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Concluding Thoughts Two years ago, after two decades of homesteading—life without revisions—I reread Parsons’ Structure of Social Action. There is no “other” in the book, and hence no social action past the title. [...]theory is scientific knowledge, and is here being delegated to the actor, in the form of a point of view. The complicity of other is a fundamental uncertainty in the pursuit of standing, through roles.

Although there are limited clinical data to support the use of exercise training as a means to reduce mortality and morbidity in patients with heart failure, current guidelines state that exercise is beneficial. The objective of this trial is to determine whether exercise training reduces all-cause mortality or all-cause hospitalization for patients with left ventricular systolic dysfunction and heart failure symptoms. After undergoing baseline assessments to determine whether they can safely exercise, patients are randomized to either usual care or exercise training. Patients in the exercise training arm attend 36 supervised facility-based exercise training sessions. Exercise modalities are cycling or walking. After completing 18 sessions, patients initiate home-based exercise and then transition to solely home-based exercise after completing all 36 sessions. Patients return for facility-based training every 3 months to reinforce their exercise training program. Patients are followed for up to 4 years. Physiologic, quality-of-life, and economic end points that characterize the effect of exercise training in this patient population will be measured at baseline and at intervals throughout the trial. Blood samples will be collected to examine biomarkers such as brain natriuretic peptide, tumor necrosis factor, and C-reactive protein. Because of its relatively low cost, high availability, and ease of use, exercise training is an intervention that could be accessible to most patients with heart failure. The HF-ACTION trial is designed to definitively assess the effect of exercise training on the clinically relevant end points of mortality, hospitalization, and quality of life in patients with heart failure.

Patients with systolic heart failure often have concomitant left ventricular (LV) diastolic dysfunction. Although in animal models diastolic dysfunction is associated with worsening exercise capacity and prognosis, information regarding these relationships in patients with established systolic heart failure (HF) is sparse. HF-ACTION was a large, multicenter National Institutes of Health–funded trial of exercise training in systolic HF (LV ejection fraction [LVEF] ≤35%) and included detailed Doppler-echocardiographic (echo) and cardiopulmonary exercise testing at baseline. We tested the hypothesis that echo measures of LV diastolic function predict key cardiopulmonary exercise outcomes, including aerobic exercise capacity (peak exercise oxygen consumption, VO 2), distance in the 6-minute walk test (6MWD), and ventilatory efficiency (VE/VCO 2 slope) in patients with systolic HF. Overall, 2,331 patients (28% women, median age 59 years, median LVEF 25%) were enrolled. There were significant bivariate correlations between echo diastolic function variables and peak VO 2 (inverse) and VE/VCO 2 slope (direct) that were strongest for ratio of early diastolic peak transmitral (MV) to myocardial tissue velocity (E/E'), peak MV early-to-late diastolic velocity ratio (E/A), and left atrial dimension (range of absolute r = 0.16-0.28). Both MV E/A and E/E' were more strongly related to all 3 exercise variables than was LVEF. The relationships of E/A and E/E' with 6MWD were weaker than with peak VO 2 or VE/VCO 2 slope. A multivariable model with peak VO 2 as the dependent variable, which included MV E/A and 9 demographic predictors including age, sex, race, body mass index, and New York Heart Association class, explained 40% of the variation in peak VO 2, with MV E/A explaining 6% of the variation. Including LVEF in the model explained less than an additional 1% of the variance in peak VO 2. In a multivariable model for VE/VCO 2 slope, MV E/A was the strongest independent echo predictor, explaining 10% of the variance. The relationship of LV diastolic function variables with 6MWD was weaker than with peak VO 2 or VE/VCO 2 slope. In patients with systolic HF, LV early diastolic function is a modest independent predictor of aerobic exercise capacity and appears to be a better predictor than LVEF.

Aims N‐terminal pro‐b‐type natriuretic peptide (NT‐proBNP) values may be influenced by patient factors beyond the severity of illness, including atrial fibrillation (AF), renal dysfunction, or increased body mass index (BMI). We hypothesized that these factors may influence the achievement of NT‐proBNP targets and clinical outcomes. Methods A total of 894 patients with heart failure with reduced ejection fraction were enrolled in The Guiding Evidence‐Based Therapy Using Biomarker Intensified Treatment trial. NT‐proBNP was analysed every 3 months. Results Forty per cent of patients had AF, the median estimated glomerular filtration rate (eGFR) was 59 mL/min/1.73 m2 [interquartile range (IQR) 43–76], and median BMI was 29 kg/m2 (IQR 25–34). Patients with AF, eGFR < 60 mL/min/1.73 m2, or a BMI < 29 kg/m2 had a higher level of NT‐proBNP at randomization and over all study visits (all P values < 0.001). Over 18 months, the rate of change of NT‐proBNP was less for patients with AF (compared with those without AF, P = 0.037) and patients with an eGFR < 60 mL/min/1.73 m2 (compared with eGFR > 60 mL/min/1.73 m2, P < 0.001). The rate of change of NT‐proBNP was similar for patients with a BMI above or below the median value. Using the 90 day NT‐proBNP, patients with AF, lower eGFR, or lower BMI were less likely to achieve the target NT‐proBNP < 1000 pg/mL than patients without AF, higher eGFR, or higher BMI, respectively. None of these differed between the Usual Care or Guided Care arm for AF, eGFR, or BMI (Pinteractions all NS). Conclusions Patients with AF, a lower BMI, or worse renal function are less likely to achieve a lower or target NT‐proBNP. Clinicians should be aware of these factors both when interpreting NT‐proBNP levels and making therapeutic decisions about heart failure therapies.

Cardiopulmonary exercise testing (CPX) in patients with systolic heart failure (HF) is important for determining HF prognosis and helping guide timing of heart transplantation. Although approximately 20% to 30% of patients with HF are obese (body mass index [BMI] >30 kg/m 2), the impact of BMI on CPX results is not well established. The objective of this study was to assess the relationship between BMI and CPX variables, including peak oxygen uptake (VO 2) at ventilatory threshold, oxygen pulse, and ventilation–carbon dioxide production ratio. Consecutive patients with systolic HF (n = 2,324) enrolled in the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training trial who had baseline BMI recorded were included in this study. Subjects were divided into strata based on BMI: underweight (BMI <18.5 kg/m 2), normal weight (BMI 18.5-24.9 kg/m 2), overweight (BMI 25.0-29.9 kg/m 2), obese I (BMI 30-34.9 kg/m 2), obese II (BMI 35-39.9 kg/m 2), and obese III (BMI ≥40 kg/m 2). Obese III, but not overweight; obese I; or obese II was associated with decreased peak VO 2 (mL kg −1 min −1) compared to normal weight status. Increasing BMI category was inversely related to ventilation/carbon dioxide production (V E/V CO2) ratio ( P < .0001). On multivariable analysis, BMI was a significant independent predictor of peak VO 2 (partial R 2 = 0.07, P < .0001) and V E/V CO2 slope (partial R 2 = 0.03, P < .0001) in patients with chronic systolic HF. Body mass index is significantly associated with key CPX fitness variables in patients with HF. The influence of BMI on the prognostic value of CPX in HF requires further evaluation in longitudinal studies.

The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) Cross-Trial Statistics Group gathered lessons learned from statisticians responsible for the design and analysis of the 11 ACTIV therapeutic master protocols to inform contemporary trial design as well as preparation for a future pandemic. The ACTIV master protocols were designed to rapidly assess what treatments might save lives, keep people out of the hospital, and help them feel better faster. Study teams initially worked without knowledge of the natural history of disease and thus without key information for design decisions. Moreover, the science of platform trial design was in its infancy. Here, we discuss the statistical design choices made and the adaptations forced by the changing pandemic context. Lessons around critical aspects of trial design are summarized, and recommendations are made for the organization of master protocols in the future.

Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) was a multicenter, randomized controlled trial designed to examine the safety and efficacy of aerobic exercise training versus usual care in 2,331 patients with systolic heart failure (HF). In HF-ACTION patients with rest transthoracic echocardiographic measurements, the predictive value of 8 Doppler echocardiographic measurements—left ventricular (LV) diastolic dimension, mass, systolic (ejection fraction) and diastolic (mitral valve peak early diastolic/peak late diastolic [E/A] ratio, peak mitral valve early diastolic velocity/tissue Doppler peak early diastolic myocardial velocity [E/E′] ratio, and deceleration time) function, left atrial dimension, and mitral regurgitation severity—was examined for a primary end point of all-cause death or hospitalization and a secondary end point of cardiovascular disease death or HF hospitalization. Also compared was the prognostic value of echocardiographic variables versus peak oxygen consumption (Vo2). Mitral valve E/A and E/E′ ratios were more powerful independent predictors of clinical end points than the LV ejection fraction but less powerful than peak Vo2. In multivariate analyses for predicting the primary end point, adding E/A ratio to a basic demographic and clinical model increased the C-index from 0.61 to 0.62, compared with 0.64 after adding peak Vo2. For the secondary end point, 6 echocardiographic variables, but not the LV ejection fraction or left atrial dimension, provided independent predictive power over the basic model. The addition of E/E′ or E/A to the basic model increased the C-index from 0.70 to 0.72 and 0.73, respectively (all p values <0.0001). Simultaneously adding E/A ratio and peak Vo2 to the basic model increased the C-index to 0.75 (p <0.0005). No echocardiographic variable was significantly related to the change from baseline to 3 months in exercise peak Vo2. In conclusion, the addition of echocardiographic LV diastolic function variables improves the prognostic value of a basic demographic and clinical model for cardiovascular disease outcomes.

In this trial, 1-year GVHD-free, relapse-free survival after stem-cell transplantation was 52.7% in the cyclophosphamide–tacrolimus–mycophenolate mofetil group and 34.9% in the tacrolimus–methotrexate group.