Patients with worsening heart failure with reduced ejection fraction (HFrEF) spend a large proportion of time in the hospital and other health care facilities. The benefits of guideline-directed medical therapy (GDMT) in the outpatient setting have been shown in large randomized controlled trials. However, the decision to initiate, continue, switch, or withdraw HFrEF medications in the inpatient setting is often based on multiple factors and subject to significant variability across providers. Based on available data, in well-selected, treatment-naïve patients who are hemodynamically stable and clinically euvolemic after stabilization during hospitalization for HF, elements of GDMT can be safely initiated. Inpatient continuation of GDMT for HFrEF appears safe and well-tolerated in most hemodynamically stable patients. Hospitalization is also a potential time for switching from an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker to sacubitril/valsartan therapy in eligible patients, and is the subject of ongoing study. Therapy withdrawal or need for dose reduction is rarely required, but if needed identifies a particularly at-risk group of patients with progressive HF. If recurrent intolerance to neurohormonal blockers is observed, these patients should be evaluated for advanced HF therapies. There is an enduring need for using the teachable moment of HFrEF hospitalization for optimal initiation, continuation, and switching of GDMT to improve post-discharge patient outcomes and the quality of chronic HFrEF care.

Cachexia, in the form of unintentional weight loss >5% in 12 months or less, and secondary sarcopenia in the form of muscle wasting are serious conditions that affect clinical outcomes. A chronic disease state such as chronic kidney disease (CKD) often contributes to these wasting disorders. The purpose of this review is to summarize the prevalence of cachexia and sarcopenia, their relationship with kidney function, and indicators for evaluating kidney function in patients with CKD. It is estimated that approximately half of all persons with CKD will develop cachexia with an estimated annual mortality rate of 20%, but few studies have been conducted on cachexia in CKD. Hence, the true prevalence of cachexia in CKD and its effects on kidney function and patient outcomes remain unclear. Some studies have highlighted the concept of protein-energy wasting (PEW) which usually include sarcopenia and cachexia. Several studies have examined kidney function and CKD progression in patients with sarcopenia. Most studies use serum creatinine levels to estimate kidney function. However, creatinine may be influenced by muscle mass, and creatinine-based glomerular filtration rate may overestimate kidney function in patients with reduced muscle mass or muscle wasting. Cystatin C, which is least affected by muscle mass, has been used in some studies, and creatinine-to-cystatin-C ratio has emerged as an important prognostic marker. A previous study incorporating 428 320 participants reported that participants with CKD and sarcopenia had a 33% higher hazard of mortality compared with those without (7% to 66%, P = 0.011), and that those with sarcopenia were twice as likely to develop end-stage kidney disease (hazard ratio: 1.98; 1.45 to 2.70, P < 0.001). Future studies on cachexia and sarcopenia in patients with CKD are needed to report rigorously defined cachexia concerning kidney function. Moreover, in studies on sarcopenia with CKD, it is desirable to accumulate studies using cystatin C to accurately estimate kidney function.

Evidence for cardiovascular outcomes with older-generation antihyperglycemic drugs in the management of type 2 diabetes is based on aggregated data from prior randomized controlled trials and observational studies that were not focused on prespecified cardiovascular end points. Newer antihyperglycemic medications have undergone a rigorous evaluation of cardiovascular outcomes through randomized controlled trials since the US Food and Drug Administration imposed a mandatory requirement for all glucose-lowering drugs in 2008. The three classes of drugs that have been most extensively studied are dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter-2 (SGLT2) inhibitors, the latter two reporting significant reductions in adverse cardiovascular outcomes independent of their glycemic effect. Remarkably, it was the evidence from SGLT2 inhibitors cardiovascular outcome trials that prompted further evaluation of the drug class in patients with heart failure irrespective of their diabetes status, demonstrating a broader cardiometabolic effect of these drugs. In this review, we assess the evidence for cardiovascular outcomes with common older- and newer-generation glucose-lowering drugs in the management of type 2 diabetes. We also discuss emerging glucose-lowering drugs with novel metabolic targets that influence the risk of adverse cardiovascular events and expand on the role of these drugs beyond the management of type 2 diabetes.

Importance

Guideline-directed medical therapy (GDMT) remains underutilized on a global level, with significant disparities in access to treatment worldwide. The potential global benefits of quadruple therapy on patients with heart failure with reduced ejection fraction (HFrEF) have not yet been estimated.

Objective

To assess the projected population-level benefit of optimal GDMT use globally among patients with HFrEF.

Design, setting, and participants

Estimates for HFrEF prevalence, contraindications to GDMT, treatment rates, and the number needed to treat for all-cause mortality at 12 months were derived from previously published sources. Potential lives saved from optimal implementation of quadruple therapy among patients with HFrEF was calculated globally and a sensitivity analysis was conducted to account for uncertainty in the existing data.

Main outcomes and measures

All-cause mortality.

Results

Of an estimated 28.89 million people with HFrEF worldwide, there were 8 235 063 (95% CI, 6 296 020-10 762 972) potentially eligible for but not receiving β-blockers, 20 387 000 (95% CI, 15 867 004-26 184 996) eligible for but not receiving angiotensin receptor-neprilysin inhibitors, 12 223 700 (95% CI, 9 376 895-15 924 973) eligible for but not receiving mineralocorticoid receptor antagonists, and 21 229 170 (95% CI, 16 537 400-27 242 688) eligible for but not receiving sodium glucose cotransporter-2 inhibitors. Optimal implementation of quadruple GDMT could potentially prevent 1 188 277 (95% CI, 767 933-1 914 561) deaths over 12 months. A large proportion of deaths averted were projected in Southeast Asia, Eastern Mediterranean and Africa, and the Western Pacific regions.

Conclusions and relevance

Improvement in use of GDMT could result in substantial mortality benefits on a global scale. Significant heterogeneity also exists across regions, which warrants additional study with interventions tailored to country-level differences for optimization of GDMT worldwide.

BACKGROUND: Initiation and up-titration of guideline-directed medical therapies (GDMTs) for heart failure with reduced ejection fraction (HFrEF) remains suboptimal, in part because of concerns regarding tolerability and adverse events (AEs). OBJECTIVES: The authors sought to compare rates of AE in patients randomized to GDMT medication vs placebo in a meta-analysis of landmark cardiovascular outcomes trials. METHODS: The authors assessed rates of reported AE in 17 landmark HFrEF clinical trials across each class of GDMT in the placebo and intervention arms. The overall rates of AE for each drug class, the absolute difference in frequency in AEs between the placebo and intervention arms, and the odds of each AE according based on randomization strata were calculated. RESULTS: AE were reported commonly in trials across each class of GDMT, with 75% to 85% of participants reporting at least 1 AE. There was no significant difference in the frequency of AE between the intervention and placebo arms, except for angiotensin-converting enzyme inhibitors (87.0% [95% CI: 85.0%-88.8%] vs 82.0% [95% CI: 79.8%-84.0%], absolute difference: +5% with intervention; P < 0.001). There was no significant difference in drug discontinuation because of AE between placebo and intervention arms in angiotensin-converting enzyme inhibitors, mineralocorticoid receptor antagonists, sodium glucose cotransporter 2 inhibitors, or angiotensin receptor neprilysin inhibitor/angiotensin II receptor blocker trials. Patients randomized to beta-blocker were significantly less likely to stop study drug because of AE than placebo (11.3% [95% CI: 10.3%-12.3%] vs 13.7% [95% CI: 12.5%-14.9%], absolute difference: -1.1%; P = 0.015). When individual types of AE were assessed, the initiation of an intervention vs placebo resulted in small differences in absolute frequency of AE that were largely not statistically significant. CONCLUSIONS: In clinical trials of GDMT for HFrEF, AEs are observed frequently. However, rates of AE are similar between active medication and control, suggesting these may reflect the high risk nature of the heart failure disease state rather than be attributive to a specific therapy.

BACKGROUND:Although individual cardiac biomarkers are associated with heart failure risk and all-cause mortality in HIV-infected individuals, their combined use for prediction has not been well studied. METHODS AND RESULTS:Unsupervised k-means cluster analysis was performed blinded to the study outcomes in 332 HIV-infected participants on 8 biomarkers: ST2, NT-proBNP (N-terminal pro-B-type natriuretic peptide), hsCRP (high-sensitivity C-reactive protein), GDF-15 (growth differentiation factor 15), cystatin C, IL-6 (interleukin-6), D-dimer, and troponin. We evaluated cross-sectional associations of each cluster with diastolic dysfunction, pulmonary hypertension (defined as echocardiographic pulmonary artery systolic pressure ≥35 mm Hg), and longitudinal associations with all-cause mortality. The biomarker-derived clusters partitioned subjects into 3 groups. Cluster 3 (n=103) had higher levels of CRP, IL-6, and D-dimer (inflammatory phenotype). Cluster 2 (n=86) displayed elevated levels of ST2, NT-proBNP, and GDF-15 (cardiac phenotype). Cluster 1 (n=143) had lower levels of both phenotype-associated biomarkers. After multivariable adjustment for traditional and HIV-related risk factors, cluster 3 was associated with a 51% increased risk of diastolic dysfunction (95% confidence interval, 1.12-2.02), and cluster 2 was associated with a 67% increased risk of pulmonary hypertension (95% confidence interval, 1.04-2.68), relative to cluster 1. Over a median 6.9-year follow-up, 48 deaths occurred. Cluster 3 was independently associated with a 3.3-fold higher risk of mortality relative to cluster 1 (95% confidence interval, 1.3-8.1), and cluster 2 had a 3.1-fold increased risk (95% confidence interval, 1.1-8.4), even after controlling for diastolic dysfunction, pulmonary hypertension, left ventricular mass, and ejection fraction. CONCLUSIONS:Serum biomarkers can be used to classify HIV-infected individuals into separate clusters for differentiating cardiopulmonary structural and functional abnormalities and can predict mortality independent of these structural and functional measures.

Studies with angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) in patients with heart failure with preserved ejection fraction (HFpEF) have yielded inconsistent results. To conduct a systematic review and meta-analysis of all evidence for ACE-I and ARBs in patients with HFpEF, we searched PubMed, Ovid SP, Embase, and Cochrane database to identify randomized trials and observational studies that compared ACE-I or ARBs against placebo or standard therapy in HFpEF patients. Random-effect models were used to pool the data, and I² testing was performed to assess the heterogeneity of the included studies. A total of 13 studies (treatment arm = 8676 and control arm = 8608) were analysed. Pooled analysis of randomized trials for ACE-I and ARBs (n = 6) did not show any effect on all-cause mortality [relative risk (RR) = 1.02, 95% confidence interval (CI) = 0.93-1.11, P = 0.68, I²  = 0%], while results from observational studies showed a significant improvement (RR = 0.91, 95% CI = 0.87-0.95, P = 0.005, I²  = 81.5%). In pooled analyses of all studies, ACE-I showed a reduction of all-cause mortality (RR = 0.91, 95% CI = 0.87-0.95, P = 0.01). There was no reduction in cardiovascular mortality seen, but in pooled analysis of randomized trials, there was a trend towards reduced HF hospitalization risk (RR = 0.91, 95% CI = 0.83-1.01, I²  = 0%, P = 0.074). These data suggest that ACE-I and ARBs may have a role in improving outcomes of patients with HFpEF, underscoring the need for future research with careful patient selection, and trial design and conduct.

Background

Although individual cardiac biomarkers are associated with heart failure risk and all-cause mortality in HIV-infected individuals, their combined use for prediction has not been well studied.

Methods and results

Unsupervised k-means cluster analysis was performed blinded to the study outcomes in 332 HIV-infected participants on 8 biomarkers: ST2, NT-proBNP (N-terminal pro-B-type natriuretic peptide), hsCRP (high-sensitivity C-reactive protein), GDF-15 (growth differentiation factor 15), cystatin C, IL-6 (interleukin-6), D-dimer, and troponin. We evaluated cross-sectional associations of each cluster with diastolic dysfunction, pulmonary hypertension (defined as echocardiographic pulmonary artery systolic pressure ≥35 mm Hg), and longitudinal associations with all-cause mortality. The biomarker-derived clusters partitioned subjects into 3 groups. Cluster 3 (n=103) had higher levels of CRP, IL-6, and D-dimer (inflammatory phenotype). Cluster 2 (n=86) displayed elevated levels of ST2, NT-proBNP, and GDF-15 (cardiac phenotype). Cluster 1 (n=143) had lower levels of both phenotype-associated biomarkers. After multivariable adjustment for traditional and HIV-related risk factors, cluster 3 was associated with a 51% increased risk of diastolic dysfunction (95% confidence interval, 1.12-2.02), and cluster 2 was associated with a 67% increased risk of pulmonary hypertension (95% confidence interval, 1.04-2.68), relative to cluster 1. Over a median 6.9-year follow-up, 48 deaths occurred. Cluster 3 was independently associated with a 3.3-fold higher risk of mortality relative to cluster 1 (95% confidence interval, 1.3-8.1), and cluster 2 had a 3.1-fold increased risk (95% confidence interval, 1.1-8.4), even after controlling for diastolic dysfunction, pulmonary hypertension, left ventricular mass, and ejection fraction.

Conclusions

Serum biomarkers can be used to classify HIV-infected individuals into separate clusters for differentiating cardiopulmonary structural and functional abnormalities and can predict mortality independent of these structural and functional measures.

Acute heart failure (HF) is a global pandemic with more than one million admissions to hospital annually in the US and millions more worldwide. Post-discharge mortality and readmission rates remain unchanged and unacceptably high. Although recent drug development programmes have failed to deliver novel therapies capable of reducing cardiovascular morbidity and mortality in patients hospitalized for worsening chronic HF, hospitalized HF registries and clinical trial databases have generated a wealth of information improving our collective understanding of the HF syndrome. This review will summarize key insights from clinical trials in acute HF and hospitalized HF registries over the last several decades, focusing on improving the management of patients with HF and reduced ejection fraction.