary variable (that is, whether the guideline-recommended 30% reduction threshold was met), the proportions mediated for each outcome were 64% and 26%, respectively. LIMITATION: The current findings are not readily extendable to other drugs. CONCLUSION: In patients with CKD and T2D, early albuminuria reduction accounted for a large proportion of the treatment effect against CKD progression and a modest proportion of the effect against cardiovascular outcomes. PRIMARY FUNDING SOURCE: Bayer AG.

Empagliflozin, Health Status, and Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The EMPEROR-Preserved Trial.

BACKGROUND: Patients with heart failure with preserved ejection fraction have significant impairment in health-related quality of life. In the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), we evaluated the efficacy of empagliflozin on health-related quality of life in patients with heart failure with preserved ejection fraction and whether the clinical benefit observed with empagliflozin varies according to baseline health status. METHODS: Health-related quality of life was measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and 12, 32, and 52 weeks. Patients were divided by baseline KCCQ Clinical Summary Score (CSS) tertiles, and the effect of empagliflozin on outcomes was examined. The effect of empagliflozin on KCCQ-CSS, Total Symptom Score, and Overall Summary Score was evaluated. Responder analyses were performed to compare the odds of improvement and deterioration in KCCQ related to treatment with empagliflozin. RESULTS: The effect of empagliflozin on reducing the risk of time to cardiovascular death or heart failure hospitalization was consistent across baseline KCCQ-CSS tertiles (hazard ratio, 0.83 [95% CI, 0.69-1.00], 0.70 [95% CI, 0.55-0.88], and 0.82 [95% CI, 0.62-1.08] for scores <62.5, 62.5-83.3, and ≥83.3, respectively; P trend=0.77). Similar results were seen for total heart failure hospitalizations. Patients treated with empagliflozin had significant improvement in KCCQ-CSS versus placebo (+1.03, +1.24, and +1.50 at 12, 32, and 52 weeks, respectively; P<0.01); similar results were seen for Total Symptom Score and Overall Summary Score. At 12 weeks, patients on empagliflozin had higher odds of improvement ≥5 points (odds ratio, 1.23 [95% CI, 1.10-1.37]), ≥10 points (odds ratio, 1.15 [95% CI, 1.03-1.27]), and ≥15 points (odds ratio, 1.13 [95% CI, 1.02-1.26]) and lower odds of deterioration ≥5 points in KCCQ-CSS (odds ratio, 0.85 [95% CI, 0.75-0.97]). A similar pattern was seen at 32 and 52 weeks, and results were consistent for Total Symptom Score and Overall Summary Score. CONCLUSIONS: In patients with heart failure with preserved ejection fraction, empagliflozin reduced the risk for major heart failure outcomes across the range of baseline KCCQ scores. Empagliflozin improved health-related quality of life, an effect that appeared early and was sustained for at least 1 year. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057951.

Effects of Empagliflozin in Women and Men With Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Women and men with heart failure (HF) and preserved ejection fraction may differ in their clinical characteristics and their response to therapy. The aim of this study was to evaluate the influence of sex on the effects of empagliflozin in patients with HF and preserved ejection fraction enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction). METHODS: The effects of empagliflozin on the primary outcome of cardiovascular death or hospitalization for HF and on secondary outcomes (including total HF hospitalization, cardiovascular and all-cause mortality, and Kansas City Cardiomyopathy Questionnaire scores) were compared in women and men in the overall cohort and in subgroups defined by left ventricular ejection fraction (41%-49%, 50%-59%, and ≥60%). The effects of empagliflozin on physiological measures, including changes in systolic blood pressure, uric acid, hemoglobin, body weight, and natriuretic peptide levels, were also assessed. RESULTS: Of the 5988 patients randomized, 2676 (44.7%) were women. In the placebo arm, women tended to have lower risk for adverse outcomes, including a lower risk of all-cause mortality (hazard ratio, 0.69 [95% CI, 0.56, 0.84]). Compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for HF to a similar degree in both sexes (hazard ratio, 0.81 [95% CI, 0.69, 0.96] for men; and hazard ratio, 0.75 [95% CI, 0.61, 0.92] for women; Pinteraction=0.54). Sex did not modify the relationship between empagliflozin and outcomes across ejection fraction groups. Similar results were seen for secondary outcomes and physiological measures. Compared with placebo, empagliflozin improved the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score to a similar extent in both sexes (1.38 for men versus 1.63 for women at 52 weeks; Pinteraction=0.77); the results were similar for Kansas City Cardiomyopathy Questionnaire overall summary score and total summary score. CONCLUSIONS: Empagliflozin produced similar benefits on outcomes and health status in women and men with HF and preserved ejection fraction. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03057951.

Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction. METHODS: In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure. RESULTS: During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m2 of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin. CONCLUSIONS: Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.).

Recommendations for Statistical Reporting in Cardiovascular Medicine: A Special Report From the American Heart Association.

Statistical analyses are a crucial component of the biomedical research process and are necessary to draw inferences from biomedical research data. The application of sound statistical methodology is a prerequisite for publication in the American Heart Association (AHA) journal portfolio. The objective of this document is to summarize key aspects of statistical reporting that might be most relevant to the authors, reviewers, and readership of AHA journals. The AHA Scientific Publication Committee convened a task force to inventory existing statistical standards for publication in biomedical journals and to identify approaches suitable for the AHA journal portfolio. The experts on the task force were selected by the AHA Scientific Publication Committee, who identified 12 key topics that serve as the section headers for this document. For each topic, the members of the writing group identified relevant references and evaluated them as a resource to make the standards summarized herein. Each section was independently reviewed by an expert reviewer who was not part of the task force. Expert reviewers were also permitted to comment on other sections if they chose. Differences of opinion were adjudicated by consensus. The standards presented in this report are intended to serve as a guide for high-quality reporting of statistical analyses methods and results.

Benefit-Risk Tradeoffs in Assessment of New Drugs and Devices.

Balancing benefits and risks is a complex task that poses a major challenge, both to the approval of new medicines and devices by regulatory authorities and in therapeutic decision-making in practice. Several analysis methods and visualization tools have been developed to help evaluate and communicate whether the benefit-risk profile is favorable or unfavorable. In this White Paper, we describe approaches to benefit-risk assessment using qualitative approaches such as the Benefit Risk Action Team framework developed by the Pharmaceutical Research and Manufacturers of America, and the Benefit-Risk Framework developed by the United States Food and Drug Administration; and quantitative approaches such as the numbers needed to treat for benefit and harm, the benefit-risk ratio, and Incremental Net Benefit. We give illustrative examples of benefit-risk evaluations using 4 treatment interventions including sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes; a direct antithrombin agent, dabigatran, for reducing stroke and systemic embolism in patients with nonvalvular atrial fibrillation; transcatheter aortic valve replacement in patients with symptomatic severe aortic valve stenosis; and antiplatelet agents vorapaxar and prasugrel for reducing cardiovascular events in patients at high cardiovascular risk. Regular applications of structured benefit-risk assessment, whether qualitative, quantitative, or both, enabled by easy-to-understand graphical presentations that capture uncertainties around the benefit-risk metric, may aid shared decision-making and enhance transparency of those decisions.

Noninferiority Designed Cardiovascular Trials in Highest-Impact Journals.

BACKGROUND: Noninferiority trials are increasingly being performed. However, little is known about their methodological quality. We sought to characterize noninferiority cardiovascular trials published in the highest-impact journals, features that may bias results toward noninferiority, features related to reporting of noninferiority trials, and the time trends. METHODS: We identified cardiovascular noninferiority trials published in JAMA, Lancet, or New England Journal of Medicine from 1990 to 2016. Two independent reviewers extracted the data. Data elements included the noninferiority margin and the success of studies in achieving noninferiority. The proportion of trials showing major or minor features that may have affected the noninferiority inference was determined. Major factors included the lack of presenting the results in both intention-to-treat and per-protocol/as-treated cohorts, α>0.05, the new intervention not being compared with the best alternative, not justifying the noninferiority margin, and exclusion or loss of ≥10% of the cohort. Minor factors included suboptimal blinding, allocation concealment, and others. RESULTS: From 2544 screened studies, we identified 111 noninferiority cardiovascular trials. Noninferiority margins varied widely: risk differences of 0.4% to 25%, hazard ratios of 1.05 to 2.85, odds ratios of 1.1 to 2.0, and relative risks of 1.1 to 1.8. Eighty-six trials claimed noninferiority, of which 20 showed superiority, whereas 23 (21.1%) did not show noninferiority, of which 8 also demonstrated inferiority. Only 7 (6.3%) trials were considered low risk for all the major and minor biasing factors. Among common major factors for bias, 41 (37%) did not confirm the findings in both intention-to-treat and per-protocol/as-treated cohorts and 4 (3.6%) reported discrepant results between intention-to-treat and per-protocol analyses. Forty-three (38.7%) did not justify the noninferiority margin. Overall, 27 (24.3%) underenrolled or had >10% exclusions. Sixty trials (54.0%) were open label. Allocation concealment was not maintained or unclear in 11 (9.9%). Publication of noninferiority trials increased over time (P<0.001). Fifty-two (46.8%) were published after 2010 and had a lower risk of methodological or reporting limitations for major (P=0.03) and minor factors (P=0.002). CONCLUSIONS: Noninferiority trials in highest-impact journals commonly conclude noninferiority of the tested intervention, but vary markedly in the selected noninferiority margin, and frequently have limitations that may impact the inference related to noninferiority.

Heart Failure End Points in Cardiovascular Outcome Trials of Sodium Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Critical Evaluation of Clinical and Regulatory Issues.

Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting.

Non-inferiority trials using a surrogate marker as the primary endpoint: An increasing phenotype in cardiovascular trials.

BACKGROUND/AIMS: Non-inferiority trials are increasing in cardiovascular medicine, with approval of many drugs and devices on the basis of such studies. Surrogate markers as primary endpoints have been also more frequently used for efficient assessment of cardiovascular interventions. However, there is uncertainty about their concordance with clinical outcomes. Non-inferiority design using a surrogate marker as a primary endpoint may pose particular challenges in clinical interpretation. We sought to explore the publication trends, methodology, and reporting features of non-inferiority cardiovascular trials that used a primary surrogate marker as the primary endpoint. METHODS: We searched six high-impact journals (The New England Journal of Medicine, The Journal of the American Medical Association, The Lancet, The Journal of the American College of Cardiology, Circulation, and European Heart Journal) from 1 January 1990 to 31 December 2018 and identified non-inferiority cardiovascular trials that used a surrogate marker as the primary endpoint. We assessed the non-inferiority margin reported in the manuscript and other publicly available platforms (e.g. protocol, clinicaltrials.gov). We also determined whether the included non-inferiority trials with surrogate markers as primary endpoints were followed by clinical outcome trials. RESULTS: We screened 15,553 publications and identified 247 cardiovascular trials that used a non-inferiority design. Of these, 37 had a surrogate marker as a primary endpoint (18 drug trials, 13 device trials, 6 others). All of these non-inferiority trials with surrogate outcomes were published after 2000, mostly in cardiology journals (13 in The Journal of the American College of Cardiology, 9 in European Heart Journal, 8 in Circulation, 6 in The Lancet, 1 in The New England Journal of Medicine), and their publication rate increased over time (p < 0.001 for linear trend). The median number of patients in the primary analysis was 300 (interquartile range: 202-465). The study protocol or a methods paper was publicly available for only 13 (35.1%) trials, of which the non-inferiority margin was not reported in 4 trials. In 16 studies (43.2%), the manuscript did not acknowledge the limitations of using a surrogate endpoint or the need for a definitive clinical outcome trial. Thirty-four trials (91.9%) concluded that the tested intervention met non-inferiority criteria. However, only five (13.5%) were followed by clinical outcomes trials the results of which did not always confirm non-inferiority. CONCLUSION: Non-inferiority trials that use a surrogate marker as the primary endpoint are being increasingly performed. However, these trials pose particular challenges with design, reporting, and interpretation, which are not systematically and consistently addressed or reported.

Enhancing Insights into Pulmonary Vascular Disease through a Precision Medicine Approach. A Joint NHLBI-Cardiovascular Medical Research and Education Fund Workshop Report.

The Division of Lung Diseases of the NHLBI and the Cardiovascular Medical Education and Research Fund held a workshop to discuss how to leverage the anticipated scientific output from the recently launched "Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics" (PVDOMICS) program to develop newer approaches to pulmonary vascular disease. PVDOMICS is a collaborative, protocol-driven network to analyze all patient populations with pulmonary hypertension to define novel pulmonary vascular disease (PVD) phenotypes. Stakeholders, including basic, translational, and clinical investigators; clinicians; patient advocacy organizations; regulatory agencies; and pharmaceutical industry experts, joined to discuss the application of precision medicine to PVD clinical trials. Recommendations were generated for discussion of research priorities in line with NHLBI Strategic Vision Goals that include: (1) A national effort, involving all the stakeholders, should seek to coordinate biosamples and biodata from all funded programs to a web-based repository so that information can be shared and correlated with other research projects. Example programs sponsored by NHLBI include PVDOMICS, Pulmonary Hypertension Breakthrough Initiative, the National Biological Sample and Data Repository for PAH, and the National Precision Medicine Initiative. (2) A task force to develop a master clinical trials protocol for PVD to apply precision medicine principles to future clinical trials. Specific features include: (a) adoption of smaller clinical trials that incorporate biomarker-guided enrichment strategies, using adaptive and innovative statistical designs; and (b) development of newer endpoints that reflect well-defined and clinically meaningful changes. (3) Development of updated and systematic variables in imaging, hemodynamic, cellular, genomic, and metabolic tests that will help precisely identify individual and shared features of PVD and serve as the basis of novel phenotypes for therapeutic interventions.

The rationale for Heart Team decision-making for patients with stable, complex coronary artery disease.

Stable complex coronary artery disease can be treated with coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), or medical therapy. Multidisciplinary decision-making has gained more emphasis over the recent years to select the most optimal treatment strategy for individual patients with stable complex coronary artery disease. However, the so-called 'Heart Team' concept has not been widely implemented. Yet, decision-making has shown to remain suboptimal; there is large variability in PCI-to-CABG ratios, which may predominantly be the consequence of physician-related factors that have raised concerns regarding overuse, underuse, and inappropriate selection of revascularization. In this review, we summarize these and additional data to support the statement that a multidisciplinary Heart Team consisting of at least a clinical/non-invasive cardiologist, interventional cardiologist, and cardiac surgeon, can together better analyse and interpret the available diagnostic evidence, put into context the clinical condition of the patient as well as consider individual preference and local expertise, and through shared decision-making with the patient can arrive at a most optimal joint treatment strategy recommendation for patients with stable complex coronary artery disease. In addition, other aspects of Heart Team decision-making are discussed: the organization and logistics, involvement of physicians, patients, and assisting personnel, the need for validation, and its limitations.

Same evidence different recommendations: a methodological assessment of transatlantic guidelines for the management of valvular heart disease.

OBJECTIVES: The aim of this study was to identify methodological variations leading to varied recommendations between the American College of Cardiology (ACC)/American Heart Association (AHA) and the European Society of Cardiology (ESC)/European Association for Cardio-Thoracic Surgery (EACTS) valvular heart disease guidelines and to suggest foundational steps towards standardizing guideline development. METHODS: An in-depth analysis was conducted to evaluate the methodologies used in developing the transatlantic guidelines for managing valvular heart disease. The evaluation was benchmarked against the standards proposed by the Institute of Medicine. RESULTS: Substantial discrepancies were noted in the methodologies utilized in development processes, including Writing Committee composition, evidence evaluation, conflict of interest management and voting processes. Furthermore, despite their mutual differences, both methodologies demonstrate notable deviations from the Institute of Medicine standards in several essential areas, including literature review and evidence grading. These dual variances likely influenced divergent treatment recommendations. For example, the ESC/EACTS recommends transcatheter edge-to-edge repair for patients with chronic severe mitral regurgitation ineligible for mitral valve surgery, while the ACC/AHA recommends transcatheter edge-to-edge repair based on anatomy, regardless of surgical risk. ESC/EACTS guidelines recommend a mechanical aortic prosthesis for patients under 60, while ACC/AHA guidelines recommend it for patients under 50. Notably, the ACC/AHA and ESC/EACTS guidelines have differing age cut-offs for surgical over transcatheter aortic valve replacement (<65 and <75 years, respectively). CONCLUSIONS: Variations in methodologies for developing clinical practice guidelines have resulted in different treatment recommendations that may significantly impact global practice patterns. Standardization of essential processes is vital to increase the uniformity and credibility of clinical practice guidelines, ultimately improving healthcare quality, reducing variability and enhancing trust in modern medicine.

Conflicts of interest in clinical practice: lessons learned from cardiovascular medicine.

Cardiovascular diseases represent a major burden worldwide, and clinical trials are critical to define treatment improvements. Since various conflicts of interest (COIs) may influence trials at multiple levels, cardiovascular research represents a paradigmatic example to analyze their effects and manage them effectively to re-establish the centrality of evidence-based medicine.Despite the manifest role of industry, COIs may differently affect both sponsored and non-sponsored studies in many ways. COIs influence may start from the research question, data collection and adjudication, up to result reporting, including the spin phenomenon. Outcomes and endpoints (especially composite) choice and definitions also represent potential sources for COIs interference. Since large randomized controlled trials significantly influence international guidelines, thus impacting also clinical practice, their critical assessment for COIs is mandatory. Despite specific protocols aimed to mitigate COI influence, even scientific societies and guideline panels may not be totally free from COIs, negatively affecting their accountability and trustworthiness.Shared rules, awareness of COI mechanisms and transparency with external data access may help promoting evidence-based research and mitigate COIs impact. Managing COIs effectively should preserve public trust in the cardiovascular profession without compromising the positive relationships between investigators and industry.

Non-inferiority study design: lessons to be learned from cardiovascular trials.

The non-inferiority trial design has gained popularity within the last decades to compare a new treatment to the standard active control. In contrast to superiority trials, this design is complex and is based on assumptions that cannot be validated directly. Many readers and even investigators, therefore, have difficulty grasping the full methodological nature of non-inferiority trials. Non-inferiority margins are often arbitrarily chosen such that a favourable margin can bias a trial towards declaring non-inferiority. Pitfalls of non-inferiority trials are not fully appreciated, and without having identified these shortcomings, objective conclusions from non-inferiority trials cannot be made. This methodological review elaborates on what is a non-inferiority trial, why such a trial is performed, what the hazards are, and how conclusions from non-inferiority trials are derived, by providing examples of recent cardiovascular trials.

Risk of Bias in Randomized Clinical Trials Comparing Transcatheter and Surgical Aortic Valve Replacement: A Systematic Review and Meta-analysis.

Importance: Recent European Society of Cardiology/European Association for Cardio-Thoracic Surgery (ESC/EACTS) guidelines highlighted some concerns about the randomized clinical trials (RCTs) comparing transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) for aortic stenosis. Quantification of these biases has not been previously performed. Objective: To assess whether randomization protects RCTs comparing TAVI and SAVR from biases other than nonrandom allocation. Data Sources: A systematic review of the literature between January 1, 2007, and June 6, 2022, on MEDLINE, Embase, and Cochrane Central Register of Controlled Trials was performed. Specialist websites were also checked for unpublished data. Study Selection: The study included RCTs with random allocation to TAVI or SAVR with a maximum 5-year follow-up. Data Extraction and Synthesis: Data extraction was performed by 2 independent investigators following the PRISMA guidelines. A random-effects meta-analysis was used for quantifying pooled rates and differential rates between treatments of deviation from random assigned treatment (DAT), loss to follow-up, and receipt of additional treatments. Main Outcomes and Measures: The primary outcomes were the proportion of DAT, loss to follow-up, and patients who were provided additional treatments and myocardial revascularization, together with their ratio between treatments. The measures were the pooled overall proportion of the primary outcomes and the risk ratio (RR) in the TAVI vs SAVR groups. Results: The search identified 8 eligible trials including 8849 participants randomly assigned to undergo TAVI (n = 4458) or SAVR (n = 4391). The pooled proportion of DAT among the sample was 4.2% (95% CI, 3.0%-5.6%), favoring TAVI (pooled RR vs SAVR, 0.16; 95% CI, 0.08-0.36; P < .001). The pooled proportion of loss to follow-up was 4.8% (95% CI, 2.7%-7.3%). Meta-regression showed a significant association between the proportion of participants lost to follow-up and follow-up time (slope, 0.042; 95% CI, 0.017-0.066; P < .001). There was an imbalance of loss to follow-up favoring TAVI (RR, 0.39; 95% CI, 0.28-0.55; P < .001). The pooled proportion of patients who had additional procedures was 10.4% (95% CI, 4.4%-18.5%): 4.6% (95% CI, 1.5%-9.3%) in the TAVI group and 16.5% (95% CI, 7.5%-28.1%) in the SAVR group (RR, 0.27; 95% CI, 0.15-0.50; P < .001). The imbalance between groups also favored TAVI for additional myocardial revascularization (RR, 0.40; 95% CI, 0.24-0.68; P < .001). Conclusions and Relevance: This study suggests that, in RCTs comparing TAVI vs SAVR, there are substantial proportions of DAT, loss to follow-up, and additional procedures together with systematic selective imbalance in the same direction characterized by significantly lower proportions of patients undergoing TAVI that might affect internal validity.