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Objective: To investigate the relationship of body mass index (BMI) with short- and long-term outcomes after transcatheter aortic valve replacement (TAVR)., Patients and Methods: The relationship between BMI and baseline characteristics and procedural characteristics was assessed for 31,929 patients who underwent TAVR between November 1, 2011, and March 31, 2015, from the STS/ACC TVT Registry. Registry data on 20,429 patients were linked to the Centers for Medicare and Medicaid Services to assess the association of BMI with 30-day and 1-year mortality using multivariable Cox proportional hazards models. The effect of BMI on mortality was also assessed with BMI as a continuous variable. Restricted cubic regression splines were used to model the effect of BMI and to determine appropriate cut points of BMI., Results: Among 31,929 patients, 806 (2.5%) were underweight (BMI, <18.5 kg/m 2 ), 10,755 (33.7%) had normal weight (BMI, 18.5- 24.9 kg/m 2 ), 10,691 (33.5%) were overweight (BMI, 25.0-29.9 kg/m 2 ), 5582 (17.5%) had class I obesity (BMI, 30.0-34.9 kg/m 2 ), 2363 (7.4%) had class II obesity (BMI, 35.0-39.9 kg/m 2 ), and 1732 (5.4%) had class III obesity (BMI, ≥40 kg/m 2 ). Patients in various BMI categories were different in most baseline and procedural characteristics. On multivariable analysis, compared with normal-weight patients, underweight patients had higher mortality at 30 days and at 1 year after TAVR (hazard ratio [HR], 1.35; 95% CI, 1.02-1.78 and HR, 1.41; 95% CI, 1.17-1.69, respectively), whereas overweight patients and those with class I and II obesity had a decreased risk of mortality at 1 year (HR, 0.88; 95% CI, 0.81-0.95, HR, 0.80; 95% CI, 0.72-0.89, and HR, 0.84; 95% CI, 0.72-0.98, respectively). For BMI of 30 kg/m 2 or less, each 1-kg/m 2 increase was associated with a 2% and 4% decrease in the risk of 30-day and 1-year mortality, respectively; for BMI greater than 30 kg/m 2 , a 1-kg/m 2 increase was associated with a 3% increased risk of 30-day mortality but not with 1-year mortality., Conclusion: Results of this large registry study evaluating the relationship of BMI and outcomes after TAVR support the existence of an obesity paradox among patients with severe aortic stenosis undergoing TAVR., (Copyright © 2019. Published by Elsevier Inc.)

Background: Noninvasive measurement of myocardial contractility (end-systolic wall stress-adjusted change in left ventricular ejection fraction from rest to exercise [ΔLVEF - ΔESS]) predicts heart failure, subnormal LVEFrest, and sudden death in asymptomatic patients with chronic severe aortic regurgitation (AR). Here we assess the relation of preoperative ΔLVEF - ΔESS to survival after aortic valve replacement (AVR)., Methods: Patients who underwent AVR for chronic, isolated, pure severe AR (n = 66) were followed for 13.0 ± 6.4 event-free years. Preoperative ΔLVEF - ΔESS (from combined echocardiographic and radionuclide cineangiographic data) enabled cohort stratification into 3 terciles (-1 to -11% [normal or mild] contractility deficit, -12 to -16% [moderate], and ≤-17% [severe], identical with segregation in our earlier study) to relate preoperative contractility to postoperative survival and to age- and gender-matched US census data., Results: Since AVR, 22 patients died (average annual risk [AAR] for all-cause mortality for the entire co hort = 3.15%). Preoperative ΔLVEF - ΔESS predicted postoperative survival (p = 0.009, log rank test). By contractility terciles, all-cause AARs were 1.44, 2.58, and 6.40%. Survival was lower than among US census comparators (p < 0.02), but the "mild" tercile was indistinguishable from census data (p = ns). By multivariable Cox regression, survival prediction by pre-AVR ΔLVEF - ΔESS was independent of, and superior to, prediction by age at surgery, gender, preoperative functional class, LVEFrest, LVEFexercise, change in LVEFrest to exercise, and LV diastolic or systolic dimensions (p ≤ 0.01, pre-AVR ΔLVEF - ΔESS vs. other covariates)., Conclusion: In severe AR, preoperative contractility predicts post-AVR survival and may be prognostically superior to clinical, geometric and performance descriptors, potentially impacting on patient selection for surgery., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Mitral regurgitation (MR) is one of the most prevalent valve disorders and has numerous etiologies, including primary (organic) MR, due to underlying degenerative/structural mitral valve (MV) pathology, and secondary (functional) MR, which is principally caused by global or regional left ventricular remodeling and/or severe left atrial dilation. Diagnosis and optimal management of MR requires integration of valve disease and heart failure specialists, MV cardiac surgeons, interventional cardiologists with expertise in structural heart disease, and imaging experts. The introduction of transcatheter MV therapies has highlighted the need for a consensus approach to pragmatic clinical trial design and uniform endpoint definitions to evaluate outcomes in patients with MR. The Mitral Valve Academic Research Consortium is a collaboration between leading academic research organizations and physician-scientists specializing in MV disease from the United States and Europe. Three in-person meetings were held in Virginia and New York during which 44 heart failure, valve, and imaging experts, MV surgeons and interventional cardiologists, clinical trial specialists and statisticians, and representatives from the U.S. Food and Drug Administration considered all aspects of MV pathophysiology, prognosis, and therapies, culminating in a 2-part document describing consensus recommendations for clinical trial design (Part 1) and endpoint definitions (Part 2) to guide evaluation of transcatheter and surgical therapies for MR. The adoption of these recommendations will afford robustness and consistency in the comparative effectiveness evaluation of new devices and approaches to treat MR. These principles may be useful for regulatory assessment of new transcatheter MV devices, as well as for monitoring local and regional outcomes to guide quality improvement initiatives., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Despite the global burden of cardiovascular disease, investment in cardiovascular drug development has stagnated over the past 2 decades, with relative underinvestment compared with other therapeutic areas. The reasons for this trend are multifactorial, but of primary concern is the high cost of conducting cardiovascular outcome trials in the current regulatory environment that demands a direct assessment of risks and benefits, using clinically-evident cardiovascular endpoints. To work toward consensus on improving the environment for cardiovascular drug development, stakeholders from academia, industry, regulatory bodies, and government agencies convened for a think tank meeting in July 2014 in Washington, DC. This paper summarizes the proceedings of the meeting and aims to delineate the current adverse trends in cardiovascular drug development, understand the key issues that underlie these trends within the context of a recognized need for a rigorous regulatory review process, and provide potential solutions to the problems identified., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This article summarizes the long-term clinical results of the Food and Drug Administration-approved heart valves, provides current updates to the objective performance criteria (OPC) used to evaluate new heart valve prostheses, and documents the steps that the International Organization for Standardization Committee used to arrive at the updated OPC. Data were extracted from 19 Food and Drug Administration summaries of safety and effectiveness data reports (31 series) and 56 literature articles (85 series) published from 1999 to 2012. The OPC were calculated for five valve-related complications by valve type (mechanical and bioprosthetic) and valve position (aortic and mitral)., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The United States Food and Drug Administration (FDA) has issued Guidance for Industry, subtitled Diabetes Mellitus-Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. From an academic perspective, these regulatory requirements provide undue emphasis on the results of phase 2 trials not designed to test hypotheses about clinical cardiovascular events. Phase 2 trials should be considered hypothesis formulating either alone or in their meta-analyses. Thus, this FDA guidance for industry does not adequately emphasize the importance and necessity of well designed and conducted phase 3 trials of sufficient size, dose, and duration to test the hypothesis formulated from the meta-analysis of the phase 2 trials. We believe that the guiding principle about benefits and risks of drugs should be that rational decisions for individual patients and the health of the general public should be based on a sufficient totality of evidence. When that totality of evidence is incomplete, it is appropriate to remain uncertain. We believe phase 2 trials should be performed mainly for proof of concept and dose ranging. To detect reliably the most plausible small to moderate effects of drugs, the totality of evidence must include large scale randomized phase 3 trials. These individual trials must be of sufficient size, dose, and duration as well as achieve high adherence and follow-up. They must also achieve enough clinical endpoints to distinguish reliably between the null hypothesis of no effect and the most plausible alternative hypotheses of small benefit or harm., (Copyright 2010 Elsevier Inc. All rights reserved.)

Recently, several drugs for non-cardiovascular diseases have ceased marketing because of cardiovascular risk, highlighting the importance of evaluating the cardiovascular safety of new drugs even if not intended for cardiovascular diseases. Assessing and ensuring acceptable cardiovascular safety of non-cardiovascular drugs is difficult; nonetheless, governmental regulatory agencies are likely to change the requirements for drug safety information. This article explores our recommendations for rethinking current regulatory policies, emphasizing the need for mandatory post-marketing surveillance registries and highlighting the exposures necessary to subserve the need for greater assessment of safety issues.

Recent placebo-controlled clinical trials suggest excessive adverse cardiovascular (CV) events associated with cyclooxygenase (COX)-2 selective nonsteroidal anti-inflammatory drugs (NSAIDs), developed to reduce gastrointestinal irritation associated with nonselective NSAIDs. Subsequent retrospective analyses of observational series and non-CV clinical trials suggest that CV events may occur with modest excess with all NSAIDs, nonselective and COX-2 selective, compared with nonuse of these drugs, may be dose related, and do not differ substantially in frequency among various NSAIDs. However, inadequacy of study designs, controls, and events has precluded definition of the risk-benefit relationship of COX-2 selective and nonselective NSAIDs. Resolution of this problem requires several different types of studies, necessarily including appropriately designed randomized, controlled trials comparing commonly employed nonselective and COX-2 selective NSAIDs in patients expected to benefit (ie, those with symptomatically severe arthritis) who also have coronary occlusive disease so that achievable noninferiority trial size has power sufficient to resolve relatively small differences in adverse CV (and gastrointestinal) event rates. This article explores the goals and possible designs of trials appropriate for defining risk-benefit relationship that must be known for optimal application of NSAID therapy.

The Food and Drug Administration (FDA) is responsible for assuring that drugs, devices, and biologicals available in the U.S. are effective and acceptably safe for their intended uses. Both law and regulation define the procedures to be followed by the FDA in judging the effectiveness and safety of therapies. The FDA comprises a cadre of highly skilled public servants who receive and evaluate all data collected by the manufacturer during therapy, not just the portion that reaches publication. To assist in reaching final conclusions about approvability, the FDA can empanel legally constituted advisory committees and external consultants when the need is perceived for additional specific scientific/technical expertise and substantial experience in clinical practice. Evidentiary standards for marketing approval of drugs, biologicals, and devices generally require direct demonstration of clinical benefit, rather than inferences drawn from "surrogate" pharmacologic/device-mediated effects, sufficient exposure to enable a reasonable assessment of countervailing risk, consideration of specific design elements in the pivotal clinical trials (including prespecified hypotheses [implicitly incorporated in "primary end points"], rigorous plans for statistical analyses, and so on), and assessment of persistence of effectiveness and associated stability of safety over time. Finally, sufficient information must be available so that practitioners can receive written instructions for use (the label) adequate to support the likelihood that recipients of the therapy will receive the expected benefits within the envelope of the stated risks. This article will discuss and expand on these issues, with examples.