Cardiovascular Events In Heart Failure Patients Research Articles

Metabolomics and Cardiovascular Risk in Patients with Heart Failure: A Systematic Review and Meta-Analysis.

The associations of plasma metabolites with adverse cardiovascular (CV) outcomes are still underexplored and may be useful in CV risk stratification. We performed a systematic review and meta-analysis to establish correlations between blood metabolites and adverse CV outcomes in patients with heart failure (HF). Four cohorts were included, involving 83 metabolites and 37 metabolite ratios, measured in 1158 HF patients. Hazard ratios (HR) of 42 metabolites and 3 metabolite ratios, present in at least two studies, were combined through meta-analysis. Higher levels of histidine (HR 0.74, 95% CI [0.64; 0.86]) and tryptophan (HR 0.82 [0.71; 0.96]) seemed protective, whereas higher levels of symmetric dimethylarginine (SDMA) (HR 1.58 [1.30; 1.93]), N-methyl-1-histidine (HR 1.56 [1.27; 1.90]), SDMA/arginine (HR 1.38 [1.14; 1.68]), putrescine (HR 1.31 [1.06; 1.61]), methionine sulfoxide (HR 1.26 [1.03; 1.52]), and 5-hydroxylysine (HR 1.25 [1.05; 1.48]) were associated with a higher risk of CV events. Our findings corroborate important associations between metabolic imbalances and a higher risk of CV events in HF patients. However, the lack of standardization and data reporting hampered the comparison of a higher number of studies. In a future clinical scenario, metabolomics will greatly benefit from harmonizing sample handling, data analysis, reporting, and sharing.

Impact of guideline-directed medical therapy on systolic blood pressure and cardiovascular outcomes in patients with heart failure and low blood pressure: A systematic review and meta-analysis.

Existing research indicates that patients with heart failure (HF) may have restricted access to guideline-directed medical therapy (GDMT) when their blood pressure (BP) is comparatively low. However, recent clinical trials suggest that HF patients with low BP could still benefit from certain HF medications, which have a minimal impact on BP. This systematic review and meta-analysis was conducted to determine whether this applies to all GDMT. A systematic search of MEDLINE and EMBASE was conducted for studies published from inception to 10 January 2024. Randomized controlled trials were selected if they reported on the longitudinal change of systolic BP (SBP) due to GDMT, or the risks of cardiovascular events in HF patients based on SBP categories. Weighted mean difference (WMD), hazard ratio or relative risk, and corresponding 95% confidence intervals (CI) were pooled for meta-analysis where possible. Data from 20 studies, encompassing information on 84 782 individuals, were analysed. Overall, GDMT is associated with lower SBP (WMD, -2.16; 95% CI -2.86 to -1.46), with no significant difference between baseline low and non-low BP subgroups (interaction p = 0.810). However, SBP of the treatment group increased by 5.8 mmHg from baseline in the low SBP subgroup during follow-up, while it decreased by 4.0 mmHg in the baseline non-low SBP subgroup. GDMT demonstrated similar cardiovascular benefits and risk of hypotension between low and non-low SBP subgroups (interaction p = 0.318 and 0.903, respectively). Guideline-directed medical therapy is associated with a negligible decrease in SBP, but can provide similar cardiovascular benefits in both low and non-low SBP HF patients, with no significant interaction with SBP as to hypotension. Therefore, GDMT should be initiated and maintained in HF patients with low BP.

Improved Peak Oxygen Uptake Reduces Cardiac Events After 3 Weeks of Inpatient Cardiac Rehabilitation for Chronic Heart Failure Patients.

Background: The incidence of heart failure (HF) is increasing, and the mortality from HF remains high in an aging society. Cardiac rehabilitation (CR) programs (CRP) increase oxygen uptake (V̇O2) and reduce HF rehospitalization and mortality. Therefore, CR is recommended for every HF patient. However, the number of outpatients undergoing CR remains low, with insufficient attendance at CRP sessions. In this study we evaluated the outcomes of 3 weeks of inpatient CRP (3w In-CRP) for HF patients. Methods and Results: This study enrolled 93 HF patients after acute-phase hospitalization between 2019 and 2022. Patients participated in 30 sessions of 3w In-CRP (30 min aerobic exercise twice daily, 5 days/week). Before and after 3w In-CRP, patients underwent a cardiopulmonary exercise test, and cardiovascular (CV) events (mortality, HF rehospitalization, myocardial infarction, and cerebrovascular disease) after discharge were evaluated. After 3w In-CPR, mean (±SD) peak V̇O2 increased from 11.8±3.2 to 13.7±4.1 mL/min/kg (116.5±22.1%). During the follow-up period (357±292 days after discharge), 20 patients were rehospitalized for HF, 1 had a stroke, and 8 died for any reasons. Proportional hazard and Kaplan-Meier analyses demonstrated that CV events were reduced among patients with a 6.1% improvement in peak V̇O2 than in patients without any improvement in peak V̇O2. Conclusions: 3w In-CRP for HF patients improved peak V̇O2 and reduced CV events in HF patients with a 6.1% improvement in peak V̇O2.

Stay Home! Stay Safe! First Post-Discharge Cardiologic Evaluation of Low-Risk–Low-BNP Heart Failure Patients in COVID-19 Era

Background. The COVID-19 pandemic has had a deep impact on periodic outpatient evaluations. The aim of this study was to evaluate the impact of low brain natriuretic peptide (BNP) values in predicting adverse events in heart failure (HF) patients in order to evaluate implications for safe delay of outpatient visits. Methods. This was a retrospective study. One-thousand patients (mean age: 72 ± 10 years, 561 women) with HF and BNP values <250 pg/mL at discharge were included. A 6-month follow-up was performed. The primary endpoint was a combination of deaths and readmissions for HF within 6-month after discharge. Results. At 6-month follow-up, 104 events (10.4%) were recorded (65 HF readmissions and 39 all-cause deaths). Univariate Cox analysis identified as significant predictors of outcome were age (p < 0.001, hazard ratio [HR] = 1.044), creatinine (p = 0.001, HR = 1.411), and BNP (p < 0.001, HR = 1.010). Multivariate Cox regression confirmed that BNP (p < 0.001, HR = 1.009), creatinine (p = 0.016, HR = 1.247), and age (p = 0.013, HR = 1.027) were independent predictors of events in HF patients with BNP values <250 pg/mL at discharge. Patients with BNP values >100 pg/mL and creatinine >1.0 mg/dL showed increased events rates (from 4.3% to 19.0%) as compared to those with lower values (p < 0.000, HR = 4.014). Conclusions. Low pre-discharge BNP levels were associated with low rates of cardiovascular events in HF patients, independently of the frequency of follow-up.

November 2020 at a glance: focus on comorbidities and medical treatment.

The role of glycaemic control in patients with heart failure (HF) and concomitant diabetes is controversial. Insulin treatment is associated with poorer outcomes in these patients.1, 2 McAlister et al.3 investigated the relationship between glycaemic control, i.e. glycated haemoglobin (HbA1c), and cardiovascular (CV) outcomes in patients with type 2 diabetes mellitus and atherosclerosis from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Results showed a U-shaped association between baseline HbA1c and CV outcome, with the lowest risk when HbA1c was around 7%.3 Iron deficiency impairs cardiac contractility through decreased mitochondrial function.4 Hirsch et al.5 assessed iron concentrations in non-ischaemic HF with reduced ejection fraction (HFrEF), using endomyocardial biopsies. Lower iron concentrations were associated with a greater severity of HF. Hyperkalaemia is frequent in HFrEF patients, above all when on renin–angiotensin–aldosterone system inhibitors.6, 7 An administrative database analysis showed the association of hyperkalaemia with mortality and CV events in HF patients on renin–angiotensin–aldosterone system inhibitors.8 In the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, both hypokalaemia and hyperkalaemia were associated with a higher risk of CV death, compared with potassium levels between 4.1 and 4.9 mmol/L (hazard ratio 2.40 and 1.42, respectively). No interaction between serum potassium and sacubitril/valsartan efficacy vs. enalapril was found.9 Frailty is a major independent determinant of outcomes in HF.10 A new Frailty Score has recently been developed.11 The FRAGILE-HF study was a prospective multicentre study investigating the prevalence, overlap, and prognostic implications of physical and social frailties and cognitive dysfunction in patients hospitalized with HF. Patients with a greater number of frailty domains had higher mortality and HF rehospitalization.12 The prevalence of frailty is increased in HF with preserved ejection fraction (HFpEF) patients and is associated with worse outcome.13 Similarly, frailty was highly prevalent in HFrEF patients and was associated with poor quality of life and outcomes in a retrospective analysis of PARADIGM-HF and ATMOSPHERE.14 Biomarkers, namely natriuretic peptides, play a major role in the management of HF.15 Aimo et al.16 analysed the prognostic value and the influence of age on circulating levels of biomarkers in 5301 patients with chronic HF. N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT) and soluble suppression of tumorigenesis-2 (sST2) predicted outcomes. sST2 was less influenced by age than the other two biomarkers. In the Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trial, serum uric acid (SUA) was an independent predictor of poor outcome in HFpEF. Sacubitril/valsartan reduced SUA levels and the need for SUA-related drugs.17 Sex-based differences in biomarkers, health status, and reverse cardiac remodelling in HFrEF patients treated with sacubitril/valsartan in the Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodelling During Entresto Therapy for HF (PROVE-HF) were analysed by Ibrahim et al.18 Sex is a major determinant of clinical characteristics and outcomes in patients with HFrEF and HFpEF.19-21 In the study by Ibrahim et al.18, women treated with sacubitril/valsartan had more rapid reduction in NT-proBNP plasma levels and reverse cardiac remodelling and a larger improvement in quality of life. McEwan et al.22 showed the cost-effectiveness of dapagliflozin for the treatment of HFrEF with significant life-year and quality-adjusted life-year gains for the patients treated. The Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in HF (GALACTIC-HF) trial assessed the safety and efficacy of the cardiac myosin activator omecamtiv mecarbil in HFrEF patients. The baseline characteristics of enrolled patients are presented in this issue. The trial enrolled well-treated and high-risk inpatients and outpatients, representative of recent HF registries and trials.23

Efficacy of early initiation of ivabradine treatment in patients with acute heart failure: rationale and design of SHIFT-AHF trial.

AimsElevated heart rate (HR) in heart failure (HF) is associated with worse outcomes, particularly in acute HF (AHF). HR reduction with ivabradine reduces cardiovascular events in HF patients with reduced ejection fraction. The present trial aimed to test the hypothesis that the early HR reduction using ivabradine improves clinical outcomes in patients with AHF.Methods and resultsSHIFT‐AHF is a prospective, multi‐centre, double‐blind, randomized, placebo‐controlled trial to evaluate the efficacy and safety of ivabradine when adding to standard therapy in AHF patients (SHIFT‐AHF). The trial will include 674 AHF patients with left ventricular ejection fraction < 45% and New York Heart Association functional classes III–IV. Participants were enrolled from March 2020 and will be followed up until December 2022. Patients are randomized to treatment with ivabradine or placebo (randomization 1:1). After allocation, the dose of ivabradine is titrated according to HR. Six months' follow‐up and three control visits (7, 90, and 180 days after enrolment) are required for every participant. Assessment involves clinical examination, laboratory tests, echocardiography, electrocardiography, heart rhythm, cardiac function, and quality of life. The primary endpoint is a composite of all‐cause mortality or re‐admission due to worsening HF. Secondary endpoints include the assessments of cardiac remodelling, cardiac functional capacity, and quality of life.ConclusionsThe SHIFT‐AHF trial will shed further light on the role of early HR reduction using ivabradine in patients with AHF.

P3535Prognostic value of congestion status by bioelectrical impedance analysis and natriuretic peptide levels in acute heart failure with preserved versus reduced left ventricular ejection fraction

Abstract Background N-terminal pro-brain natriuretic peptide (NT-proBNP) is a well-known predictor of acute heart failure (HF). Congestion volume status estimated by bioelectrical impedance analysis (BIA) is also associated with adverse cardiovascular events in HF patients. However, it is unclear whether these biomarkers reflecting pathophysiological pathways are different between HF with preserved (HFpEF) and reduced ejection fraction (HFrEF). Purpose The aim of this study was to investigate whether the prognostic value of NT-proBNP and extracellular water/free fat mass (ECW%) assessed by BIA is different between HFrEF and HFpEF in acute HF patients. Methods and results One hundred-and-forty-three patients admitted for acute HF between November 2013 and January 2015 were estimated for NT-proBNP levels and ECW% by BIA on admission. A total of 49 HFrEF (LVEF&lt;40%) and 75 HFpEF (LVEF≥50%) patients were included in this study (mean age: 76±14 years, male: 63%). The median of NT-proBNP levels in HFrEF patients was higher than in HFpEF (6022 [IQR: 2531–9163] pg/mL and 3179 [1076–6054] pg/mL, respectively, p=0.012). Conversely, ECW% was similar between HFrEF and HFpEF (29.0 [25.7–33.7] % and 31.7 [27.3–38.8] %, respectively, p=0.088). The primary endpoint was the composite of all-cause mortality and/or hospitalisation due to HF. During a median follow-up of 5.9 months, 16 (35.6%) and 35 (50.7%) patients were observed to have composite events in HFrEF and HFpEF, respectively, (p=0.111). Elevated NT-proBNP levels in HFrEF patients were associated with an increased risk of composite events after adjustment for traditional risk factors (hazard ratio [HR]: 2.39; 95% Confidence interval [CI]; 1.04–5.47; p=0.040), but not in HFpEF (p=0.063). Meanwhile, a high ECW% in HFrEF patients was associated with increasing composite events risk (HR: 3.30; 95% CI; 1.32–8.25; p=0.011), as well as in HFpEF patients (HR: 1.62; 95% CI; 1.03–2.55; p=0.037). Furthermore, the ECW% in addition to NT-proBNP in HFpEF patients resulted in a significant improvement in prediction for composite events (net reclassification improvement 0.67 [95% CI 0.24–1.11]; p=0.002 and integrated discrimination improvement 0.12 [0.004–0.20]; p=0.004). Conclusion Elevated levels of NT-proBNP in acute HF were predictive for mortality and hospitalisation due to HF in HFrEF but may not be for HFpEF patients, and ECW% had a better predictive value than NT-proBNP in HFpEF patients.

Clinical utility of the 2016 ASE/EACVI recommendations for the evaluation of left ventricular diastolic function in the stratification of post-discharge prognosis in patients with acute heart failure.

Left ventricular diastolic dysfunction (LVDD) has prognostic significance in heart failure (HF). We aimed to assess the impact of LVDD grade stratified by the updated 2016 echocardiographic algorithm (DD2016) on post-discharge outcomes in patients admitted for acute HF and compare with the previous 2009 algorithm (DD2009). The study included 481 patients hospitalized for acute decompensated HF. Comprehensive echocardiography and LVDD evaluation were performed just before hospital discharge. The primary endpoint was a composite of cardiovascular death and readmission for HF. The concordance between DD2016 and DD2009 was moderate (κ = 0.44, P < 0.001); the reclassification rate was 39%. During the follow-up (median: 15 months), 127 (26%) patients experienced the primary endpoint. In the Kaplan-Meier analysis, Grade III in DD2016 showed a lower event-free survival rate than Grades I and II (log rank, P < 0.001 and P = 0.048, respectively) and was independently associated with a higher incidence of the primary endpoint than Grade I [hazard ratio 1.89; 95% confidence interval (CI) 1.17-3.04; P = 0.009]. Grade II or III in DD2016, reflecting elevation of left ventricular (LV) filling pressure, added an incremental predictive value of the primary endpoint to clinical variables irrespective of LV ejection fraction. DD2016 was comparable to DD2009 in predicting the endpoint (net reclassification improvement = 11%; 95% CI -7% to 30%, P = 0.23). Despite simplification of the algorithm for LVDD evaluation, the prognostic value of DD2016 for post-discharge cardiovascular events in HF patients was maintained and not compromised in comparison with DD2009.

Left atrial volume and cardiovascular outcomes in systolic heart failure: effect of antithrombotic treatment.

AimsLeft atrium (LA) dilation is associated with adverse cardiovascular (CV) outcomes. Blood stasis, thrombus formation and atrial fibrillation may occur, especially in heart failure (HF) patients. It is not known whether preventive antithrombotic treatment may decrease the incidence of CV events in HF patients with LA enlargement.We investigated the relationship between LA enlargement and CV outcomes in HF patients and the effect of different antithrombotic treatments.Methods and resultsTwo‐dimensional echocardiography with LA volume index (LAVi) measurement was performed in 1148 patients with systolic HF from the Warfarin versus Aspirin in Reduced Ejection Fraction (WARCEF) trial. Patients were randomized to warfarin or aspirin and followed for 3.4 ± 1.7 years. While the primary aim of the trial was a composite of ischaemic stroke, death, and intracerebral haemorrhage, the present report focuses on the individual CV events, whose incidence was compared across different LAVi and treatment subgroups.After adjustment for demographics and clinical covariates, moderate or severe LA enlargement was significantly associated with total death (hazard ratio 1.6 and 2.7, respectively), CV death (HR 1.7 and 3.3), and HF hospitalization (HR 2.3 and 2.6) but not myocardial infarction (HR 1.0 and 1.4) or ischaemic stroke (1.1 and 1.5). The increased risk was observed in both patients treated with warfarin or aspirin. In warfarin‐treated patients, a time in therapeutic range >60% was associated with lower event rates, and an interaction between LAVi and time in therapeutic range was observed for death (P = 0.034).ConclusionsIn patients with systolic HF, moderate or severe LA enlargement is associated with death and HF hospitalization despite treatment with antithrombotic medications. The possibility that achieving a more consistent therapeutic level of anticoagulation may decrease the risk of death requires further investigation.

The impact of creating mathematical formula to predict cardiovascular events in patients with heart failure

Since our retrospective study has formed a mathematical formula, α = f(x1, …, x252), where α is the probability of cardiovascular events in patients with heart failure (HF) and x1 is each clinical parameter, we prospectively tested the predictive capability and feasibility of the mathematical formula of cardiovascular events in HF patients. First of all, to create such a mathematical formula using limited number of the parameters to predict the cardiovascular events in HF patients, we retrospectively determined f(x) that formulates the relationship between the most influential 50 clinical parameters (x) among 252 parameters using 167 patients hospitalized due to acute HF; the nonlinear optimization could provide the formula of α = f(x1, …, x50) which fitted the probability of the actual cardiovascular events per day. Secondly, we prospectively examined the predictability of f(x) in other 213 patients using 50 clinical parameters in 3 hospitals, and we found that the Kaplan–Meier curves using actual and estimated occurrence probabilities of cardiovascular events were closely correlated. We conclude that we created a mathematical formula f(x) that precisely predicted the occurrence probability of future cardiovascular outcomes of HF patients per day. Mathematical modelling may predict the occurrence probability of cardiovascular events in HF patients.