Hernandez, Adrian F.

Hypertension is the single most important modifiable risk factor for preventable disability and death worldwide and disproportionately affects socially disadvantaged populations. We face a paradox—blood pressure control is low and recent trends suggest it is even declining, despite the availability of inexpensive and effective therapies. A variety of barriers on the system, patient, and healthcare provider side hinder effective drug-based risk factor management. Clinical inertia represents a major barrier on the clinician side, as well as workload and limited education. Common barriers on the patient side include limited English proficiency, low health literacy, and nonadherence with misaligned incentives, limited resources, lack of structured clinical pathways, and reimbursement issues. New innovations in the field of RNA-targeted therapies and device-based interventions could prevent and potentially even cure diseases previously designated as chronic health conditions, such as hypertension. Such novel therapies could potentially overcome several major barriers to effective treatment, including nonadherence. Drug development of novel, long-acting treatments requires consideration of specific clinical trial design aspects, including safety collection, benefit: risk assessment, the development and assessment of novel, qualitative surrogate end points, such as time-in-therapeutic range, the use of representative trial settings as well as the definition of standard of care in placebo-controlled trials, which should be of reasonably high-quality allowing for credible evaluation of effectiveness. Here, we provide an overview on barriers to effective treatment and a framework for trials assessing novel treatments for cardiovascular disease risk factors, including early and broad implementation programs.

Abstract Aims Ferric carboxymaltose (FCM) is guideline-recommended for iron deficiency (ID) in heart failure with reduced ejection fraction (HFrEF). Despite a well-established safety profile, the magnitude and clinical significance of FCM-induced hypophosphataemia in HFrEF remains unclear. This pre-specified substudy of HEART-FID evaluated serum phosphate, 1,25-dihydroxyvitamin D, and plasma parathyroid hormone (PTH) subsequent to FCM. Methods and results HEART-FID was a randomized, double-blind, placebo-controlled trial of ambulatory patients with HFrEF and ID randomized to FCM versus placebo. This substudy assessed mean change from baseline across eight visits over 6 months for the following endpoints: serum phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and PTH, in addition to the clinical severity of potential hypophosphataemia. Overall, 133 patients (n = 62 FCM, n = 71 placebo) were prospectively enrolled. Mean age was 68 ± 11 years, 55 (41.4%) were women, and 29 (21.8%) had chronic kidney disease. Phosphate levels decreased in 34 (57.6%) patients in the FCM group compared with 7 (10.3%) in the placebo group. Mean change in phosphate levels reached a nadir at day 21 (−0.36 ± 0.27 mmol/L) subsequent to FCM infusion with 28 (51%) having moderate-to-severe hypophosphataemia. Reductions in 1,25-dihydroxyvitamin D were also observed, whilst PTH increased. These biochemical changes returned to baseline levels by day 91. Serum levels of 25-hydroxyvitamin D remained stable throughout the study. No serious adverse events associated with hypophosphataemia were reported. Conclusions Transient moderate-to-severe hypophosphataemia was frequent subsequent to FCM infusion, accompanied by 1,25-dihydroxyvitamin D decrease and PTH increase. Serum levels of 25-hydroxyvitamin D remained stable. No evidence of symptomatic hypophosphataemia was reported, collectively indicating FCM-related hypophosphataemia to be clinically benign and transient in HFrEF.

Introduction: Impaired left atrial (LA) function may limit optimal cardiac performance, reflecting both LA load and atrial dysfunction in HFpEF. The link between MRI-derived LA characteristics and exercise capacity in HFpEF has not been studied. Hypothesis: We hypothesized that total LA emptying fraction (LAEF) is reduced in HFpEF vs. healthy controls and LA functional impairment would be correlated with LV diastolic dysfunction, vascular dysfunction, and exercise intolerance. As LA hypertension may increase right ventricular load and limit increases in pulmonary perfusion with exercise, the correlation of LAEF with ventilatory efficiency (VE/VCO2 slope) was also examined. Methods: Baseline exercise, echo, and cardiac MRI data from RELAX (a study of sildenafil in HFpEF) in patients in sinus rhythm with a measureable LAEF by MRI (n=100) were utilized. Healthy volunteers (n=21) were included for comparison. LAV was measured by the biplane area-length method using 2-/4-chamber SSFP CMR. LAEF was defined as total (ΔLAVmax-min), passive/conduit (ΔLAVmax-before atrial contraction ), and active (ΔLAVbefore atrial contraction-min), each divided by maximal LAV. Results: As compared to controls, LAEF (particularly passive conduit function) was reduced in HFpEF (Table 1). In HFpEF, patients with lower LAEF had a larger LA, more echo diastolic dysfunction, higher PA systolic pressure and NT-proBNP, reduced aortic distensibility, worse exercise capacity, and ventilatory inefficiency (Table 2). Conclusions: LA function is impaired in HFpEF, may serve as a marker of chronic LA hypertension and may contribute to impaired exercise intolerance and ventilatory inefficiency.

BACKGROUND: Clinical trials in heart failure (HF) traditionally use time-to-event analyses focusing on death and hospitalization for HF. These time-to-first event analyses may have more limited abilities to assess the probability of benefiting from a therapy, especially if that benefit manifests as improved functional status rather than reduced risk of death or HF hospitalization. Hierarchical end points including clinical outcomes and patient status measures allow for ranked evaluation of outcomes in 1 metric assessing whether patients randomized to intervention or control are more likely to derive an overall benefit while also allowing more patients to contribute to the primary outcome. METHODS: We review the rationale for using hierarchical end points in HF trials, provide examples of HF trials that used this type of end point, and discuss its use in the HEART-FID trial (Randomized Placebo-Controlled Trial of Ferric Carboxymaltose as Treatment for Heart Failure With Iron Deficiency), the largest HF trial to date implementing a hierarchical end point analysis for the primary outcome. RESULTS: Using a hierarchical end point as the primary outcome allows for the inclusion of different types of outcomes in 1 ranked end point, making it possible to more holistically assess the potential utility of a new therapy on patient well-being and outcomes. CONCLUSIONS: Hierarchical end points assess the potential utility of a new therapy on patient well-being and outcome more holistically than time-to-first event analysis. Trials that would not have been feasible due to decreasing rates of death and hospitalization in the HF population can use hierarchical end points to successfully power studies to identify promising HF therapies. The HEART-FID trial used hierarchical end points to better determine the role of intravenous ferric carboxymaltose in patients with HF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03037931.

BACKGROUND: Heart failure remains a global health burden, and patients hospitalized are particularly at risk, but genetic associates for subsequent death or rehospitalization are still lacking. METHODS: The genetic substudy of the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) was used to perform genome-wide association study and transethnic meta-analysis. The overall trial included the patients of self-reported European ancestry (n=2173) and African ancestry (n=507). The end point was death or heart failure rehospitalization within 180 days. Cox models adjusted for 11 a priori predictors of rehospitalization and 5 genetic principal components were used to test the association between single-nucleotide polymorphisms and outcome. Summary statistics from the 2 populations were combined via meta-analysis with the significance threshold considered P <5×10 − 8 . RESULTS: Common variants (rs2342882 and rs35850039 in complete linkage disequilibrium) located in FGD5 were significantly associated with the primary outcome in both ancestry groups (European Americans: hazard ratio [HR], 1.38; P =2.42×10 −6 ; African ancestry: HR, 1.51; P =4.43×10 − 3 ; HR in meta-analysis, 1.41; P =4.25×10 −8 ). FGD5 encodes a regulator of VEGF (vascular endothelial growth factor)-mediated angiogenesis, and in silico investigation revealed several previous genome-wide association study hits in this gene, among which rs748431 was associated with our outcome (HR, 1.20; meta P <0.01). Sensitivity analysis proved FGD5 common variants survival association did not appear to operate via coronary artery disease or nesiritide treatment ( P >0.05); and the signal was still significant when changing the censoring time from 180 to 30 days (HR, 1.39; P =1.59×10 −5 ). CONCLUSIONS: In this multiethnic genome-wide association study of ASCEND-HF, single-nucleotide polymorphisms in FGD5 were associated with increased risk of death or rehospitalization. Additional investigation is required to examine biological mechanisms and whether FGD5 could be a therapeutic target. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00475852.

Abstract Whether initiation of statins could increase survival free of dementia and disability in adults aged ≥75 years is unknown. PREVENTABLE, a double‐blind, placebo‐controlled randomized pragmatic clinical trial, will compare high‐intensity statin therapy (atorvastatin 40 mg) with placebo in 20,000 community‐dwelling adults aged ≥75 years without cardiovascular disease, disability, or dementia at baseline. Exclusion criteria include statin use in the prior year or for >5 years and inability to take a statin. Potential participants are identified using computable phenotypes derived from the electronic health record and local referrals from the community. Participants will undergo baseline cognitive testing, with physical testing and a blinded lipid panel if feasible. Cognitive testing and disability screening will be conducted annually. Multiple data sources will be queried for cardiovascular events, dementia, and disability; survival is site‐reported and supplemented by a National Death Index search. The primary outcome is survival free of new dementia or persisting disability. Co‐secondary outcomes are a composite of cardiovascular death, hospitalization for unstable angina or myocardial infarction, heart failure, stroke, or coronary revascularization; and a composite of mild cognitive impairment or dementia. Ancillary studies will offer mechanistic insights into the effects of statins on key outcomes. Biorepository samples are obtained and stored for future study. These results will inform the benefit of statins for increasing survival free of dementia and disability among older adults. This is a pioneering pragmatic study testing important questions with low participant burden to align with the needs of the growing population of older adults.

Rationale: Cardiovascular disease remains the leading cause of death in women. To address its determinants including persisting cardiovascular risk factors amplified by sex and race inequities, novel personalized approaches are needed grounded in the engagement of participants in research and prevention. Objective: To report on a participant-centric and personalized dynamic registry designed to address persistent gaps in understanding and managing cardiovascular disease in women. Methods and Results: The American Heart Association and Verily launched the Research Goes Red registry (RGR) in 2019, as an online research platform available to consenting individuals over the age of 18 years in the United States. RGR aims to bring participants and researchers together to expand knowledge by collecting data and providing an open-source longitudinal dynamic registry for conducting research studies. As of July 2021, 15 350 individuals have engaged with RGR. Mean age of participants was 48.0 48.0±0.2 years with a majority identifying as female and either non-Hispanic White (75.7%) or Black (10.5%). In addition to 6 targeted health surveys, RGR has deployed 2 American Heart Association-sponsored prospective clinical studies based on participants’ areas of interest. The first study focuses on perimenopausal weight gain, developed in response to a health concerns survey. The second study is designed to test the use of social media campaigns to increase awareness and participation in cardiovascular disease research among underrepresented millennial women. Conclusions: RGR is a novel online participant-centric platform that has successfully engaged women and provided critical data on women’s heart health to guide research. Priorities for the growth of RGR are centered on increasing reach and diversity of participants, and engaging researchers to work within their communities to leverage the platform to address knowledge gaps and improve women’s health.

Introduction: Despite the use of different definitions for worsening heart failure (WHF) in prior clinical trials and registries, an in-hospital WHF event has consistently been associated with worse patient outcomes. WHF is being considered as a potential endpoint to support drug approval. We combined patients from two acute HF trials conducted by the HF Network (ROSE-AHF and DOSE-AHF) to understand how different WHF definitions are associated with event rates. Methods: WHF was defined as persistent or worsening HF requiring rescue therapy including IV vasoactive agents, ultrafiltration, or mechanical support over 72 hours after randomization in ROSE and also included additional open label loop or thiazide diuretic in DOSE. We assessed the relationship between WHF and the composite endpoint (CE) of re-hospitalization, emergency room visits for HF and mortality through 60 days. We also assessed for a differential relationship of WHF from 0-24 hours, 24-48 hours and 48-72 hours post-randomization. Results: The overall incidence of WHF was 14.6% (24.1% in DOSE and 6.3% in ROSE). Patients who developed WHF had lower baseline systolic blood pressure, less peripheral edema and higher BUN. In the combined dataset, WHF was associated with an increase in the CE (hazard ratio [HR] 1.64; 95% confidence interval [CI] 1.11-2.42; p-value 0.01). However, the association between WHF and 60-day outcomes was significant in ROSE but not in DOSE (Table). The development of WHF between 48-72 hours compared with 0-24 hours or 24-48 hours was associated with improved outcomes ([HR] 0.48, 95% CI 0.27 - 0.88, p-value 0.02 and [HR] 0.45, 95% CI 0.26 - 0.78, p-value 0.004, respectively). Conclusions: A WHF definition that incorporated intensification of diuretics increased the event rate but was not associated with worse 60-day outcomes. The timing of a WHF event also had a differential association with outcomes. These data support the use of a standardized WHF definition in clinical trials.

Abstract Aims Associations between growth differentiation factor-15 (GDF-15), cardiovascular outcomes, and exercise capacity among patients with a recent hospitalization for heart failure (HHF) and heart failure with reduced ejection fraction (HFrEF) are unknown. We utilized data from the ‘Functional Impact of GLP-1 for Heart Failure Treatment’ (FIGHT) study to address these knowledge gaps. Methods and results FIGHT was a randomized clinical trial testing the effect of liraglutide (vs. placebo) among 300 participants with HFrEF and a recent HHF. Multivariable regression models evaluated associations between baseline GDF-15 and change in GDF-15 (per 1000 pg/mL increase from baseline to 30 days) with clinical outcomes (at 180 days) and declines in exercise capacity (6 min walk distance ≥ 45 m). At baseline (n = 249), median GDF-15 value was 3221 pg/mL (interquartile range 1938–5511 pg/mL). Participants in the highest tertile of baseline GDF-15 were more likely to be male and have more co-morbidities. After adjustment, an increase in GDF-15 over 30 days was associated with higher risk of death or HHF [hazard ratio 1.35, 95% confidence interval (CI) 1.11–1.64]. In addition, higher baseline GDF-15 (per 1000 pg/mL until 6000 pg/mL) and an increase in GDF-15 over 30 days were associated with declining 6 min walk distance (odds ratio 1.26, 95% CI 1.02–1.55 and odds ratio 1.37, 95% CI 1.12–1.69, respectively). GDF-15 levels remained stable among participants randomized to liraglutide. Conclusions An increase in GDF-15 over 30 days among patients in HFrEF was independently associated with an increased risk of cardiovascular events and declining exercise capacity. These results support the value of longitudinal GDF-15 trajectory in informing risk of heart failure disease progression.