- Academic Editors
†These authors contributed equally.
Background: Patients with non-ST-elevation acute coronary syndrome
(NSTE-ACS) consists of a heterogenic population and improvement in identification
of a specific risk profile is needed. In this study we aimed to obtain better
insight in the role of different biomarkers for patients undergoing a routine
invasive diagnostic strategy within 24 hours after admission. Methods:
An Immediate or Early Invasive Strategy in Non-ST-Elevation Acute Coronary Syndrome
(OPTIMA-2) study was a randomized controlled prospective open-label multicentre
trial, randomizing NSTE-ACS patients. An invasive strategy was either immediate
(
Non-ST-elevation acute coronary syndrome (NSTE-ACS) consists of a heterogenic group of patients and can be considered a high-risk condition if not treated in a swift and appropriate way. In the risk assessment of patients with NSTE-ACS cardiac biomarkers form an integral part. The extent of ischemia, in-hospital risk for recurrent events as well as risk for future events could be further specified with the aid of cardiac biomarkers. Several studies have been performed targeting the optimal biomarker’s risk assessment in NSTE-ACS patients [1, 2, 3]. In particular, high-sensitive TroponinT (hsTropT) and creatine kinase myocardial-band (CK-MB) are well known and recommended by major guidelines [4, 5]. Biomarkers such as high-sensitivity C-reactive protein (hsCRP) and N-terminal proB-type natriuretic peptide (NTpro-BNP) are relatively easy to obtain at low-cost, but less used in clinical practice [6, 7, 8, 9, 10]. NT-proBNP is well known in the clinical evaluation of congestive heart failure (CHF). It is secreted by cardiomyocytes in a situation of increased wall stress. Higher serum levels of NT-proBNP are demonstrated in myocardial ischemia due to up-regulation of B-type natriuretic peptide (BNP) gene expression and correlate with the extent of coronary artery disease [11, 12]. In addition, hsCRP is a well-established marker for inflammation in coronary artery disease [13]. In unstable coronary artery disease, it is related to a long-term cardiovascular (CV) mortality risk [14].
The “An Immediate or Early Invasive Strategy in Non-ST-Elevation Acute Coronary
Syndrome” (OPTIMA-2) trial has been published previously [15]. This study was
primarily designed to observe the influence of timing of an immediate invasive
strategy in NSTE-ACS patients in relation to infarct size and risk for adverse
cardiovascular events. Patients were randomized either to a direct invasive
strategy (
The OPTIMA-2 trial was a prospective, open-label, randomized controlled trial
(Netherlands Trial Register identifier: NTR3861) performed at the OLVG hospital
in Amsterdam, the Netherlands [15]. Subject with at least one high-risk criterium
for NSTE-ACS who experienced chest pain in the 24 hours before admission were
selected for study participation. We defined high-risk criteria were defined as:
horizontal or downsloping ST depression more than 1mm in two contiguous leads,
dynamic ST- or T-wave changes
After admittance to the hospital hs-cTnT levels were measured every 6 hours for the first 48-hours. Peak hs-cTnT was determined as the highest value measured within this first 48-hours after admission [15]. Per protocol, the NTpro-BNP and hsCRP levels were determined at admission. The immunoassays for hsTroponin, NTpro-BNP and hsCRP were performed using the Roche Cobas 8000 system. The used assays during the complete study enrolment period were: Elecsys Troponin-T hs Roche, Elecsys proBNP hs Roche and Tina-quant C-reactive protein Roche (Roche Diagnostics Ltd., Rotkreuz, Switserland). The cutoff value based of the upper 99th percentile was 152 ng/L for NT-proBNP, 10 mg/L for hsCRP and 14 ng/L for hs-cTnT. Fresh serum samples were collected and analyzed in the hospital’s laboratory within one our of collection.
In case of significant abnormalities at initial CAG it was by operator’s decision whether to perform direct percutaneous coronary intervention (PCI) or to first discuss the patient in the hospital’s heart team and than decide the appropriate form of treatment: conservative, PCI or coronary artery bypass graft (CABG) surgery. Echocardiography was performed within 72-hours after hospitalization and at 30-day follow-up. Left ventricular function (LVF) was defined as left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS), both expressed in percentage. LVF was determined for all patients by an experienced investigator, who was blinded for treatment allocation [16].
The primary endpoint of our current sub-analysis was clinical event rate at 1-year follow-up in relation to peak hs-cTnT, NT-proBNP and hsCRP at admission. Clinical events were defined as major adverse cardiac events (MACE): composite of all-cause death, myocardial infarction (MI) and unplanned revascularization; net adverse clinical events (NACE): composite of MACE and major bleeding (all bleeding according to the Bleeding Academic Research Consortium (BARC) scale types 3 through 5). Biomarkers were each sub-divided in tertiles before analysis. Secondary endpoints were the comparison of median/mean biomarker levels of patients experiencing a clinical event within the first year and the relation of biomarkers in comparison to recovery of left ventricular function, determined by the LVEF and GLS.
Follow-up was in person at 30 days after discharge. At that point a follow-up echocardiogram was made. After 1-year follow-up by telephone was done. In case we were not able to reach a patient we contacted local authorities to find out whether this patient was still alive.
Statistical analysis was done with SPSS (version 26.0 for Windows, SPSS, Inc., Chicago, IL, USA). The number of clinical events within the first year were compared for each tertile group for NT-proBNP, hsCRP and peak hs-cTnT. A comparison was made by using the chi-square test for categorical variables. In addition, an univariate survival analyses was performed for tertiles of NT-proBNP and hsCRP at admission in relation to MACE and NACE rate within the first year.
For the secondary analysis biomarker levels of patients experiencing a clinical
event within the first year of follow-up were compared to biomarker levels of
patients that were event-free in the first year. Baseline and biomarker findings
were analyzed making use of a Student t test or Wilcoxon rank-sum test. After
log-rank transformation, the mean NT-proBNP at admission and at discharge yielded
normally distributed data and a Student t test was chosen as the most
appropriate way of analysis. To assess the correlation for those specific
biomarkers with (change in) LVF, we analyzed the data using univariate linear
regression analysis. Beta coefficients were calculated with 95% CI. In case of
statistically significant beta coefficients, relevant biomarkers were included in
the multivariate regression model. Tests were 2-tailed and a value of p
Patients were included in the period of March 2013 and November 2018. We included a total of 249 patients in the OPTIMA-2 study [15]. Table 1 shows the baseline characteristics of the complete study population.
Subjects (n = 249) | ||
Age, yrs | 65.6 | |
Gender, male | 181 (72.7) | |
Body mass index, kg/m |
28.1 | |
Duration of chest pain before admission, hours (IQR)* | 3.0 (1.3–9.0) | |
ST depression |
60 (24) | |
hsTropT |
185 (74) | |
Inclusion by clinical characteristics only | 46 (18.5) | |
Nt-proBNP, ng/L admission | 606 (1668) | |
Nt-proBNP, ng/L discharge | 820 (1774) | |
hsCRP, mg/L admission | 6.2 (13.5) | |
hsCRP, mg/L discharge | 17.1 (31.5) | |
GRACE-risk score† | 115.0 | |
Cardiac History | ||
Previous MI | 56 (22.5) | |
Previous CABG | 19 (7.6) | |
Previous PCI | 58 (23.3) | |
Known congestive heart failure | 2 (0.8) | |
Risk Factors | ||
Hypertension | 120 (48.2) | |
Current smoking | 92 (36.9) | |
Diabetes | 49 (19.7) | |
Hypercholesterolemia | 79 (31.7) | |
Positive family history | 68 (27.3) | |
Peripheral artery disease | 12 (4.8) | |
Age over 60 years | 140 (56.2) | |
Values are mean IQR, interquartile range; ULN, upper limit normal; Ntpro-BNP, N-terminal proB-type natriuretic peptide; hsCRP, high-sensitivity C-reactive protein; GRACE, global registry of acute coronary events; MI, myocardial infarction; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; SD, standard deviation; hsTropT, high-sensitive TroponinT. |
In total 72.7% of the patients were male. The mean age at the time of
hospitalisation was 65.6 years (standard deviation (SD)
Biomarkers were divided into tertiles and compared for several clinical events
at 1-year follow-up. The hs-cTnT levels were divided in the following tertiles:
Peak hsTroponinT | NT-proBNP | hsCRP | ||||||||||
T1 (n = 83) | T2 (n = 81) | T3 (n = 83) | p-value | T1 (n = 69) | T2 (n = 66) | T3 (n = 69) | p-value | T1 (n = 76) | T2 (n = 85) | T3 (n = 83) | p-value | |
Death (%) | 2 (2) | 3 (4) | 2 (2) | 0.82 | 0 (0) | 2 (3) | 3 (4) | 0.21 | 1 (1) | 3 (4) | 3 (4) | 0.80 |
Recurrent MI (%) | 1 (1) | 6 (7) | 4 (5) | 0.14 | 4 (6) | 3 (5) | 2 (3) | 0.77 | 3 (4) | 3 (4) | 5 (6) | 0.86 |
Recurrent Revascularization (%) | 4 (5) | 2 (2) | 4 (5) | 0.71 | 4 (6) | 4 (7) | 1 (1) | 0.39 | 4 (5) | 2 (2) | 4 (5) | 0.78 |
MACE (%) | 5 (6) | 11 (14) | 9 (11) | 0.24 | 8 (12) | 8 (12) | 6 (9) | 0.89 | 8 (11) | 6 (7) | 11 (13) | 0.60 |
NACE (%) | 8 (10) | 13 (16) | 10 (12) | 0.40 | 10 (14) | 9 (14) | 7 (10) | 0.84 | 11 (14) | 7 (8) | 13 (16) | 0.47 |
Values are number of patients (%). p-values were calculated from the chi-square test. NTpro-BNP, N-terminal proB-type natriuretic peptide; hsCRP, high-sensitivity C-reactive protein; T1, Tertile 1; T2, Tertile 2; T3, Tertile 3; MI, myocardial infarction; MACE, major adverse cardiac events; NACE, net adverse clinical events; hsTropT, high-sensitive TroponinT. |
Biomarker | MACE | Cox proportional-hazards regression | NACE | Cox proportional-hazards regression | |
---|---|---|---|---|---|
No (%) | HR (95% CI) | No (%) | HR (95% CI) | ||
hsTroponinT | |||||
T1 | 5 (6) | 1 (Ref) | 8 (10) | 1 (Ref) | |
T2 | 11 (14) | 2.56 (0.85–7.72) | 13 (16) | 1.87 (0.73–4.79) | |
T3 | 9 (11) | 1.90 (0.61–5.92) | 10 (12) | 1.28 (0.48–3.43) | |
NT-pro-BNP* | |||||
T1 | 8 (12) | 1 (Ref) | 10 (14) | 1 (Ref) | |
T2 | 8 (12) | 1.05 (0.26–2.46) | 9 (14) | 0.93 (0.35–2.46) | |
T3 | 6 (9) | 0.80 (0.37–2.99) | 7 (10) | 0.74 (0.26–2.07) | |
hsCRP* | |||||
T1 | 8 (11) | 1 (Ref) | 11 (14) | 1 (Ref) | |
T2 | 6 (7) | 0.65 (0.21–1.95) | 7 (8) | 0.53 (0.19–1.45) | |
T3 | 11 (13) | 1.30 (0.49–3.42) | 13 (16) | 1.01 (0.46–2.62) | |
* Values at admission.
MACE, major adverse cardiac events; NACE, net adverse clinical events; NTpro-BNP, N-terminal proB-type natriuretic peptide; hsCRP, high-sensitivity C-reactive protein; HR, hazards ratio; CI, confidence interval; Ref, reference category; hsTropT, high-sensitive TroponinT. |
Kaplan-Meier figures. (a) NT-proBNP tertiles in relation to the occurence of MACE. (b) NT-proBNP tertiles in relation to the occurence of NACE. (c) hs-CRP tertiles in relation to the occurence of MACE. (d) hs-CRP tertiles in relation to the occurence of NACE. NTpro-BNP, N-terminal proB-type natriuretic peptide; MACE, major adverse cardiac events; NACE, net adverse clinical events; hsCRP, high-sensitivity C-reactive protein.
If mean biomarker levels were compared, a trend was observed towards higher
admission NT-proBNP levels in patients that deceased after the first year of
follow-up in comparison to the patients that were alive (after log-rank
transformation: 1.93
Death | Recurrent Myocardial Infarction | Recurrent Revascularization | MACE | NACE | |||||||||||
Yes (n = 7) | No (n = 238) | p-value | Yes (n = 11) | No (n = 238) | p-value | Yes (n = 10) | No (n = 239) | p-value | Yes (n = 25) | No (n = 224) | p-value | Yes (n = 31) | No (n = 218) | p-value | |
Peak hsTroponinT, ng/L* (SD) | 78.0 (852) | 76.5 (1285) | 0.89 | 232.0 (2846) | 71.5 (1152) | 0.06 | 119.0 (1755) | 78.0 (1247) | 0.38 | 183.0 (2103) | 70.5 (1141) | 0.06 | 115.0 (1920) | 71.5 (1154) | 0.29 |
NT-proBNP, pmol/L† (admission; SD) | 1.93 (0.49) | 1.42 (0.58) | 0.05 | 1.42 (0.64) | 1.44 (0.58) | 0.91 | 1.23 (0.47) | 1.45 (0.59) | 0.27 | 1.44 (0.60) | 1.44 (0.58) | 0.96 | 1.41 (0.65) | 1.44 (0.58) | 0.79 |
NT-proBNP, pmol/L† (discharge; SD) | 2.02 (0.38) | 1.51 (0.65) | 0.12 | 1.54 (1.03) | 1.52 (0.64) | 0.94 | 1.38 (0.71) | 1.52 (0.65) | 0.56 | 1.59 (0.77) | 1.51 (0.64) | 0.65 | 1.47 (0.77) | 1.52 (0.64) | 0.76 |
hsCRP, mg/L (IQR)* (admission; SD) | 2.20 (34.5) | 2.35 (12.0) | 0.32 | 2.90 (11.6) | 2.30 (13.6) | 0.51 | 2.70 (2.5) | 2.30 (13.7) | 0.67 | 2.90 (21.5) | 2.30 (12.2) | 0.62 | 2.50 (21.4) | 2.30 (11.8) | 0.82 |
hsCRP, mg/L (IQR)* (discharge; SD) | 5.40 (63.5) | 5.20 (30.5) | 0.99 | 15.0 (54.9) | 5.1 (29.7) | 0.05 | 4.60 (41.1) | 5.20 (31.0) | 0.48 | 7.25 (52.4) | 5.10 (27.5) | 0.12 | 6.15 (49.2) | 5.15 (27.8) | 0.33 |
*Values are median (SD). p value was calculated by the Wilcoxon rank-sum test. † Values are mean (SD). Values after log-rank transformation. p value was calculated by student T-test. MACE, major adverse cardiac events; NACE, net adverse clinical events; NTpro-BNP, N-terminal proB-type natriuretic peptide; hsCRP, high-sensitivity C-reactive protein; IQR, interquartile range; SD, standard deviation; hsTropT, high-sensitive TroponinT. |
Both, NT-proBNP and hs-CRP correlated significantly to the baseline
echocardiogram GLS in a univariate regression analysis. At 30-day follow-up
echocardiography, admission NT-proBNP (coefficient 0.021 (95% CI =
0.009–0.033), p
The main finding of the present analysis: we did not observe a significantly increased risk of developing clinical events within the first year of follow up according to the height of admission peak hs-cTnT, NT-proBNP or hsCRP levels. In patients with recurrent MI or MACE within the first year we did observe a trend towards a higher peak hs-cTnT, and in patients that deceased withing one year higher NT-proBNP levels at admission were observed.
Previously, the relationship between different biomarkers and clinical outcomes
in NSTE-ACS has been analyzed. An important study conducted by Omland et
al. [7] showed the prognostic value of NT-proBNP in 609 patients with STEMI and
NSTE-ACS. Median NT-proBNP levels in the sub-acute phase of these patients were
significantly lower in long-term (median follow-up of 51 months) surviving
patient compared to diseased patients (313 ng/L vs 922 ng/L, p =
To the best of our knowledge, no data is yet available investigating different biomarkers as a predictor for adverse clinical outcomes in high-risk NSTE-ACS patients treated in accordance with the current clinical practice guidelines (i.e., both an early invasive strategy as well as potent P2Y12 inhibitors) [20]. The optimal adherence to the current guideline’s timing recommendation as well as optimal medical therapy could be an explanation for the difference in findings between our current study and some of the previous trials mentioned above. However, within the first year of follow-up, the event rate in our study was quite low so no definitive conclusions can be drawn by the current results. Furthermore, the correlation between NT-proBNP and recovery of LVEF is remarkable. It is plausible that patients with significant increase in NT-proBNP levels were those with a larger area of myocardial ischemia. Since both timing strategies, direct and early, resulted in short delay to revascularization, sufficient circumstances for recovery of myocardial function are expected. This might explain a relatively large difference between baseline and 30-day follow-up LVEF. Still, we should consider the current study results as hypothesis generating. It is key to obtain more data of cardiac biomarkers in relation to patient’s risk for NSTE-ACS patient treated according to the current treatment standard.
Several limitations should be mentioned regarding the current study. Firstly,
the original OPTIMA-2 study was conducted in a randomized controlled setting and
the power calculation was primarily done to show a difference in area under the curve (AUC) of CK-MB
between patients treated in an urgent (
Our results show that biomarker levels at and during admission for NSTE-ACS do not add value regarding risk for recurrent events when patients are treated by an early invasive strategy that includes modern anticoagulant and antiplatelet therapy. In addition, higher NT-proBNP and hsCRP levels do predict an increased left ventricular recovery at follow up, probably because of the lager area of myocardium at risk.
CABG, coronary artery bypass graft; CI, confidence interval; CK-MB, creatine kinase-MB; hsCRP, high-sensitivity C-reactive protein; hs-cTnT, high-sensitivity troponin T; MACE, major adverse cardiac events; NACE, net adverse clinical events; NSTE-ACS, non-ST-elevation acute coronary syndrome; NSTEMI, non-ST-elevation myocardial infarction; NT-proBNP, N-terminal proB-type natriuretic peptide; STEMI, ST-elevation myocardial infarction; TnI, troponin I.
The datasets generated and/or analyzed during the current study are not publicly available due to local rules an national laws but are available from the corresponding author on reasonable request.
NDF, MAV and RKR designed the research study. NDF performed the research. MAV, AACMH and RKR provided help and advice on design and manuscript formation. NDF analyzed the data. NDF, MAV, AACMH and RKR wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
All (local) medical ethics committees approved the trial (Medical Research Ethics Committees United (MEC-U) NL41414.100.12). The study complied with the principles set out in the declaration of Helsinki. Written informed consent was obtained from each patient.
We thank Joost Vanhommerig for his aid with the statistical analysis.
The OPTIMA-2 study was funded by AstraZeneca and BV Cardio-research OLVG. The funders had no influence in any way in the design and conduct of the study, in the collection, analysis, and interpretation of the data, and in the preparation, review, or approval of the manuscript.
The authors declare no conflict of interest.
Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.