|Year : 2021 | Volume
| Issue : 6 | Page : 114-119
Role of Cardio-biomarkers (NT-Pro BNP and Troponin I) in cardiac risk stratification of patients undergoing major vascular surgeries
Rakesh Kumar Jha, Vembu Anand, Vikram Patra, Rishi Dhillan, Rohit Mehra, T Suresh Reddy
Department of Vascular Surgery, Army Hospital R&R, New Delhi, India
|Date of Submission||01-Nov-2020|
|Date of Acceptance||07-Dec-2020|
|Date of Web Publication||20-Jan-2022|
Department of Vascular Surgery, Army Hospital R&R, New Delhi
Source of Support: None, Conflict of Interest: None
Objective: The objective is to assess the role of cardio-biomarkers, namely, N-Terminal Pro-hormone Beta Natriuretic Peptide (NT-ProBNP) and Cardiac Troponin I (cTnI) in prediction of postoperative cardiac events (POCEs) in noncardiac patients undergoing major vascular surgery and compare their efficacy with Revised Cardiac Risk Indices (RCRI) in preoperative period. Materials and Methods: Quantitative analysis of cTnI and NT-ProBNP was done in pre- and post-operative period in patients, who underwent elective major vascular surgeries between April 2018 and April 2020 at a tertiary care hospital. The ability of both the cardio-biomarkers, either alone or in combination were assessed for the prediction of POCE and results were compared with RCRI in preoperative period. The relationship between postoperative quantitative values of both the biomarkers and development of POCE were also analyzed. Results: A total of 170 patients were enrolled and the incidence of POCE was observed in 15.9% (27) of our patients. The “cut-off” values of cTnI, and NT-ProBNP in preoperative period were found to be 0.011 μg/L and 335 pg/mL and in postoperative period were 0.024 μg/L and 438 pg/mL, respectively. In preoperative period, biomarkers, either alone or in combination, outperformed RCRI in prediction of POCE and when individual biomarker was assessed, NT-ProBNP had better efficacy than cTnI. In postoperative period, predictive ability of both the biomarkers were similar, however, combination of both significantly improved the prediction of POCE as represented by increase in area under the curve, sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy. Conclusion: As compared to RCRI, cardio-biomarkers were better predictor of POCE in preoperative period and their efficacy in forecasting POCE continued even in postoperative period.
Keywords: Cardiac troponin I, myocardial ischaemia after noncardiac surgery, N-Terminal Pro hormone B-type natriuretic peptide (NT-ProBNP), postoperative cardiac events, revised cardiac risk index
|How to cite this article:|
Jha RK, Anand V, Patra V, Dhillan R, Mehra R, Reddy T S. Role of Cardio-biomarkers (NT-Pro BNP and Troponin I) in cardiac risk stratification of patients undergoing major vascular surgeries. Indian J Vasc Endovasc Surg 2021;8, Suppl S2:114-9
|How to cite this URL:|
Jha RK, Anand V, Patra V, Dhillan R, Mehra R, Reddy T S. Role of Cardio-biomarkers (NT-Pro BNP and Troponin I) in cardiac risk stratification of patients undergoing major vascular surgeries. Indian J Vasc Endovasc Surg [serial online] 2021 [cited 2022 May 25];8, Suppl S2:114-9. Available from: https://www.indjvascsurg.org/text.asp?2021/8/6/114/336014
| Introduction|| |
Patients with peripheral arterial disease (PAD) have a higher incidence of adverse cardiac events in postoperative period as compared to patients without PAD. Postoperative cardiac events (POCE) are broadly divided into two categories: major and minor cardiac events. Acute myocardial infarction (AMI), congestive cardiac failure (CCF) and cardio vascular deaths (CVD) are considered as major, whereas, myocardial ischaemia after noncardiac surgery (MINS), unstable anginal pectoris, and arrhythmias are considered as minor cardiac events. Incidence of POCE varies in different studies. In a meta-analysis, conducted by Flu et al., the incidence of MINS and AMI was found between 14%–47% and 1%–26% respectively.
Over the years, several clinical scores have been developed to predict POCE in vascular patients; however, none of them have gained wider acceptability due to complexity of calculation and limited predictive ability. At present, Revised Cardiac Risk Index (RCRI) is the most validated clinical score, used for cardiovascular risk assessment for patients undergoing major vascular surgery; however, it wrongly classifies patients in low or intermediate risk groups and does not include dynamic events like urgency and extent of surgical procedure, which alter patient's cardiac risk.
Cardiac Troponin I (cTnI) is a cardiac specific protein, which is highly sensitive for myocardial injury and infarction. Similarly, N-Terminal Pro hormone B-type natriuretic peptide (NT-proBNP) is mainly secreted from the left ventricle in response to wall stress. There are numerous studies available which advocate prognostic role of cTnI and NT-ProBNP in prediction of POCE in noncardiac surgical patients. However, limited studies are available on prognostic role of these cardio-biomarker in “vascular patients.” A study by Golubovic et al. highlighted the fact that the patients with detectable cTnI in preoperative period have higher incidence of adverse cardiac events in postoperative period. A meta-analysis by Rodseth et al. also revealed that NT-ProBNP elevation above the optimal discriminatory threshold in perioperative period was significantly associated with AMI and early postoperative (<30-day) cardiac mortality.
Cardio-biomarkers (cTnI and NT-ProBNP) improve risk stratification by the identification of “clinically silent” cardiac disease in preoperative period which is represented by biomarkers elevation alone and cannot be detected by noninvasive or invasive tests. Besides, it is neither prudent nor cost-effective to conduct stress tests or coronary angiography (CAG) for all asymptomatic or low risk patients. Cardio-biomarkers also help in early detection of cardiac ischemia in postoperative period, where clinical features of cardiovascular disease may be masked by factors such as ventilation, sedation, pain, analgesia, drugs, and fluid and which is reflected by biomarker elevation alone, without clinical symptomatology or changes in electro-cardiogram (ECG)/2-dimensional echocardiography (2D Echo). Measuring these biomarkers in pre- and post-operative period objectively provide better prediction of POCE. Although various studies have shown promising role of cardio-biomarkers in the prediction of POCE, their validation in vascular patients require more research. Hence, this study will not only add further to the existing knowledge of cardio-biomarkers as a predictive tool, but will also provide their comparative efficacy against RCRI in prediction of POCE in vascular patients, which has not been studied earlier in available literature.
| Materials and Methods|| |
This is a single-center, prospective, observational study conducted by the department of vascular surgery at a tertiary care hospital. The research was performed after taking approval from institutional ethical and research committee and obtaining written informed consent from patients prior enrollment.
All patients, without known or established cardiac illness, who underwent elective major vascular surgery (Open/Endovascular/Hybrid) between April 2018 and April 2020.
Patients with age <18 years, renal dysfunction (serum creatinine >2), established CAD, vascular trauma, acute limb ischemia, unwilling to participate in the study and lost to follow-up (<30 days of surgery), were excluded from the study.
Demographic profile (age, gender, comorbidities, etc.,) of patients was recorded and all the patients were evaluated with arterial duplex, computed tomography/magnetic resonance angiography in preoperative period. Diagnosis (aortic/aorto-iliac/iliac/fem-Pop/carotid/SCA disease) was established and intervention (open/endovascular/hybrid) was planned as per standard treatment guidelines. Besides routine hematological and biochemical tests, X-ray chest, 12-lead ECG, and 2D-Echo were carried out for all the patients and evaluation was done by a cardiologist and an anesthesiologist in preoperative period. A clinical risk score, i.e., RCRI class was assigned to all the patients. Cardiac stress tests and CAG were conducted only for selective patients as and when advised by the cardiologist in pre- and post-operative period.
cTnI and NT-ProBNP assay were done twice for all patients-once within 24 h prior to surgery and second after 48 h of surgery. Cardio-biomarker assay was done even earlier in patients who developed adverse cardiac events within 48 h of surgery. The venous blood samples were collected in a sterile ethylenediaminetetraacetic acid tube and quantitative values were obtained using AQT90 FLEX immunoassay analyzer (RADIOMETER). Patients were monitored with continuous ECG monitoring in intensive care unit/vascular ward up to 48 h after surgery and even longer in selective patients and all patients were followed up till 30th postoperative day for the occurrence of POCE by clinical examination, chest X-ray, serial ECG monitoring (on postoperative day 1, 3, 7 and 30) and 2D Echo (on 30th postoperative day), biomarker assay and stress tests as advised by the cardiologist. The primary endpoint of the study was all cause mortality and secondary endpoint was development of POCE.
MINS was defined as elevation of cTn values above the 99th percentile of upper reference limit alone without any ECG changes and with or without anginal symptoms. AMI was defined as troponin elevation with at least one of the following findings as per “third universal definition:” (i) symptoms of myocardial ischemia, (ii) ECG evidence of acute ischemia, ST-T wave changes (elevation/depression), or left bundle branch block, (iii) development of new pathological Q waves, and (iv) 2D ECHO showing loss of viable myocardium or a new abnormal left ventricular wall motion. The diagnosis of CCF was made by cardiologist by the presence of signs of the left ventricular dysfunction and independent confirmation by radiologist on chest X-ray. CVD was defined as any death with a cardiac cause or sudden death not ascribed to any other illness.
Descriptive analysis of various parameters was expressed as means and standard deviation. Categorical data were expressed as absolute number and percentage. Independent Student t– test was used for testing of mean between independent groups whereas, cross tables were generated and Chi-square test was used for testing the associations. The accuracy of NT-ProBNP, cTnI and RCRI for the prediction of POCE were assessed by receiver operating characteristic (ROC) analysis and the optimal cut off values were calculated using the formula, minimum ([1 − Sn]2 + [1 − Sp]2) with the best combination of sensitivity and specificity. The efficacy of individual and combined biomarkers and RCRI were compared by analyzing sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy. P < 0.05 was considered statistically significant. All analysis was done using SPSS software, version 24.0 (Armonk, NY: IBM Corp).
| Results|| |
A total of 170 patients were included in the study and baseline characteristics of patients (demographic profile, comorbidities, RCRI class, arterial segments involved, intervention modalities, and mortality distribution) were recorded and analyzed [Table 1].
Postoperative cardiac events
In our study, 27 out of 170 patients developed POCE, comprising of 15.9% of total patients. Three patients had more than one cardiac event (two events each) and each event was considered as an incidence. Considering 30 events in 27 patients, breakdown of POCE is listed in [Table 2].
Comparative efficacy of preoperative cardio-biomarker verses revised cardiac risk index in prediction of postoperative cardiac event
In preoperative period, NT-ProBNP was detectable in all patients whereas, cTnI was detectable in only 17.6% (30/170) of patients. Mean values of cTnI and NT-ProBNP in patients with POCE were 0.013 ± 0.002 and 487 ± 252 and non-POCE were 0.011 ± 0.001 and 234 ± 164 respectively and. The calculated P values of preoperative Trop I and NT Pro BNP in prediction of POCE were 0.011 and <0.0001, which were statistically significant.
From ROC curve analysis, optimal “cut-off” values and area under the curve (AUC) of preoperative cTnI, NT-proBNP and RCRI were determined to be 0.011 mcg/L (AUC = 0.779, 95% confidence interval [CI]: 0.599–959), 335 pg/mL (AUC = 0.925, 95% CI: 0.801–1.000) and 1 risk factor (RCRI Class II) (AUC = 0.641, 95% CI: 0.526–0.756), respectively [Figure 1].
|Figure 1: Comparative receiver operating characteristic analysis of preoperative cardio-biomarkers and Revised Cardiac Risk Index in prediction of postoperative cardiac event|
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Considering the above threshold values, comparative study of biomarkers either alone or in combination against RCRI, were done for the prediction of POCE, in terms of sensitivity, specificity, PPV, NPV, and overall accuracy and results were analyzed [Table 3].
|Table 3: Comparison of revised cardiac risk indices verses preoperative cardio-biomarkers in prediction of postoperative cardiac events|
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Efficacy of cardio-biomarkers in prediction of postoperative cardiac event in postoperative period
In postoperative period, NT-ProBNP was detectable in all patients (170/170), whereas, cTnI was detectable in only 25% of patients (43/170). Mean value of cTnI and NT-ProBNP of patients with POCE were higher (0.063 ± 0.046 and 814 ± 441) as compared to non-POCE (0.015 ± 0.005 and 262 ± 178) which were statistically significant (P < 0.0001 for both).
From ROC curve analysis, optimal cut off values and AUC of postoperative cTnI and NT-proBNP were determined to be 0.024 μg/L (AUC = 0.876, 95% CI: 0.780–0.972) and 438 pg/mL (AUC = 0.877, 95% CI: 0.766–0.989), respectively [Figure 2].
|Figure 2: Receiver operating characteristic analysis of postoperative cardio-biomarkers in prediction of postoperative cardiac event|
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Considering the above threshold values, the ability of biomarkers to predict POCE either alone or in combination was assessed in terms of sensitivity, specificity, PPV, NPV, and overall accuracy [Table 4].
|Table 4: Efficacy of postoperative cardio-biomarker in prediction of postoperative cardiac events|
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| Discussion|| |
The aim and objectives of our study were to assess the role of cardio-biomarkers (cTnI and NT-ProBNP) as a risk stratification tool in prediction of POCE in noncardiac patients undergoing major vascular surgery and compare the efficacy of both the biomarkers with RCRI in preoperative period.
In our study, overall incidence of POCE was 15.9%. Incidence of minor cardiac events, represented by MINS, developed in 7.1% of patients and major adverse cardiac events took place in 10.5% of patients with subdistribution of AMI in 4.7%, CCF in 3.5% and cardiac death in 2.4% of patients [Table 2]. The occurrence of MINS in our study (7.1%) was comparable with the result of a study performed by Górka et al. which included 475 patients with elective abdominal aortic aneurysm (AAA) repair and peripheral arterial surgeries, in which MINS was observed in 9.9% of patients. The incidence of MINS was found higher (14%– 47%) in a meta-analysis conducted by Flu et al. and 19.1% in another meta-analysis conducted by Biccard and Rodseth. The higher incidence of MINS in both the meta-analysis can be explained by inclusion of high-risk surgery (open AAA/lower extremity/carotid surgery) performed over high risk patients, i.e., patients with CAD and chronic kidney disease (CKD) in their studies. Whereas, in our study, majority of patients were managed with endovascular (46.5%) or hybrid (26.5%) procedure. Furthermore, patients with CAD/CKD were excluded from our study.
Major cardiac events occurred in our patients, were comparable with the result observed in the study conducted by Yang et al. over 365 vascular patients, in which 13.4% of patients developed major cardiac events (AMI in 7.1%, CCF in 9.9% and cardiac death in 0.3%). Similar result was observed in a multi-center study by Gualandro et al. in which major cardiac events occurred in 12.6% of patients (AMI in 6.9%, congestive heart failure in 4.8% and cardiac arrest in 1.4% of patients).
There is no general consensus on optimal cut off value of NT-pro-BNP and Trop I for in preoperative period. Optimal threshold value of NT-ProBNP in preoperative period was found to be ranging from 201 pg/mL to 512 pg/ml in various studies. In our study, it was calculated to be 335 pg/mL (normal reference range –70–133 ng/L), which was comparable with the outcome of three independent studies by Yang et al. Rajagopalan et al. and Schouten et al. in which cut off values were 302 pg/mL, 359 pg/mL, and 350 pg/mL respectively.
We could not find any study, which determines preoperative cut off value of Trop I in prediction of POCE, however, a study conducted by Howell et al. on vascular patients revealed that cTnI was detectable in limited number of their patients and all of them had values within normal reference range. In our study, cTnI was detectable in only 17.6% of patients with optimal and all values were within normal reference range (0.010–0.023 μg/L).
Considering the optimal cut off value in preoperative period, sensitivity and specificity of NT-proBNP in prediction of POCE were between 70% and 88% in different studies, which were comparable with our result in which sensitivity and specificity were 92.3% and 87.5%, respectively. From ROC curve analysis sensitivity and specificity of cTnI in our study were found to be 76.9% and 81.3% which were comparable with the study outcome by Godet et al. over 329 patients undergoing infra-renal aortic surgery in which sensitivity and specificity were 75% and 89%, respectively.
The comparative analysis of cardio-biomarkers in preoperative period revealed that ability of NT-ProBNP (AUC = 0.925, 95% CI: 0.801–1.000) for prediction of POCE was better than cTnI (AUC = 0.779, 95% CI: 0.599–959) and ROC analysis of both the biomarkers in combination showed increase in (AUC = 0.962, CI: 0.875–1.000) with significant P (<0.0001) [Figure 1] and improvement in sensitivity (93.7%), specificity (100.0%), PPV (100.0%), and overall accuracy (96.5%) [Table 3].
We could not find any comparative study between efficacy of RCRI and preoperative cardio-biomarker for prediction of POCE. However, ROC analysis of biomarkers (cTnI and NT-ProBNP) and RCRI in our study, revealed that the predictive ability of NT-ProBNP (AUC = 0.925) and cTnI (AUC = 0.779) either alone or in combination (AUC = 0.962) were much better than RCRI (AUC = 0.641) in prediction of POCE as represented by improvement in AUC, sensitivity, specificity, NPV, PPV, and overall accuracy [Table 3].
There was no uniformity on optimal cut off values of NT-proBNP and cTnI even in postoperative period. Threshold value of NT-ProBNP was found ranging from 201 pg/mL to 3980 pg/mL in various studies,, and cTnI value was found to be 0.68 μg/L in a study conducted by Howell et al. In our study, the optimal cut off values of cTnI and NT-proBNP were determined to be 0.024 μg/L and 438 pg/mL in postoperative period. The higher cut off value of cTnI in the study mentioned above can be explained by population and assay variability and exclusion of CAD and CKD patients from our study, who have more cardiac stress and strain in perioperative period.
In postoperative period, cTnI had sensitivity, specificity, PPV, and NPV of 83.0% and 100.0%, 100.0%, and 85.5% respectively in our study, which were comparable with the result of Godet et al. in which sensitivity and specificity were 75% and 89% and a multi-center study by Howell et al. in which PPV and NPV were 100% and 98.3%, respectively. Sensitivity and Specificity of of NT-ProBNP were 88.9% and 84.2% in our study, which were comparable with the result of various studies in which sensitivity and specificity were between 62% and 100%.,, The comparative analysis of both the cardio-biomarkers in postoperative period revealed that the ability of cTnI in prediction of POCE (AUC = 0.876,) was almost similar to NT-ProBNP (AUC = 0.877) [Figure 2] whereas combined assessment of both the biomarkers showed improvement in AUC, sensitivity and overall accuracy to 0.956%, 91.2% and 92.6% respectively [Table 4].
Our study has certain limitations: This is a single-center study with relatively smaller sample size (n = 170). Various other factors which influence POCE, for example, smoking, comorbidities, perioperative medications, duration and extent of surgery, and type of anesthesia were not studied.
| Conclusion|| |
Patients undergoing major vascular surgery have an increased risk of perioperative cardiac morbidity and mortality. The identification of patient at risk of adverse cardiac event, prior to surgery, is of paramount importance. Search for an ideal risk stratification tool, which can accurately predict POCE, is an evolving process. At present, RCRI is being widely used as a risk stratification tool for “vascular patients,” which has got various limitations. Cardio-biomarkers have shown promising results in prediction of POCE in the perioperative period in both surgical as well as nonsurgical patients. In our study, the efficacy of cardio biomarkers (cTnI and NT Pro BNP) was compared with RCRI in preoperative period for prediction of POCE and it revealed that both the cardio-biomarkers outperformed RCRI, either alone or in combination. When individual biomarkers were assessed, NT Pro BNP was found to have better prediction of POCE as compared to cTnI in preoperative period. Postoperatively, both the biomarkers were equally efficacious in predicting POCE. However, the combination of cTnI and NT-proBNP significantly improved the prediction of POCE even in postoperative period. Based on our study, it was concluded that NT Pro BNP and cTnI assay should be used as a risk stratification tool in pre- as well as post-operative period for vascular patients, without known cardiac illness, undergoing major vascular surgery and RCRI can be replaced by biomarkers assay in preoperative period. However, further multi-center studies with a greater number of patients are required to form stronger conclusions and standardization of optimal discriminatory or “cut-off” values of biomarkers in perioperative period.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]