Aims
The aim of this study was to evaluate whether biomarkers reflecting pathophysiological pathways are different between heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) ...and whether the prognostic value of biomarkers is different in HFpEF vs. HFrEF.
Methods and results
A total of 458 HFrEF (LVEF ≤40%) and 112 HFpEF (LVEF ≥50%) patients aged ≥60 years with NYHA class ≥II from TIME‐CHF were included. Endpoints are 18‐month overall and HF hospitalization‐free survival. After correction for baseline characteristics that differed between the HF types, i.e. age, gender, body mass index, systolic blood pressure, cause of HF, and AF, HFpEF patients exhibited higher soluble interleukin 1 receptor‐like 1 ST2; 37.6 (28.5–54.7) vs. 35.7 (25.6–52.2), P = 0.02, high sensitivity C‐reactive protein (hsCRP; 8.54 (3.39–25.86) vs. 6.66 (2.42–15.39), P = 0.01), and cystatin‐C 1.94 (1.57–2.37) vs. 1.75 (1.39–2.12), P = 0.01. In contrast, HFrEF patients exhibited higher NT‐proBNP 2142 (1473–4294) vs. 4202 (2239–7411), P < 0.001, high sensitivity troponin T hsTnT; 27.7 (16.8–48.0) vs. 32.4 (19.2–59.0), P = 0.03, and haemoglobin 124 (110–135) vs. 134 (122–145), P < 0.001. In addition to these clinical characteristics, NT‐proBNP, haemoglobin, cystatin‐C, hsTnT, and ST2 improved the area under the curve from 0.86 (0.82–0.89) to 0.91 (0.87–0.94; P < 0.001) for discriminating HFpEF from HFrEF. There were no significant interactions between HFpEF and HFrEF when considering the prognostic value of the investigated biomarkers (P > 0.10 for both endpoints), except for cystatin‐C which had less prognostic impact in HFpEF (P < 0.01).
Conclusion
Biomarker levels suggest a different amount of activation of several pathophysiological pathways between HFpEF and HFrEF. No important differences in the prognostic value of biomarkers in HFpEF vs. HFrEF were found except for cystatin‐C, and for NT‐proBNP in the NT‐proBNP‐guided study arm only, both of which had less prognostic value in HFpEF.
Trial registration
ISRCTN43596477
Aims
Diagnosing heart failure with preserved ejection fraction (HFpEF) is challenging. The newly proposed HFA‐PEFF algorithm entails a stepwise approach. Step 1, typically performed in the ambulatory ...setting, establishes a pre‐test likelihood. The second step calculates a score based on echocardiography and natriuretic peptides. The aim of this study is to validate the diagnostic value and establish the clinical impact of the second step of the HFA‐PEFF score.
Methods and results
The second step of the HFA‐PEFF score was evaluated in two independent, prospective cohorts, i.e. the Maastricht cohort (228 HFpEF patients and 42 controls) and the Northwestern Chicago cohort (459 HFpEF patients). In Maastricht, the HFA‐PEFF score categorizes 11 (4%) of the total cohort with suspected HFpEF in the low‐likelihood (0–1 points) and 161 (60%) in the high‐likelihood category (5–6 points). A high HFA‐PEFF score can rule in HFpEF with high specificity (93%) and positive predictive value (98%). A low score can rule out HFpEF with a sensitivity of 99% and a negative predictive value of 73%. The diagnostic accuracy of the score is 0.90 (0.84–0.96), by the area under the curve of the receiver operating characteristic curve. However, 98 (36%) are classified in the intermediate‐likelihood category, where additional testing is advised. The distribution of the score shows a similar pattern in the Northwestern (Chicago) and Maastricht HFpEF patients (53% vs. 65% high, 43% vs. 34% intermediate, 4.8% vs. 1.3% low).
Conclusion
This study validates and characterizes the HFA‐PEFF score in two independent, well phenotyped cohorts. We demonstrate that the HFA‐PEFF score is helpful in clinical practice for the diagnosis of HFpEF.
The Simpson’s method is the standard technique to determine left ventricular (LV) ejection fraction (EF) on echocardiography. The large inter-observer variability of measuring LVEF is well documented ...but not fully understood. A graphical analysis was used to elaborate what contributes to the inter-observer difference. Forty-two cardiologists (32 male, 39 ± 7 years) evaluated the LVEF using the Simpson’s method on 15 different echocardiograms (2 and 4 chamber view (2CH/4CH)); the program did not show the result of EF to prevent a bias. End-diastolic (ED) and end-systolic (ES) frames were predefined ensuring measurement at the same time point of the cardiac cycles. After standardization of the LV contour, the differences of the individual contours compared to a reference contour were measured. Also, the spreading of lateral/medial mitral annulus contours and the apex were depicted. A significant spreading of LV-contours was seen with larger contours leading to higher EFs (p < 0.001). Experience did not influence the determination of LVEF. ED-volumes showed more spreading than ES-volumes ((3.6 mm (IQR: 2.6–4.0) vs. 3.4 mm (IQR: 2.8–3.8), p < 0.001). Also, the differences were larger for the 2CH compared to the 4CH (p < 0.001). Variability was significantly larger for lateral than septal wall (p < 0.001) as well as the anterior compared to the inferior wall (p < 0.001). There was a relevant scattering of the apex and medial/ lateral mitral annulus ring. There was a large variability of LV-volumes and LVEF as well as position of mitral valve ring and apex. There were global differences (apical 2CH or 4CH), regional aspects (LV walls) and temporal factors (ED vs. ES). Thus, multiple factors contributed to the large variability.
Trial registration
: The study was registered at “Netherlands Trial Register” (
www.trialregister.nl
; study number: NL5131).
The relationship between longitudinal clinical congestion pattern and heart failure outcome is uncertain. This study was designed to assess the prevalence of congestion over time and to investigate ...its impact on outcome in chronic heart failure.
A total of 588 patients with chronic heart failure older than 60 years of age with New York Heart Association (NYHA) functional class ≥II from the TIME-CHF study were included. The endpoints for this study were survival and hospitalization-free heart failure survival. Orthopnea, NYHA ≥III, paroxysmal nocturnal dyspnea, hepatomegaly, peripheral pitting edema, jugular venous distension, and rales were repeatedly investigated and related to outcomes. These congestion-related signs and symptoms were used to design a 7-item Clinical Congestion Index.
Sixty-one percent of patients had a Clinical Congestion Index ≥3 at baseline, which decreased to 18% at month 18. During the median interquartile range follow-up of 27.2 14.3-39.8 months, 17%, 27%, and 47% of patients with baseline Clinical Congestion Index of 0, 1-2, and ≥3 at inclusion, respectively, died (P <.001). Clinical Congestion Index was identified as an independent predictor of mortality at all visits (P <.05) except month 6 and reduced hospitalization-free heart failure survival (P <.05). Successful decongestion was related to better outcome as compared to persistent congestion or partial decongestion (log-rank P <0.001).
The extent of congestion as assessed by means of clinical signs and symptoms decreased over time with intensified treatment, but it remained present or relapsed in a substantial number of patients with heart failure and was associated with poor outcome. This highlights the importance of appropriate decongestion in chronic heart failure.
Aim
Diagnosing heart failure with preserved ejection fraction (HFpEF) in the non‐acute setting remains challenging. Natriuretic peptides have limited value for this purpose, and a multitude of ...studies investigating novel diagnostic circulating biomarkers have not resulted in their implementation. This review aims to provide an overview of studies investigating novel circulating biomarkers for the diagnosis of HFpEF and determine their risk of bias (ROB).
Methods and results
A systematic literature search for studies investigating novel diagnostic HFpEF circulating biomarkers in humans was performed up until 21 April 2020. Those without diagnostic performance measures reported, or performed in an acute heart failure population were excluded, leading to a total of 28 studies. For each study, four reviewers determined the ROB within the QUADAS‐2 domains: patient selection, index test, reference standard, and flow and timing. At least one domain with a high ROB was present in all studies. Use of case‐control/two‐gated designs, exclusion of difficult‐to‐diagnose patients, absence of a pre‐specified cut‐off value for the index test without the performance of external validation, the use of inappropriate reference standards and unclear timing of the index test and/or reference standard were the main bias determinants. Due to the high ROB and different patient populations, no meta‐analysis was performed.
Conclusion
The majority of current diagnostic HFpEF biomarker studies have a high ROB, reducing the reproducibility and the potential for clinical care. Methodological well‐designed studies with a uniform reference diagnosis are urgently needed to determine the incremental value of circulating biomarkers for the diagnosis of HFpEF.
Published studies have generated mixed, controversial results regarding the cost-effectiveness of heart failure disease management programs (HF-DMPs). This study assessed the cost-effectiveness of an ...HF-DMP in ambulatory patients compared with usual care (UC).
In the prospective randomized REMADHE trial, we evaluated incremental costs per quality-adjusted life-year (QALY) and life-year (LY) gained as effectiveness ratios (ICERs) over a study period of 2.47 ± 1.75 years.
The REMADHE HF-DMP was more effective and less costly than UC in terms of both QALYs and LYs (95% and 55% chance of dominance, respectively). Average saving was US$7345 (2.5%–97.5% bootstrapped confidence interval −16,573 to +921). The chance of DMP being cost-effective at a willingness to pay US$10,000 per QALY or LY was 99% and 96%, respectively. Cost-effectiveness of HF-DMP was highest in subgroups with left ventricular ejection fraction <35%, age >50 years, male sex, New York Heart Association (NYHA) functional class ≥III, and ischemic etiology. The chance of DMP being cost-effective at a willingness to pay US$10,000 per QALY was ≥90% in all subgroups apart from NYHA functional class I–II, where it was 70%. Even when the intervention costs increased by 500% or when excluding outliers in costs, DMP had a high chance of being cost-effective (87%–99%).
The HF-DMP of the REMADHE trial, which encompasses long-term repeated education alongside telephone monitoring, has a high probability of being cost-effective in ambulatory patients with HF.
Aim
Fibroblast growth factor 23 (FGF23) is an intensively studied biomarker at the crossroads of cardiovascular disease, heart failure (HF) and chronic kidney disease. Independent associations ...between increasing FGF23 levels and cardiovascular events were found in many, but not all studies. By analysing data from the TIME‐CHF cohort, we sought to investigate the prognostic value of FGF23 in an elderly, multimorbid HF patient cohort. We determined differences between intact (iFGF23) and C‐terminal FGF23 (cFGF23) regarding their prognostic value and their levels over time in different HF subgroups according to left ventricular ejection fraction (LVEF).
Methods and results
In this multicentre trial of 622 patients with symptomatic HF aged ≥60 years, we determined iFGF23 and cFGF23 at baseline, 3, 6 and 12‐month follow‐up. In unadjusted analyses, cFGF23 significantly predicted all HF‐related outcomes at all time points. The predictive value of iFGF23 was less and not statistically significant at baseline. After multivariable adjustments, the association between both cFGF23 and iFGF23 and outcome lost statistical significance apart from cFGF23 at month 3. Overall, patients with preserved and mid‐range LVEF had higher levels of iFGF23 and cFGF23 than those with reduced LVEF. Levels decreased significantly during the first 3 months in mid‐range and reduced LVEF patients, but did not significantly change over time in those with preserved LVEF.
Conclusions
Fibroblast growth factor 23 is of limited value regarding risk prediction in this elderly HF population. Potentially heterogeneous roles of FGF23 in different LVEF groups deserve further investigation.
Galectin-3 predicts prognosis in heart failure (HF) and may help to select HF patients in need of intensified therapy.
This retrospective post hoc analysis included 219 patients from the Trial of ...Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME-HF) and 631 patients from Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca (GISSI-HF) with HF who had reduced ejection fraction and available galectin-3 plasma concentrations. The interaction between galectin-3, β-blockers, renin-angiotensin system (RAS) blockade, and spironolactone on outcome was evaluated in TIME-CHF and validated in GISSI-HF. End points were all-cause mortality and the composite of mortality with HF hospitalization or any hospitalization.
High galectin-3 concentrations were associated with adverse outcome in both cohorts and remained significantly associated with death after multivariate adjustment hazard ratio 2.42 (95% CI 1.17-5.01), P = 0.02, in TIME-CHF; 1.47 (1.02-2.10), P = 0.04, in GISSI-HF). In TIME-CHF, patients with low galectin-3 plasma concentrations had a better prognosis when β-blockers were up-titrated, whereas patients with high galectin-3 plasma concentrations did not (interaction P < 0.05 for mortality and death with or without hospitalization). Opposite trends were seen for RAS blockade but were not statistically significant. Patients with high galectin-3 plasma concentrations had neutral prognosis when receiving spironolactone, whereas patients with low galectin-3 plasma concentrations had worse prognosis when receiving spironolactone (interaction P < 0.10 for death with or without hospitalization). In the GISSI-HF validation cohort, these interactions were confirmed for β-blockers (P < 0.05 for all end points) and consistent for RAS blockade (P < 0.10 for death with or without hospitalization), but inconsistent for spironolactone.
Galectin-3 is a mediocre prognostic marker, and galectin-3 concentrations interact with the treatment effect of β-blockers and possibly RAS blockade in patients with systolic HF.
Aims
Diagnosis of heart failure with preserved ejection fraction (HFpEF) can be challenging. This study aimed to evaluate the potential of a webtool to enhance the scoring accuracy when applying the ...complex HFA‐PEFF and H2FPEF algorithms, which are commonly used for diagnosing HFpEF.
Methods and results
We developed an online tool, the HFpEF calculator, that enables the automatic calculation of current HFpEF algorithms. We assessed the accuracy of manual vs. automatic scoring, defined as the percentage of correct scores, in a cohort of cardiologists with varying clinical experience. Cardiologists scored eight online clinical cases using a triple cross‐over design (i.e. two manual–two automatic–two manual–two automatic). Data were analysed in study completers (n = 55, 29% heart failure specialists, 42% general cardiologists, and 29% cardiology residents). Manually calculated scores were correct in 50% (HFA‐PEFF: 50% 50–75; H2FPEF: 50% 38–50). Correct scoring improved to 100% using the HFpEF calculator (HFA‐PEFF: 100% 88–100, P < 0.001; H2FPEF: 100% 75–100, P < 0.001). Time spent on clinical cases was similar between scoring methods (±4 min). When corrections for faulty algorithm scores were displayed, cardiologists changed their diagnostic decision in up to 67% of cases. At least 67% of cardiologists preferred using the online tool for future cases in clinical practice.
Conclusions
Manual calculation of HFpEF diagnostic algorithms is often inaccurate. Using an automated webtool to calculate HFpEF algorithms significantly improved correct scoring. This new approach may impact the eventual diagnostic decision in up to two‐thirds of cases, supporting its routine use in clinical practice.
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