Biomarkers for eligibility and surrogate endpoints in heart failure trials

Background: In heart failure (HF) with reduced ejection fraction (HFrEF), randomized controlled trials have provided effective treatments, but prognosis still remains poor. HF with mid-range EF (HFmrEF) has no evidencebased therapy and represents a newly characterized and relevant population for future trials. Trials in HF with preserved EF (HFpEF) have failed to provide any effective treatment, with several concerns about their design. Aims: Overall aim is to provide evidence to improve trial design in HF, investigating the use of natriuretic peptides (NPs) as surrogate endpoint, and as eligibility criterion to foster the enrichment of trials for cardiovascular (CV) vs. non-CV events. Specific aims were: • to assess the associations between changes in NP [B-type NP (BNP) and N-Terminal pro-BNP (NTproBNP)] levels over time and prognosis in chronic HFpEF and HFmrEF (Study I) and in acute decompensated HFpEF (Study II); • to compare levels, the independent determinants of levels and the prognostic role of NT-proBNP across EF categories (Study III); • to evaluate the associations between NT-proBNP and CV and non-CV outcomes across EF categories and in specific subgroups, and the associations between HF therapies and outcomes according to NTproBNP levels (Study IV). Changes in NT-proBNP and prognosis in chronic HFpEF and HFmrEF: We studied 650 HFpEF/HFmrEF outpatients enrolled in the Swedish Heart Failure registry (SwedeHF) between 2000 and 2012, reporting serial NT-proBNP assessments. A reduction in NT-proBNP at the median time of 7 months from the first measurement was associated with a reduction of mortality/HF hospitalization risk by 54% in the overall population, by 51% in HFpEF and by 61% in HFmrEF. Changes in BNP/NTproBNP levels and prognosis in acute decompensated HFpEF: From the Karolinska-Rennes (KaRen) study, 361 patients with acute decompensated HFpEF and BNP/NTproBNP measurements at the baseline and at the 4-8 weeks follow-up visit were analyzed. Changes in NPs from baseline to follow-up visit were not significantly associated with the risk of mortality/HF hospitalization although a trend toward a reduction in risk following the reduction in levels was observed. Levels, predictors of levels and prognostic/discriminatory role of NT-proBNP across EF categories: We analyzed 9,847 outpatients with HFpEF (18%), HFmrEF (22%) or HFrEF (60%) with at least one NTproBNP assessment, enrolled in the SwedeHF between 2000 and 2012. NT-proBNP levels were significantly higher in HFrEF (2,288 pg/ml) vs. HFpEF (1.428 pg/ml) and HFmrEF (1,540 pg/ml). Across EF categories, there were several different independent determinants for NT-proBNP levels, with atrial fibrillation more important in HFmrEF and HFpEF, diabetes and hypertension in HFmrEF, and age and body mass in HFrEF and HFmrEF, whereas there were no differences for renal function, New York Heart Association class, heart rate and anemia. NT-proBNP >vs. ≤median was associated with increased risk of mortality and mortality/ hospitalization with hazard ratios significantly higher in HFmrEF and HFpEF vs. HFrEF. NT-proBNP had greater area under the curve for death/HF hospitalization in HFmrEF vs. HFpEF and HFrEF. NT-proBNP levels and risk of CV/non-CV events across EF categories: We studied 15,849 patients with HFpEF (23%), HFmrEF (21%) and HFrEF (56%) and at least one NT-proBNP assessment, enrolled in SwedeHF between 2000 and 2012. Increasing NT-proBNP levels were associated with a steeper increase in CV vs. non-CV event rates in HFpEF vs. HFmrEF vs. HFrEF. CV to non-CV event ratio increased together with the increase in NT-proBNP in HFpEF and HFrEF, but only in the lower range in HFmrEF. The association between HF treatments (angiotensin converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers) and CV/non-CV events risk was consistent in NT-proBNP ≤ and >median. Conclusions: The association between NT-proBNP levels and prognosis across the EF spectrum, together with the association between reduction in NT-proBNP levels and improvement in prognosis in HFpEF, HFmrEF and HFrEF supports the use of NT-proBNP as surrogate endpoint in phase II trials in chronic HF. We did not observe any significant association between changes in BNP/NT-proBNP and prognosis in acute decompensated HFpEF. The observed relationship between NT-proBNP levels and CV and non-CV events supports the use of NTproBNP for eligibility and enrichment for CV events in HF trials, but the cut-off levels should consider the differences in comorbidities across the EF spectrum. Potential treatment response according to NT-proBNP levels deserves further investigation

Use of Renin–Angiotensin–Aldosterone System Inhibitors in Older Patients with Heart Failure and Reduced Ejection Fraction

Patients enrolled in randomised clinical trials may not be representative of the real-world population of people with heart failure (HF). Older patients are frequently excluded and this limits the strength of evidence which supports the use of specific HF treatments in this patient group. Lack of evidence together with fear of adverse effects, drug interactions and lower tolerance may lead to the undertreatment of older patients and a less favourable outcome. Renin–angiotensin–aldosterone system (RAAS) inhibitors are the cornerstone of treatment for patients with HF with reduced ejection fraction (HFrEF), but despite the class I recommendation for all patients regardless of age in the guidelines, there are signs that RAAS inhibitors are underused among older patients. Large registry- based studies suggest that RAAS inhibitors may be at least as effective in older patients as younger ones, but these findings need to be confirmed by randomised clinical trials

Molecular mechanism of endothelial and vascular aging: implications for cardiovascular disease

Western societies are aging due to an increasing life span, decreased birth rates, and improving social and health conditions. On the other hand, the prevalence of cardiovascular (CV) and cerebrovascular (CBV) diseases rises with age. Thus, in view of the ongoing aging pandemic, it is appropriate to better understand the molecular pathways of aging as well as age-associated CV and CBV diseases. Oxidative stress contributes to aging of organs and the whole body by an accumulation of reactive oxygen species promoting oxidative damage. Indeed, increased oxidative stress produced in the mitochondria and cytosol of heart and brain is a common denominator to almost all CV and CBV diseases. The mitochondrial adaptor protein p66Shc and the family of deacetylase enzymes, the sirtuins, regulate the aging process, determine lifespan of many species and are involved in CV diseases. GDF11, a member of TGFβ superfamily with homology to myostatin also retards the aging process via yet unknown mechanisms. Recent evidence points towards a promising role of this novel ‘rejuvenation' factor in reducing age-related heart disease. Finally, telomere length is also involved in aging and the development of age-related CV dysfunction. This review focuses on the latest scientific advances in understanding age-related changes of the CV and CBV system, as well as delineating potential novel therapeutic targets derived from aging research for CV and CBV disease

Evidence-based Therapy in Older Patients with Heart Failure with Reduced Ejection Fraction

Older patients are becoming prevalent among people with heart failure (HF) as the overall population ages. However, older patients are largely under-represented, or even excluded, from randomised controlled trials on HF with reduced ejection fraction, limiting the generalisability of trial results in the real world and leading to weaker evidence supporting the use and titration of guideline-directed medical therapy (GDMT) in older patients with HF with reduced ejection fraction. This, in combination with other factors limiting the application of guideline recommendations, including a fear of poor tolerability or adverse effects, the heavy burden of comorbidities and the need for multiple therapies, classically leads to lower adherence to GDMT in older patients. Although there are no data supporting the under-use and under-dosing of HF medications in older patients, large registry-based studies have confirmed age as one of the major obstacles to treatment optimisation. In this review, the authors provide an overview of the contemporary state of implementation of GDMT in older groups and the reasons for the lower use of treatments, and discuss some measures that may help improve adherence to evidence-based recommendations in older age groups

Persistent High Burden of Heart Failure Across the Ejection Fraction Spectrum in a Nationwide Setting

Background Heart failure (HF) has a dramatic impact on worldwide health care systems that is determined by the growing prevalence of and the high exposure to cardiovascular and noncardiovascular events. Prognosis remains poor. We sought to compare a large population with HF across the ejection fraction (EF) spectrum with a population without HF for patient characteristics, and HF, cardiovascular, and noncardiovascular outcomes. Methods and Results Patients with HF registered in the Swedish HF registry in 2005 to 2018 were compared 1:3 with a sex-, age-, and county-matched population without HF. Outcomes were cardiovascular and noncardiovascular mortality and hospitalizations. Of 76 453 patients with HF, 53% had reduced EF, 23% mildly reduced EF, and 24% preserved EF. Compared with those without HF, patients with HF had more cardiovascular and noncardiovascular comorbidities and worse socioeconomic status. Incidence of cardiovascular and noncardiovascular events was higher in people with HF versus non-HF, with increased risk of all-cause (hazard ratio [HR], 2.53 [95% CI, 2.50-2.56]), cardiovascular (HR, 4.67 [95% CI, 4.59-4.76]), and noncardiovascular (HR, 1.49 [95% CI, 1.46-1.52]) mortality, 2- to 5-fold higher risk of first/repeated cardiovascular and noncardiovascular hospitalizations, and ~4 times longer in-hospital length of stay for any cause. Patients with HF with reduced EF had higher risk of HF hospitalizations, whereas those with HF with preserved EF had higher risk of all-cause and noncardiovascular hospitalization and mortality. Conclusions Patients with HF exert a high health care burden, with a much higher risk of cardiovascular, all-cause, and noncardiovascular events, and nearly 4 times as many days spent in hospital compared with those without HF. These epidemiological data may enable strategies for optimal resource allocation and HF trial design

The management of heart failure in Sweden—the physician’s perspective: a survey

AimsTo assess the barriers to guideline-directed medical therapy (GDMT) use in heart failure (HF), diagnostic workup and general knowledge about HF among physicians in Sweden.MethodsA survey about the management of HF was sent to 828 Swedish physicians including general practitioners (GPs) and specialists during 2021–2022. Answers were reported as percentages and comparisons were made by specialty (GPs vs. specialists).ResultsOne hundred sixty-eight physicians participated in the survey (40% females, median age 43 years; 41% GPs and 59% specialists). Electrocardiography and New York Heart Association class evaluations are mostly performed once a year by GPs (46%) and at every outpatient visit by specialists (40%). Echocardiography is mostly requested if there is clinical deterioration (60%). One-third of participants screen for iron deficiency only if there is anemia. Major obstacles to implementation of different drug classes in HF with reduced ejection fraction are related to side effects, with no significant differences between specialties. Device implantation is deemed appropriate regardless of aetiology (69%) and patient age (86%). Specialists answered correctly to knowledge questions more often than GPs. Eighty-six percent of participants think that GDMT should be implemented as much as possible. Most participants (57%) believe that regular patient assessment in nurse-led HF clinics improve adherence to GDMT.ConclusionObstacles to GDMT implementation according to physicians in Sweden mainly relate to potential side effects, lack of specialist knowledge and organizational aspects. Further efforts should be placed in educational activities and structuring of nurse-led clinics