The limitations of the explanatory clinical trial framework include the high expense of implementing explanatory trials, restrictive entry criteria for participants, and redundant logistical processes. These limitations can result in slow evidence generation that is not responsive to population health needs, yielding evidence that is not generalizable. Clinically integrated trials, which integrate clinical research into routine care, represent a potential solution to this challenge and an opportunity to support learning health systems. The operational and design features of clinically integrated trials include a focused scope, simplicity in design and requirements, the leveraging of existing data structures, and patient participation in the entire trial process. These features are designed to minimize barriers to participation and trial execution and reduce additional research burdens for participants and clinicians alike. Broad adoption and scalability of clinically integrated trials are dependent, in part, on continuing regulatory, healthcare system, and payer support. This analysis presents a framework of the strengths and challenges of clinically integrated trials and is based on a multidisciplinary expert “Think Tank” panel discussion that included representatives from patient populations, academia, non-profit funding agencies, the U.S. Food and Drug Administration, and industry.

AbstractAimsClinical trials in heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) commonly have detailed eligibility criteria. This may contribute to challenges with efficient enrolment and questions regarding the generalizability of trial findings.Methods and resultsPatients with HFmrEF/HFpEF from a large US healthcare system were identified through a computable phenotype applied in linked imaging and electronic health record databases. We evaluated shared eligibility criteria from five recent/ongoing HFmrEF/HFpEF trials (PARAGON‐HF, EMPEROR‐Preserved, DELIVER, FINE‐ARTS, and SPIRRIT‐HFpEF) and compared clinical and echocardiographic features as well as outcomes between trial‐eligible and trial‐ineligible patients. Among 5552 patients with HFpEF/HFmrEF, 792 (14%) were eligible for trial consideration, having met all criteria assessed. Causes of ineligibility included lack of recent loop diuretics (37%), significant pulmonary disease (24%), reduced estimated glomerular filtration rate (17%), recent stroke/transient ischaemic attack (13%), or low natriuretic peptides (12%); 53% of ineligible patients had >1 reason for exclusion. Compared with eligible patients, ineligible patients were younger (age 71 vs. 75 years, P < 0.001) with higher rates of coronary artery disease (66% vs. 59%, P < 0.001) and peripheral vascular disease (40% vs. 33%, P < 0.001), but less mitral regurgitation, lower E/e′ ratio, and smaller left atrial sizes. Both eligible and ineligible patients demonstrated high rates of structural heart disease consistent with HFpEF [elevated left atrial size or left ventricular (LV) hypertrophy/increased LV mass], although this was slightly higher among eligible patients (95% vs. 92%, P = 0.001). The two cohorts demonstrated similar LV global longitudinal strain along with a similar prevalence of atrial fibrillation/flutter, hypertension, and obesity. Ineligible patients had similar all‐cause mortality (33% vs. 33% at 3 years) to those eligible but lower rates of heart failure hospitalization (20% vs. 28% at 3 years, P < 0.001).ConclusionsAmong patients with HFmrEF/HFpEF from a large health system, approximately one in seven were eligible for major trials based on key criteria applied through a clinical computable phenotype. These findings highlight the large proportion of patients with HFmrEF/HFpEF ineligible for contemporary trials for whom the generalizability of trial findings may be questioned and further investigation would be beneficial.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous entity with complex pathophysiology and manifestations. Phenomapping is the process of applying statistical learning techniques to patient data to identify distinct subgroups based on patterns in the data. Phenomapping has emerged as a technique with potential to improve the understanding of different HFpEF phenotypes. Phenomapping efforts have been increasing in HFpEF over the past several years using a variety of data sources, clinical variables, and statistical techniques. This review summarizes methodologies and key takeaways from these studies, including consistent discriminating factors and conserved HFpEF phenotypes. We argue that phenomapping results to date have had limited implications for clinical care and clinical trials, given that the phenotypes, as currently described, are not reliably identified in each study population and may have significant overlap. We review the inherent limitations of aggregating and utilizing phenomapping results. Lastly, we discuss potential future directions, including using phenomapping to optimize the likelihood of clinical trial success or to drive discovery in mechanisms of the disease process of HFpEF.

Introduction: An 11-factor random forest model has been previously developed among ambulatory patients for identifying potential wild-type amyloidogenic TTR cardiomyopathy (wtATTR-CM), but model performance in a large sample of patients hospitalized for HF has not been evaluated. Methods: This study included Medicare beneficiaries hospitalized for HF in the Get With The Guidelines-HF® Registry from 2008-2019. Patients with and without a diagnosis of wtATTR-CM were compared. ICD9/10 codes were used as proxies to identify wtATTR-CM patients on inpatient/outpatient claims within ±6 months of hospitalization. Within a cohort matched 1:1 by age and sex, univariable logistic regression was used to evaluate relationships between each of the 11 factors of the established ATTR-CM model and wtATTR-CM. Discrimination and calibration of the 11-factor model was assessed. Results: Among 205,545 patients hospitalized for HF across 608 US hospitals, 627 patients (0.31%) had a diagnosis code for wtATTR-CM. wtATTR-CM patients were more likely to be male (69% vs 47%), Black race (23% vs 9%), and had lower systolic blood pressure (median 124 vs 139 mmHg). Univariable analysis within the 1:1 matched cohort of each of the 11-factors in the wtATTR-CM model found pericardial effusion, carpal tunnel syndrome, lumbar spinal stenosis, and elevated serum enzymes (e.g., troponin elevation) to be strongly associated with wtATTR-CM ( Figure, Panel A ). The 11-factor model showed modest discrimination with c-statistic of 0.65 ( Figure, Panel B ), with good calibration within the matched cohort ( Figure, Panel C ). Conclusions: Among patients hospitalized for HF in US practice, the number of wtATTR-CM as defined by diagnosis codes was low. Patients with a diagnosis of wtATTR-CM have a distinct clinical profile, and most factors within the prior 11-factor model were associated with greater odds of wtATTR-CM diagnosis. In this population, the wtATTR-CM model demonstrated modest discrimination.

Importance:Prior studies have suggested patients with heart failure (HF) from rural areas have worse clinical outcomes. Contemporary differences between rural and urban hospitals in quality of care and clinical outcomes for patients hospitalized for HF remain poorly understood.Objective:To assess quality of care and clinical outcomes for US patients hospitalized for HF at rural vs urban hospitals.Design, Setting, and Participants:This retrospective cohort study analyzed 774 419 patients hospitalized for HF across 569 sites in the Get With The Guidelines-Heart Failure (GWTG-HF) registry between January 1, 2014, and September 30, 2021. Postdischarge outcomes were assessed in a subset of 161 996 patients linked to Medicare claims. Data were analyzed from August 2022 to January 2023.Main Outcomes and Measures:GWTG-HF quality measures, in-hospital mortality, length of stay, and 30-day mortality and readmission outcomes.Results:This study included 19 832 patients (2.6%) and 754 587 patients (97.4%) hospitalized at 49 rural hospitals (8.6%) and 520 urban hospitals (91.4%), respectively. Of 774 419 included patients, 366 161 (47.3%) were female, and the median (IQR) age was 73 (62-83) years. Compared with patients at urban hospitals, patients at rural hospitals were older (median [IQR] age, 74 [64-84] years vs 73 [61-83] years; standardized difference, 10.63) and more likely to be non-Hispanic White (14 572 [73.5%] vs 498 950 [66.1%]; standardized difference, 34.47). In adjusted models, patients at rural hospitals were less likely to be prescribed cardiac resynchronization therapy (adjusted risk difference [aRD], -13.5%; adjusted odds ratio [aOR], 0.44; 95% CI, 0.22-0.92), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (aRD, -3.7%; aOR, 0.71; 95% CI, 0.53-0.96), and an angiotensin receptor-neprilysin inhibitor (aRD, -5.0%; aOR, 0.68; 95% CI, 0.47-0.98) at discharge. In-hospital mortality was similar between rural and urban hospitals (460 of 19 832 [2.3%] vs 20 529 of 754 587 [2.7%]; aOR, 0.86; 95% CI, 0.70-1.07). Patients at rural hospitals were less likely to have a length of stay of 4 or more days (aOR, 0.75; 95% CI, 0.67-0.85). Among Medicare beneficiaries, there were no significant differences between rural and urban hospitals in 30-day HF readmission (adjusted hazard ratio [aHR], 1.03; 95% CI, 0.90-1.19), all-cause readmission (aHR, 0.97; 95% CI, 0.91-1.04), and all-cause mortality (aHR, 1.05; 95% CI, 0.91-1.21).Conclusions and Relevance:In this large contemporary cohort of US patients hospitalized for HF, care at rural hospitals was independently associated with lower use of some guideline-recommended therapies at discharge and shorter length of stay. In-hospital mortality and 30-day postdischarge outcomes were similar at rural and urban hospitals.

HomeCirculationVol. 147, No. 21New Paradigms to Address Long-Term Exercise Adherence, An Achilles Heel of Lifestyle Interventions Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBNew Paradigms to Address Long-Term Exercise Adherence, An Achilles Heel of Lifestyle Interventions Anthony E. Peters, William E. Kraus and Robert J. Mentz Anthony E. PetersAnthony E. Peters Correspondence to: Anthony E. Peters, MD, MS, Duke Clinical Research Institute, 300 West Morgan St, Durham, NC 27701. Email E-mail Address: [email protected] https://orcid.org/0000-0003-4313-030X Division of Cardiology (A.E.P., W.E.K., R.J.M.), Duke University School of Medicine, Durham, NC. Duke Clinical Research Institute, Durham, NC (A.E.P., R.J.M.). , William E. KrausWilliam E. Kraus https://orcid.org/0000-0003-1930-9684 Division of Cardiology (A.E.P., W.E.K., R.J.M.), Duke University School of Medicine, Durham, NC. Duke Molecular Physiology Institute (W.E.K.), Duke University School of Medicine, Durham, NC. and Robert J. MentzRobert J. Mentz https://orcid.org/0000-0002-3222-1719 Division of Cardiology (A.E.P., W.E.K., R.J.M.), Duke University School of Medicine, Durham, NC. Duke Clinical Research Institute, Durham, NC (A.E.P., R.J.M.). Originally published22 May 2023https://doi.org/10.1161/CIRCULATIONAHA.123.064161Circulation. 2023;147:1565–1567Regular physical activity is widely recommended for the primary and secondary prevention of cardiovascular disease (CVD), and formal cardiac rehabilitation programs are indicated for a range of cardiovascular and postsurgical conditions. Heart failure (HF) is one of the conditions for which multicomponent cardiac rehabilitation and even exercise training alone improve both exercise capacity and clinical outcomes.1,2 As a result, cardiac rehabilitation (including exercise training, medication education, dietary recommendations, and psychosocial support) and exercise training alone are codified in US and European guidelines for management of patients with HF regardless of ejection fraction, as class 1 to 2a recommendations. Of note, the efficacy of exercise intervention is significantly affected by adherence.2 Short-term adherence rates of up to ~80% can be achieved in rigorous clinical trials of exercise interventions,2 but longer-term sustainability remains either poor or untested globally. This is particularly true once individuals transition out of in-person supervised sessions to the home environment. Several clinical factors are associated with adherence, but these account for very little of the variance in individual adherence.2 This leaves an enormous gap in the knowledge base necessary to sustain exercise therapy in this high-risk population. Traditional efforts to improve adherence (as detailed in the following) have demonstrated important, albeit modest benefits.3 For HF in particular, there are relatively few recent or ongoing clinical trials investigating adherence to exercise. Increased efforts through alternative paradigms may be necessary to reduce the knowledge gap around effective methods to enhance adherence (including in diverse populations). From this perspective, we briefly review traditional methods to optimize adherence in exercise for CVD, with HF as a case study, and discuss innovative strategies to overcome barriers to long-term adherence.Adherence and Traditional MethodsThe definition of exercise adherence varies across studies. It is typically recorded as percentage of visits attended or minutes per week of prescribed exercise completed.1–3 The greatest adherence rates historically have been achieved through supervised in-person visits under clinical trial conditions. Transitioning to local facility or home-based exercise regimens has posed challenges for maintenance of adherence.1 Traditional methods to target long-term engagement have included specific exercise prescriptions, education programs, activity logs, remote monitoring, motivational interviewing/coaching, problem-solving support, logistical/transportation assistance, home environment assessments, and resource provision (eg, home supplies and local parks or fitness facilities).2,3 These interventions have supported a degree of intervention sustainability, but results have been variable and relatively modest if successful in improving adherence rates in HF.3 For example, the HEART Camp (Heart Failure Exercise and Resistance Training Camp) multicomponent intervention (81% HF with reduced ejection fraction, 19% HF with preserved ejection fraction [HFpEF]) is one of the few studies to have demonstrated long-term efficacy associated with better adherence at 12 months and 18 months, but adherence rates remained modest overall (42% versus 28% in usual care at 12 months, and 35% versus 19% at 18 months).4 HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) was the largest global extended trial of exercise training in HF with reduced ejection fraction, with sites in the United States, Canada, and France. It included several features to target adherence, including measuring session attendance, providing activity logs, performing telephone and clinic follow-up, and monitoring heart rate data during the home exercise training phase. Nevertheless, adherence (defined as exercise minutes per week at or above exercise prescription, as measured by participant reporting) attenuated to 40% with median exercise time more than 15% to 20% below target over the first 12 months in this closely followed cohort.1 The recent OptimEx-Clin program, studying exercise intensities in HFpEF across 5 European sites, demonstrated ~48% to 59% adherence (defined as ≥70% of scheduled exercise sessions) in the 9-month home-based phase of the program.5New Strategies for Exercise AdherenceWith this background, new strategies may be required to drive longer-term sustainability. For example, one might consider loading and maintenance dose theory in exercise for HF states (Figure). This principle—long-term pharmacologic and device therapy with adjustments over time—is well-established across multiple fields, including oncology and HF. On the other hand, exercise interventions, often because of resource and financial constraints, typically are utilized as initial intensive therapy and transitioned back to patient-directed home or local exercise habits, but the long-term legacy effects of exercise interventions in HF are unproven. Utilization of intermittent, in-person maintenance doses of exercise training could improve both efficacy and long-term adherence. These intermittent doses could be deployed as scheduled, planned regimens, or triggered by recurrences, which, once stabilized, could be treated with reloading of exercise training dose (as in chemotherapy regimens). Overcoming reimbursement barriers (varying across countries) and leveraging technology such as mobile health platforms (particularly in rural communities where direct access to exercise locations may be more difficult) may prove critical to success of this paradigm. Still, the investment may be justified, particularly in a condition such as HFpEF, where there are few effective therapies and for which physical inactivity likely plays a driving role in the underlying pathophysiology and disease progression.Download figureDownload PowerPointFigure. Emerging innovative paradigms for adherence and sustainability in exercise interventions for heart failure.Another strategy would be to consider risk stratification specific to adherence or sustainability risk. For example, barriers to adherence could be assessed at initiation of intervention, with patients then stratified depending on risk assessment for poor adherence into lower-touch, lower-cost regimens versus closer-monitoring, higher-cost regimens. This could help address the issue of limited in-person facility resources and also help the drive toward greater equity by increasing services in at-risk, underserved populations. This is a paradigm for future consideration, given the current inability to predict the variance in long-term adherence with traditional models; a combination of advanced modeling or direct participant interviews and surveys may be necessary to close this gap in understanding and enabling this approach.Third, the use of behavioral economics strategies in direct patient care is an area of growing interest in CVD; however, this approach remains relatively underutilized, particularly in exercise interventions for patients with HF. Using tools such as insurance incentives, commitment contracts, and social networks has the potential to promote greater longevity and sustainability in achieving exercise targets; these strategies could be phenotype-directed to address issues of patient heterogeneity, prominent in HFpEF, for example. Small, short-term studies have efficacy in increasing physical activity in cardiovascular patients, but further research is necessary in the HF field.Each of these strategies might be reasonably used in industrialized countries or developing nations, although facility access and transportation may present challenges for intermittent dosing of exercise therapy and behavior economics strategies would vary across regional settings. Across all of these strategies, trials focusing primarily on the outcome of intermediate-term and long-term adherence may be most beneficial for the field; this could come through studies across the early phases of the National Institutes of Health Stage Model for Behavioral Intervention Development including basic science (stage 0), intervention development and pilot testing (stage 1), and traditional efficacy testing (stage II). For example, stage I/II studies might be pursued in the form of a platform trial, assessing adherence over time across intervention strategies and pivoting through interim analyses. Sample sizes could be more modest for these initial trials, particularly in HFpEF, for example, followed by larger trials with broader eligibility (eg, variety of settings; primary/tertiary, rural/urban facilities) including clinical outcomes and adherence outcomes. Several lines of research would be useful, including developing improved data on barriers to greater adherence or reasons for withdrawal from intervention programs; determination of minimal necessary exercise "dosing" in specific disease states such as HF; and a greater understanding of the complex cardiovascular–peripheral–neurologic pathways driving motivation for and response to exercise. Technology-enabled platforms for telemonitoring, prompts, and therapeutic training may help support testing of these paradigms. Moreover, the lexicon used in these efforts should be chosen with care. The reframing of pharmacologic "noncompliance" to "barriers to adherence" for medication use represents one patient-centered approach. This reframing may prove to be equally important in exercise interventions, which are intrinsically more challenging for patients, particularly those with exertion-limiting conditions such as HF.ConclusionsTraditional models have produced a strong body of evidence regarding the mechanisms and clinical benefits of exercise and rehabilitation interventions in CVD. However, long-term adherence to exercise once in-person interventions cease in CVD disease states such as HF remains poor or unproven. Innovative paradigms, such as intermittent dosing, risk stratification by barriers to adherence, and behavioral economics tools, may be required to overcome this Achilles heel of exercise therapy.Article InformationAcknowledgmentsThe authors thank Patrick Lane of Sceyence Studios for assistance in developing the Figure.Sources of FundingNone.Disclosures Dr Peters is supported by the National Heart, Lung and Blood Institute (T32HL069749) and has received honoraria from Cytokinetics. Dr Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. The other author reports no relevant disclosures.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 1567.Circulation is available at www.ahajournals.org/journal/circCorrespondence to: Anthony E. Peters, MD, MS, Duke Clinical Research Institute, 300 West Morgan St, Durham, NC 27701. Email anthony.peters@duke.eduReferences1. O'Connor CM, Whellan DJ, Lee KL, Keteyian SJ, Cooper LS, Ellis SJ, Leifer ES, Kraus WE, Kitzman DW, Blumenthal JA, et al; HF-ACTION Investigators. Efficacy and safety of exercise training in patients with chronic heart failure HF-ACTION randomized controlled trial.JAMA. 2009; 301:1439–1450. doi: 10.1001/jama.2009.454CrossrefMedlineGoogle Scholar2. Nelson MB, Gilbert ON, Duncan PW, Kitzman DW, Reeves GR, Whellan DJ, Mentz RJ, Chen H, Hewston LA, Taylor KM, et al. Intervention adherence in REHAB-HF: predictors and relationship with physical function, quality of life, and clinical events.J Am Heart Assoc. 2022; 11:e024246. doi: 10.1161/JAHA.121.024246LinkGoogle Scholar3. Tierney S, Mamas M, Woods S, Rutter MK, Gibson M, Neyses L, Deaton C. What strategies are effective for exercise adherence in heart failure? A systematic review of controlled studies.Heart Fail Rev. 2012; 17:107–115. doi: 10.1007/s10741-011-9252-4CrossrefMedlineGoogle Scholar4. Pozehl BJ, McGuire R, Duncan K, Kupzyk K, Norman J, Artinian NT, Deka P, Krueger SK, Saval MA, Keteyian SJ. Effects of the HEART Camp trial on adherence to exercise in patients with heart failure.J Card Fail. 2018; 24:654–660. doi: 10.1016/j.cardfail.2018.06.007CrossrefMedlineGoogle Scholar5. Mueller S, Winzer EB, Duvinage A, Gevaert AB, Edelmann F, Haller B, Pieske-Kraigher E, Beckers P, Bobenko A, Hommel J, et al; OptimEx-Clin Study Group. Effect of high-intensity interval training, moderate continuous training, or guideline-based physical activity advice on peak oxygen consumption in patients with heart failure with preserved ejection fraction: a randomized clinical trial.JAMA. 2021; 325:542–551. doi: 10.1001/jama.2020.26812CrossrefMedlineGoogle Scholar eLetters(0) eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate. Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page. Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails May 23, 2023Vol 147, Issue 21 Advertisement Article Information Metrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.123.064161PMID: 37216438 Originally publishedMay 22, 2023 Keywordscardiac rehabilitationexerciselife stylePDF download Advertisement Subjects Exercise Heart Failure Lifestyle Secondary Prevention

While heart rate variability (HRV) is an established marker of cardiovascular health, the extent to which continuously measured HRV changes over time and the relationship between these changes and clinical outcomes are less clear. We performed a health system analysis of 225 patients implanted with a cardiac defibrillator or cardiac resynchronization device (CRT) with continuous HRV recording capabilities. We found that continuously measured HRV changed modestly over 2 years. Low baseline HRV, which is associated with low parasympathetic tone and/or increases in sympathetic tone, pertains a worse clinical prognosis as reflected by a significant association with all-cause hospitalization. Observed changes in HRV over 6-months of follow-up were not associated with subsequent outcomes.

Background: Heart failure (HF) guidelines recommend assessment of left ventricular ejection fraction (LVEF) to classify patients and guide therapy implementation. However, LVEF alone may be insufficient to adequately characterize patients with HF, especially those with mildly reduced or preserved LVEF. Recommendations on additional testing are lacking, and there are limited data on use of echocardiographic features beyond LVEF in patients with heart failure with mildly reduced or preserved LVEF. Methods: In patients with HF with mildly reduced or preserved LVEF identified in a large US health care system, the association of the following metrics with mortality was evaluated: LV global longitudinal strain (LV GLS>–16), left atrial volume index (>28 mL/m 2 ), left ventricular hypertrophy (LVH), and E/e´>13 and e´<9. A multivariable model for mortality was constructed including age, sex, and key comorbidities followed by stepwise selection of echocardiographic features. Characteristics and outcomes of subgroups with normal versus abnormal LV GLS and LVEF were evaluated. Results: Among 2337 patients with complete echocardiographic data assessed between 2017 and 2020, the following features were associated with all-cause mortality on univariate analysis over 3 years of follow-up: E/e´+e´, LV GLS, left atrial volume index (all P <0.01). In the multivariable model ( C -index=0.65), only abnormal LV GLS was independently associated with all-cause mortality (HR, 1.35 [95% CI, 1.11–1.63]; P =0.002). Among patients with LVEF>55%, 498/1255 (40%) demonstrated abnormal LV GLS. Regardless of specific LVEF, patients with abnormal LV GLS demonstrated a higher burden of multiple comorbidities and higher event rates compared with patients with normal LV GLS. Conclusions: In a large, real-world HF with mildly reduced or preserved LVEF population, echocardiographic features, led by LV GLS, were associated with adverse outcomes irrespective of LVEF. A large proportion of patients demonstrate adverse myocardial function by LV GLS despite preserved LVEF and may represent a key cohort of interest for HF medical therapies and future clinical studies.

Journal Article Advancing the evidence for diuretic therapy for heart failure: implications of the ADVOR and TRANSFORM-HF trials Get access Anthony E Peters, Anthony E Peters Division of Cardiology, Duke University School of Medicine, 27701 Durham, NC USADuke Clinical Research Institute, 27701 Durham, NC USA Corresponding author. Email: anthony.peters@duke.edu Search for other works by this author on: Oxford Academic Google Scholar Robert J Mentz, Robert J Mentz Division of Cardiology, Duke University School of Medicine, 27701 Durham, NC USADuke Clinical Research Institute, 27701 Durham, NC USA Search for other works by this author on: Oxford Academic Google Scholar Stephen J Greene Stephen J Greene Division of Cardiology, Duke University School of Medicine, 27701 Durham, NC USADuke Clinical Research Institute, 27701 Durham, NC USA Search for other works by this author on: Oxford Academic Google Scholar European Heart Journal - Cardiovascular Pharmacotherapy, Volume 9, Issue 4, June 2023, Pages 299–300, https://doi.org/10.1093/ehjcvp/pvad002 Published: 13 January 2023 Article history Received: 30 November 2022 Revision received: 16 December 2022 Accepted: 12 January 2023 Published: 13 January 2023 Corrected and typeset: 30 January 2023

BACKGROUND:In the REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial, a novel, early, transitional, multidomain rehabilitation intervention improved physical function, frailty, quality of life (QOL), and depression in older patients hospitalized for acute decompensated heart failure (ADHF), but the potential impact of baseline obesity on this intervention has not been studied. OBJECTIVES:This study assessed for treatment interactions by body mass index (BMI) subgroups for a novel rehabilitation intervention in ADHF. METHODS:Three-month outcomes including Short Physical Performance Battery (SPPB) (primary outcome), 6-minute walk distance (6MWD), and Kansas City Cardiomyopathy Questionnaire (KCCQ) were assessed by baseline BMI (≥30 kg/m2 vs <30 kg/m2). Six-month end points included all-cause rehospitalization and death. All analyses were adjusted for age, sex, clinical site, and ejection fraction category, and 3-month outcomes were also adjusted for baseline measure. The prespecified significance level for treatment interaction by BMI category was P ≤ 0.10. RESULTS:Of 349 trial participants, 204 (58%) had BMI ≥30 kg/m2 and 145 (42%) <30 kg/m2. Compared with patients with BMI <30 kg/m2, participants with BMI ≥30 kg/m2 were younger (age 71 ± 7 years vs 75 ± 9 years), more frequently women (57% vs 46%), and had significantly worse baseline physical function and QOL. Although interaction P values for 3-month outcomes by BMI were not significant (interaction P > 0.15 for overall measures), adjusted SPPB effect sizes were nominally larger for participants with BMI ≥30 kg/m2 compared with those with BMI <30 kg/m2: +1.7 (95% CI: 0.8-2.7) vs +1.1 (95% CI: -0.1 to 2.2). This difference in SPPB effect size was due largely to improvements in the balance component of the SPPB for participants with BMI ≥30 kg/m2: +0.6 (95% CI: 0.2-1.0) vs 0.0 (-0.6 to 0.5) for those with BMI <30 kg/m2 (interaction P = 0.02). In contrast, adjusted 6MWD and KCCQ effect sizes were smaller for participants with BMI ≥30 kg/m2 compared with those with BMI <30 kg/m2: +21 meters (-17 to 59) vs +53 meters (6-100), and +5.0 (-4 to 14) vs +11 (-0.5 to 22), respectively. There was no significant interaction by BMI for 6-month clinical outcomes (all interaction P > 0.30). CONCLUSIONS:Older patients with ADHF benefit from the rehabilitation therapy regardless of BMI. Benefits for patients with obesity may be more evident in the multidomain measure of physical function (SPPB), compared with the 6MWD or KCCQ, which may be driven, in part, by the unique aspects of the novel rehabilitation intervention. (A Trial of Rehabilitation Therapy in Older Acute Heart Failure Patients [REHAB-HF]; NCT02196038).

The management of heart failure with preserved ejection fraction (HFpEF) is rapidly evolving. The pharmacologic treatment of patients with HFpEF includes symptom management with diuretics and optimization of comorbidities, including hypertension, obesity, diabetes mellitus, and atrial fibrillation. Specific therapies, including angiotensin II receptor blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, and sodium-glucose cotransporter-2 inhibitors, are well tolerated and can reduce the risk of HF hospitalization, particularly in those on the lower end of the HFpEF left ventricular ejection fraction spectrum. Ongoing trials should continue to inform optimal therapy in this evolving field.

ABSTRACTBackgroundEjection fraction (EF) is a key component of heart failure (HF) classification, including the increasingly codified HF with mildly reduced EF (HFmrEF) category. However, the biologic basis of HFmrEF as an entity distinct from HF with preserved EF (HFpEF) and reduced EF (HFrEF) has not been well characterized.MethodsThe EXSCEL trial randomized participants with type 2 diabetes (T2DM) to once-weekly exenatide (EQW) vs. placebo. For this study, profiling of ∼5000 proteins using the SomaLogic SomaScan platform was performed in baseline and 12-month serum samples from N=1199 participants with prevalent HF at baseline. Principal component analysis (PCA) and ANOVA (FDR p<0.1) were used to determine differences in proteins between three EF groups, as previously curated in EXSCEL (EF>55% [HFpEF], EF 40-55% [HFmrEF], EF<40% [HFrEF]). Cox proportional hazards was used to assess association between baseline levels of significant proteins, and changes in protein level between baseline and 12-month, with time-to-HF hospitalization. Mixed models were used to assess whether significant proteins changed differentially with exenatide vs. placebo therapy.ResultsOf N=1199 EXSCEL participants with prevalent HF, 284 (24%), 704 (59%) and 211 (18%) had HFpEF, HFmrEF and HFrEF, respectively. Eight PCA protein factors and 221 individual proteins within these factors differed significantly across the three EF groups. Levels of the majority of proteins (83%) demonstrated concordance between HFmrEF and HFpEF, but higher levels in HFrEF, predominated by the domain of extracellular matrix regulation,e.g.COL28A1 and tenascin C [TNC]; p<0.0001. Concordance between HFmrEF and HFrEF was observed in a minority of proteins (1%) including MMP-9 (p<0.0001). Biologic pathways of epithelial mesenchymal transition, ECM receptor interaction, complement and coagulation cascades, and cytokine receptor interaction demonstrated enrichment among proteins with the dominant pattern,i.e.HFmrEF-HFpEF concordance. Baseline levels of 208 (94%) of the 221 proteins were associated with time-to-incident HF hospitalization including domains of extracellular matrix (COL28A1, TNC), angiogenesis (ANG2, VEGFa, VEGFd), myocyte stretch (NT-proBNP), and renal function (cystatin-C). Change in levels of 10 of the 221 proteins from baseline to 12 months (including increase in TNC) predicted incident HF hospitalization (p<0.05). Levels of 30 of the 221 significant proteins (including TNC, NT-proBNP, ANG2) were reduced differentially by EQW compared with placebo (interaction p<0.0001).ConclusionsIn this HF substudy of a large clinical trial of people with T2DM, we found that serum levels of most proteins across multiple biologic domains were similar between HFmrEF and HFpEF. HFmrEF may be more biologically similar to HFpEF than HFrEF, and specific related biomarkers may offer unique data on prognosis and pharmacotherapy modification with variability by EF.

Background: Differences between patients hospitalized for heart failure with reduced ejec-tion fraction (HFrEF) vs HF with preserved EF (HFpEF) are not well-characterized, particularly as pertains to in-hospital decongestion and longitudinal patient-reported outcomes. The objective of this analysis was to compare patient-reported and clinical outcomes between patients hospitalized with HFrEF vs HFpEF.Methods and Results: The Acute Study of Clinical Effectiveness of Nesiritide in Decompen-sated Heart Failure (ASCEND-HF) trial enrolled 7141 patients hospitalized for HF with reduced or preserved EF. We assessed the association between an EF < 40% vs an EF >40% with in -hos-pital decongestion, risk of rehospitalization and mortality, and quality of life as measured by the EuroQOL 5 Dimensions (EQ-5D). Among 5800 patients (81%) with complete EF data, 4782 (82%) had an EF <40% and 1018 (18%) had an EF >40%. Both groups demonstrated similar rates of decongestion by weight change and urine volume through 24 hours, a similar risk of 30-day mortality and HF rehospitalization, and a similar 180-day mortality. Patients with HFpEF had worse EQ-5D scores at hour 24 (median 0.76, [interquartile range (IQR) 0.51-0.84] vs 0.78 [IQR 0.57-0.84]; P = .01) that persisted through discharge (0.81 [IQR 0.69-0.86] vs 0.83 [IQR 0.71-1.00]; P < .001) and the 30-day follow-up (0.78 [IQR 0.60-0.85] vs 0.83 [IQR 0.71-1.00]; P < .001). After adjustment, these differences were attenuated and not statisti-cally significant.Conclusions: In this large, multinational cohort of patients hospitalized for HF, patients with an EF < 40% vs an EF >40% experienced similar in-hospital decongestion and postdischarge clinical outcomes. Patients with an EF >40% reported worse in-hospital and postdischarge patient-reported health status, but these measures were similar to HFrEF after accounting for other clinical factors. (J Cardiac Fail 2022;28:1652-1660)

The role of digoxin in clinical practice has narrowed over time. Data on digoxin toxicity trends and outcomes are variable and lack granularity for treatment outcomes. This study aimed to address data gaps in digoxin toxicity trends and outcomes in patients treated with or without digoxin immune fab (DIF). This single-center analysis examined patients with signs/symptoms concerning digoxin toxicity, defined as hospital admission or emergency department visit with elevated digoxin serum concentrations (> 2 ng/ml) and/or a primary diagnosis code of digoxin toxicity and/or DIF order. Between 2000 and 2020, 727 patients were identified with signs concerning for digoxin toxicity with a mortality rate of 12.7% during admission and 42.7% at 1 year. DIF was ordered in 9% of cases. Incidence of digoxin toxicity per 1,000 patients with a digoxin prescription and frequency of DIF treatment fluctuated over time without a clear trend toward increase or reduction. DIF-treated patients demonstrated a heavier co-morbidity burden and lower presenting heart rates (median 53 [39.5 to 69.5] vs 77 [64.0 to 91.5] beats/min, p < 0.001), worse renal function (median estimated glomerular filtration rate, 30.3 [14.8 to 48.6] vs 40.0 [24.2 to 61.2] ml/min/1.73 m(2), p = 0.013), and higher potassium (median 4.5 [4.0 to 5.3] vs 4.3 [3.9 to 4.8] mEq/L, p = 0.022). Compared with a matched cohort, DIF-treated patients experienced a nonsignificant, numerically lower in-hospital mortality (8.2% vs 15.8%, p = 0.199) and 30-day all-cause hospitalization (14.3% vs 24.7%, p = 0.112) and similar 6-month and 1-year hospitalization and mortality. In conclusion, digoxin toxicity remains a pertinent public health issue despite reduction in digoxin utilization. DIF therapy is used in a medically complex population with a high-acuity illness at presentation and is associated with nonsignificant trends toward reduced in-hospital mortality and early readmission that are attenuated over time. (c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY- license (http://creativecommons.org/licenses/bync-nd/4.0/)

Efficiency in clinical trial recruitment and enrollment remains a major challenge in many areas of clinical medicine. In particular, despite the prevalence of heart failure with preserved ejection fraction (HFpEF), identifying patients with HFpEF for clinical trials has proven to be especially challenging. In this manuscript, we review strategies for contemporary clinical trial recruitment and present insights from the results of the DELIVER Electronic Health Record (EHR) Screening Initiative. The DELIVER trial was designed to evaluate the effects of dapagliflozin on clinical outcomes in patients with HFpEF. Within this trial, the multicenter DELIVER EHR Screening Initiative utilized EHR-based techniques in order to improve recruitment at selected sites in the United States. For this initiative, we developed and deployed a computable phenotype from the trial's eligibility criteria along with additional EHR tools at interested sites. Sites were then surveyed at the end of the program regarding lessons learned. Six sites were recruited, trained, and supported to utilize the EHR methodology and computable phenotype. Sites found the initiative to be helpful in identifying eligible patients and cited the individualized expert technical support as a critical factor in utilizing the program effectively. We found that the major challenge of implementation was the process of converting traditional inclusion/exclusion criteria into a computable phenotype within an established and ongoing trial. Other significant challenges noted by sites were the following: impact of the COVID-19 pandemic, engagement/support by local institutions, and limited availability of internal EHR experts/resources to execute programming. The study represents a proof-of-concept in the ability to utilize EHR-based tools in clinical trial recruitment for patients with HFpEF and provides important lessons for future initiatives. ClinicalTrials.gov Identifier: NCT03619213.

Introduction: Torsemide is a loop diuretic that inhibits the Na+/K+/2Cl- cotransporter type 2 in the thick ascending loop of Henle, leading to increased excretion of urinary sodium and chloride and associated diuresis. While furosemide remains the dominant diuretic utilized in current practice, increasing evidence supports potential advantages of torsemide in heart failure (HF) and/or renal disease. Areas covered: This narrative review covers the evidence for use of torsemide in HF and renal disease. Comparative effectiveness with regards to clinical outcomes is reviewed, as well as the ongoing multicenter trial, TRANSFORM-HF, comparing the effect of torsemide versus furosemide among patients with HF. Expert opinion: Compared with furosemide, torsemide has favorable pharmacodynamics/pharmacokinetics including higher bioavailability, longer duration of effect, minor renal excretion, decreased kaliuresis, and enhanced natriuresis/diuresis. These properties may be further supported by differential effects on RAAS regulation and fibrosis modulation as compared with other diuretics. The limited current body of evidence indicates that torsemide may be superior to furosemide with respect to improving HF functional status and reducing HF hospitalization, and there are mixed data regarding effect on reducing overall cardiovascular hospitalizations/mortality. Further, randomized data are necessary to definitively determine if torsemide can reduce risk of mortality and hospitalization among patients with HF.

Abstract Aims Non‐alcoholic fatty liver disease leads to progressive liver fibrosis and appears to be a frequent co‐morbid disease in heart failure with preserved ejection fraction (HFpEF). It is well known that liver fibrosis severity predicts future liver‐related morbidity and mortality, but its impact on outcomes in patients with HFpEF remains unknown. This analysis aimed to describe the prevalence of liver fibrosis, as assessed using surrogate biomarkers, in patients with HFpEF and the association of such biomarkers in predicting clinical outcomes in these patients. Methods and results Patients with HFpEF from TOPCAT Americas were included in the analysis. The non‐alcoholic fatty liver disease fibrosis score (NFS) and fibrosis‐4 (FIB‐4) scores were calculated using a combination of clinical characteristics and laboratory parameters. Risk of advanced fibrosis was classified as low, intermediate, and high. For the 1423 with sufficient data, we used Cox regression analysis to test the association between the risk of fibrosis severity and the combined primary endpoint of all cardiovascular death, aborted cardiac arrest, and hospitalization for heart failure. Advanced fibrosis, as determined by high fibrosis scores, was present in 37.57% by the NFS and 8.02% by the FIB‐4. Higher risk of advanced hepatic fibrosis was associated with older age. In unadjusted models, the risk of advanced fibrosis was associated with the primary cardiovascular outcome [NFS high vs. low, hazard ratio (HR) 1.709 (95% confidence interval, CI 1.238–2.358, P = 0.0011) and FIB‐4 high vs. low, HR 1.561 (95% CI 1.139–2.140, P = 0.0056)]. After multivariable adjustment, this association was diminished [NFS high vs. low, HR 1.349 (95% CI 0.938–1.939, P = 0.1064) and FIB‐4 high vs. low, HR 1.415 (95% CI 0.995–2.010, P = 0.0531)]. Conclusions Our study suggests that advanced liver fibrosis, as estimated by fibrosis risk scores, may not be uncommon in patients with HFpEF, and there appears to be a limited independent association between liver fibrosis risk scores and clinical outcomes related to heart failure events.