Multi-Biomarker Points and Outcomes in Patients Hospitalized for Heart Failure: Insights From the China PEACE Prospective Heart Failure Study

Objective To quantitatively characterize the pattern of systemic impairment reflected by conventional biomarkers and assess how it relates to clinical outcomes and quality of life among patients hospitalized for heart failure (HF). Methods Patients hospitalized for HF from 52 hospitals in China were enrolled between 2016 and 2018. They were divided into developing and validating cohorts; the developing cohort was used for calculating the weights of biomarkers and constructing the multi-biomarker panel, while the validating one was used for evaluating the relationship between multi-biomarker points and outcomes. In total, five conventional biomarkers reflecting various pathophysiological processes were included in the panel: N-terminal pro-B type natriuretic peptide, high-sensitivity troponin T, hemoglobin, albumin, and creatinine. The weights of the biomarkers were defined based on their relationship with cardiovascular death, and each patient had a multi-biomarker point ranging from 0 to 12. The primary clinical outcome was cardiovascular death, and the other clinical outcomes included rehospitalization for HF, all-cause death, and all-cause rehospitalization in 1-year. The quality of life was measured using Kansas City Cardiovascular Questionnaire. Multi-variable Cox proportional hazard models were used to assess the risks of clinical outcomes, and generalized linear models were used to evaluate the quality of life. Results In total, 4,693 patients hospitalized for HF were included in this analysis; the median (interquartile range, IQR) age was 67 (57–75) years old and 1,763 (37.6%) were female. The median multi-biomarker point was 5 (IQR, 2–6). There were 18.0% of patients in the low point group (<2), 29.4% in the mid-low point group (2–4), 27.8% in the mid-high point group (5–6), and 24.7% in the high point group (>6). Compared with those in the low point group, the patients in the high point group had a significantly excess risk of cardiovascular death (adjusted hazard ratio: 5.69, 95% CI, 3.33–9.70). Furthermore, patients with higher points were also more prone to worse quality of life. Conclusion Systemic impairment reflected by abnormal conventional biomarker values was common amongst patients hospitalized for HF and had substantially cumulative adverse influence on clinical outcomes and quality of life.


TABLE OF CONTENTS
Figure S1 Study patient population development flow chart.
Table S1 Number of patients in each local collaborate center.
Data S1 Methods of biomarker assays. Table S2 Number and missing rates of biomarker assays included in multi-biomarker panel.
Data S2 Adjudication criteria for cause of death.                    Data S1. Methods of biomarker assays.

N-terminal pro-B type natriuretic peptide (NT-proBNP)
NT-proBNP was measured using the Roche E601. The limit of detection was 5 ng/L. The intra-assay coefficient of variation was ≤ 3.25%, and the inter-assay coefficient of variation was ≤ 8%.
High sensitivity Troponin T (hs-cTNT) Hs-cTNT was measured using the Roche E601. The limit of detection was 3 ng/L. The intra-assay coefficient of variation was ≤ 8.15%, and the inter-assay coefficient of variation was ≤ 9.78%.

Creatinine
Creatinine was measured using the Beckman Coulter AU680. The limit of detection was 3.15 μmol/L. The intra-assay coefficient of variation was ≤ 3.75%, and the inter-assay coefficient of variation was ≤ 5%.
Alanine aminotransferase (ALT) ALT was measured using the Beckman Coulter AU680. The limit of detection was 1 U/L. The intra-assay coefficient of variation was ≤ 5%, and the inter-assay coefficient of variation was ≤ 6.67%.
High sensitivity CRP (hsCRP) 9 HsCRP was measured using the Beckman Coulter AU680. The limit of detection was 0.02 mg/L. The intra-assay coefficient of variation was ≤ 6.21%, and the inter-assay coefficient of variation was ≤ 8.28%.

Total cholesterol (TC)
TC was measured using the Beckman Coulter AU680. The limit of detection was 0.07 mmol/L. The intra-assay coefficient of variation was ≤ 2.50%, and the inter-assay coefficient of variation was ≤ 3.33%.

Low-density lipoprotein cholesterol (LDL-C)
LDL-C was measured using the Beckman Coulter AU680. The limit of detection was 0.012 mmol/L. The intra-assay coefficient of variation was ≤ 3.97%, and the inter-assay coefficient of variation was ≤ 3.97%.

Triglycerides
Triglycerides was measured using the Beckman Coulter AU680. The limit of detection was 0.01 mmol/L. The intra-assay coefficient of variation was ≤ 6.25%, and the inter-assay coefficient of variation was ≤ 8.33%.

10
High-density lipoprotein cholesterol (HDL-C) HDL-C was measured using the Beckman Coulter AU680. The limit of detection was 0.002 mmol/L. The intra-assay coefficient of variation was ≤ 7.50%, and the inter-assay coefficient of variation was ≤ 10%.

Cardiovascular death
Cardiovascular death includes death resulting from an acute myocardial infarction (MI), sudden cardiac death, death due to heart failure (HF) worsen, death due to stroke, and death due to other cardiovascular causes.

1) Acute Myocardial Infarction
The term MI should only be used when there is evidence of myocardial necrosis consistent with myocardial ischemia in an appropriate clinical context.
In general, the diagnosis of MI requires the following to be true:

2) Sudden Cardiac Death
Sudden death refers to meet the following circumstances: • Witnessed death (i.e. participant seen at the time of death or within the preceding few days); and • No evidence of an alternative cardiovascular or non-vascular cause of death (including no evidence to suggest Type 3 myocardial infarction)

3) Worsening Heart Failure
Heart failure is defined as the patient exhibits worsening symptoms of heart failure on presentation, has objective evidence of worsening of heart failure, and receives initiation or intensification of treatment specifically for heart failure.

4) Stroke
Stroke is defined as an acute symptomatic episode of focal or global neurological dysfunction caused by brain, spinal, or retinal vascular injury as a result of hemorrhage or infarction.

5) Other cardiovascular death
Death due to other cardiovascular disease includes deaths that are likely to be due to specific cardiovascular disorders (e.g. valvular heart disease, non-ischemic cardiomyopathy, primary arrhythmia, pulmonary embolism, primary pulmonary hypertension, ruptured aortic 14 aneurysm, acute limb ischemia), and deaths due to surgical and non-surgical investigations and procedures for other cardiovascular disease.

Non-cardiovascular death
Non-cardiovascular death was considered if an unequivocal and documented noncardiovascular cause could be established as the primary cause of death (e.g., malignancy, infection, respiratory disease, liver disease,).

Presumed cardiovascular death / unknown death
Presumed cardiovascular death / unknown death was considered if there is no evidence of an alternative cardiovascular or non-vascular cause of death (including sudden cardiac death). Abbreviation: HR: hazard ratio; CI: confidential interval; NT-proBNP: N-terminal pro-B type natriuretic peptide; Hs-cTNT: high-sensitivity troponin T; Anemia: Hemoglobin < 120 g/L in men or hemoglobin < 110 g/L in women; DM: diabetes mellitus, glycosylated hemoglobin A 1c ≥ 6.5%; HsCRP: high-sensitivity C-reactive protein; SBP: systolic blood pressure; HR: heart rate; NYHA: New York Heart Association; HFrEF: heart failure with reduced ejection fraction; HFmrEF: heart failure with mildly reduced ejection fraction; HFpEF: heart failure with preserved ejection fraction; ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blockers; CCB: calcium channel blocker.
Note: Biomarker with lowest (anemia) hazard ratio (HR) value was defined as "2" weight, and the weights of other biomarkers were calculated by their HRs (keep round number). Each patient had a multi-biomarker point score ranges from 0 to 12 points. 20 Table S6. Multi-biomarker points (calculated using hazard ratios) and subgroups.  heart failure with reduced ejection fraction; HFmrEF: heart failure with mildly reduced ejection fraction; HFpEF: heart failure with preserved ejection fraction; PCI: percutaneous heart failure with reduced ejection fraction; HFmrEF: heart failure with mildly reduced ejection fraction; HFpEF: heart failure with preserved ejection fraction; PCI: percutaneous 30 coronary intervention; ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blockers; CCB: calcium channel blocker. Abbreviation: HF: heart failure; IQR: interquartile range; HFrEF: heart failure with reduced ejection fraction; HFmrEF: heart failure with mildly reduced ejection fraction; HFpEF: heart failure with preserved ejection fraction; NT-proBNP: N-terminal pro-B type natriuretic peptide; Hs-cTNT: high-sensitivity troponin T; Anemia: hemoglobin < 120 g/L in men or hemoglobin < 110 g/L in women.