Background: Non-cardiac vascular surgery (NCVS) can have an elevated risk of peri-procedural complications. Prediction of the outcomes following surgical interventions provides an important advantage of risk stratification. This study aims to assess the predictive utility of pre-operative NT-proBNP levels on the cardiovascular (CV) outcomes of abdominal aortic aneurysm (AAA) repair. Methods: A retrospective data analysis of all the patients who underwent AAA repair, both open surgical repair (OSR) and endovascular aneurysm repair (EVAR), was performed in our tertiary care hospital from 2002 to 2018. Results: A total of 99 AAAs repair (63 EVAR and 36 OSR) were included in the study. Five (5.05%) patients experienced Myocardial Infarction (MI) in the post-operative period. Median preoperative NT-proBNP levels in patients with post-intervention MI were significantly higher than the ones without MI (1431 pg/mL vs 192 pg/mL, P=0.03). Similarly, higher median preoperative NT-proBNP levels was found in patients with 30-day postoperative mortality (944 pg/mL vs 197 pg/mL, P=0.136) and 30-day morbidity (352 pg/mL vs 192 pg/mL, P=0.021). Conclusion: Preoperative NT-proBNP levels were higher in patients with adverse surgical outcomes after the aortic intervention. Predictive utility of NT-proBNP and routine measurement of this biomarker could potentially improve CV risk stratification in NCVS.
VASCULAR DISEASE MANAGEMENT 2020;17(8):E165-E169.
Key words: NT-proBNP, abdominal aortic aneurysm, risk stratification
Non-cardiac vascular surgery (NCVS) possesses an elevated risk of peri-procedural complications.1,2 Approximately 1 in every 5 patients will experience a myocardial infarction (MI) or death in 18 months after any vascular surgery.3 Perioperative intervention may decrease major adverse cardiac events (MACE) in NCVS.4 Identification and early detection of the risk factors is a vital strategy to improve cardiovascular (CV) outcome. In this regard, operative risk stratifications by the application of natriuretic peptides as a marker for postoperative outcomes is gaining increasing interest in recent years.5-8
B-type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (NT-proBNP)
NT-proBNP is a ventricular pro-hormone cleaved to release BNP in response to excessive myocardium stretching, secondary to increased intravascular pressure in both the ventricles.9-12 NT-proBNP is found in higher concentrations in plasma and is more stable with a longer half-life than BNP. Both BNP and NT-proBNP play an important role in fluid and blood pressure regulation by vasodilation, cardiac load modification, and stimulation of vascular remodeling.13-16 Furthermore, they act on the kidneys to increase sodium excretion, and induce diuresis as well as natriuresis.17,18 High levels are seen in atherosclerosis and atrial fibrillation (AF).19 They are increasingly used as biochemical markers of heart failure (HF) and left ventricular systolic dysfunction.12,16,20,21
The primary aim of this study is to assess the predictive utility of pre-operative NT-proBNP levels on the CV outcomes of the patients undergoing AAA repairs. Similarly, we also wanted to explore whether elevated pre-operative NT-proBNP levels in comparison to the non-elevated levels were associated with other adverse clinical outcomes in terms of postoperative complications, 30-day postoperative morbidity and mortality, and length of hospital stay.
This study is based on the retrospective data analysis of patients undergoing aortic interventions between 2002 to 2018 at our tertiary referral vascular center. Patients with the available pre-operative NT-proBNP levels taken within one year before the scheduled surgery were included in this study. NT-proBNP levels above 300 pg/mL were used as a cut-off point in this study to distinguish elevated vs non-elevated NT-proBNP.10
A thorough search of the medical records was performed to assess the pre-procedural CV status. We excluded clinical entities associated with higher levels of natriuretic peptides, such as AF, aortic stenosis, unstable coronary syndromes, decompensated HF, and impaired renal function. Emergency vascular intervention and incorrectly collected samples or missing records were excluded. Perioperative outcomes in patients with and without elevated NT-proBNP levels were compared. All surgical interventions were performed under general anesthesia.
Outcome variables and endpoints:
The primary outcome of this study is the incidence of post-procedural MI. The secondary outcomes include the procedure-related complications, 30-day mortality and morbidity, and duration of hospital stay. The Society for Vascular Surgery (SVS) reporting standards were utilized to define procedure-related complications for each specific procedure type.22,23
Both open surgical repair (OSR) and endovascular aneurysm repair (EVAR) were included in this study as aortic interventions without distinctions. All revascularization procedures were performed by the same surgeon.
Data collection and statistical analysis
Data were retrieved retrospectively from our patient database (Vascubase 5.2™; Consensus Medical, Richmond, BC, Canada), including the patient’s clinical notes to extract any missing data. Pre-operative NT-proBNP levels were noted in all the patients. All data, including surgical procedure and post-operative outcome, were entered into Statistical Package for the Social Sciences (SPSS) (IBM Corp, Armonk, New York, USA) for analysis. Data summarization and reporting are performed using mean, median, and standard deviations (SD) as appropriate. The t-test (normal distribution) or Mann Whitney U (non-normal distribution) for continuous outcomes and Pearson’s Chi-square test for categorical variables were used to compare the two groups. A P-value <0.05 was used for the level of significance.
Ethical considerations and data protection
This study is based on retrospective data analysis. All the patients had given prior consent for biochemical testing, imaging, and interventions. Ethical approval was obtained from the Hospital Ethics Committee. Collected data were coded and stored on a password protected electronic storage system to maintain data integrity.
Ninety-nine AAA repairs (63 EVAR and 36 OSR), out of 674 total elective AAA surgeries, were included in this study as outlined in Table 1. Five (5.05%) patients experienced MI in the postoperative period. Median preoperative NT-proBNP levels in patients with post-intervention MI were significantly higher than the ones without MI [1431 pg/mL (range: 398-2348) vs 192 pg/mL (range: 39-5592), P=0.03].
Median preoperative NT-proBNP level in patients with and without 30-day postoperative mortality was 944 pg/mL (range: 102-5592) and 197 pg/mL (range: 39-4696), respectively (P=0.136). Similarly, 10 (10.10%) patients suffered respiratory complications, 4 (4.04%) developed renal failure and required dialysis, 4 (4.04%) developed wound complications, and 2 (2.02%) had lower limb embolization. There was a significant difference in the median preoperative NT-proBNP level in patients with 30-day morbidity than those without it [352 pg/mL (range: 102-5592) vs 192 pg/mL (range: 39-4696), OR 1.47, 95% CI: 0.93-2.3, P=0.021]. For those with elevated preoperative NT-proBNP levels (>300 pg/mL), the odds ratio for 30-day morbidity was 1.47 (95% CI: 0.93-2.31). Similarly, median preoperative NT-proBNP levels were higher but did not achieve statistical significance in patients with post intervention respiratory complications [375 pg/mL (range: 115-5592) vs 197 pg/mL (range: 39-4696), P=0.14] and renal failure requiring dialysis [939 pg/mL (range: 115-5592) vs 197 pg/mL (range: 39-4696), P=0.15].
On average, patients with elevated pre-operative NT-proBNP spent significantly more days in the hospital following intervention than those without high pre-operative NT-proBNP levels (5.67 ± 7.1 vs 3.56 ± 4.6 days, P=0.012).
Prediction of the outcomes after surgical interventions provides an important advantage of risk stratification.24 At times, the benefit of the surgery needs to be weighed against the risks. Copious literature exists that examines the role of NT-proBNP pre-operative assessment in cardiac surgery and the prediction of the adverse surgical outcome.10,25,26 Elevated NT-proBNP levels are indicative signs of cardiac dysfunction; therefore, it seems intuitive that those with a poorer cardiac reserve may be less likely to have good outcomes postoperatively.27 Reyes et al28 documented that pre-operative NT-proBNP levels rise after cardiac surgery and alters patient morbidity. Routine NT-proBNP assessment is relatively cost-effective and provides an opportunity to optimize care by offering further diagnostic tests, like stress echocardiography and cardiac catheterization to the high-risk patients.29,30
Many studies have shown that risk stratification with pre-operative NT-proBNP can be used in patients undergoing or awaiting NCVS.25,26,31,32 We were particularly interested in exploring these frontiers in terms of aortic surgery. After aortic interventions, we found a significant association between high NT-proBNP levels and complications in the postoperative period, suggesting a possible risk stratification opportunity. Our conclusions emulate meta-analysis by Feringa et al,33 Zhang et al,34 and Ryding et al,35 which demonstrate that high pre-operative NT-proBNP level is one of the strongest prognostic indicators of long-term mortality and MACE after major NCVS.
The selection of high-risk patients and follow-up optimization of cardiac function is useful in NCVS, especially after high-risk aortic surgery. It is plausible that multimodal perioperative targeted intervention, if implemented, will prevent or limit any morbidity or mortality, by using either pharmacologic, diagnostic, or therapeutic means. Furthermore, the presence of high NT-proBNP may be perceived as similar to a positive stress test to recognize high-risk patients for targeted referral to a specialist. Good negative predictive value of NT-proBNP also justifies its routine use in settings such as primary care in patients with symptomatic heart failure.36
Although the significance of these findings is contextual, it may be prudent to ask why they are essential and, more importantly, how they can be applied to clinical practice. Important prognostic information can be yielded from these measurements, alluding to different therapeutic approaches in patients with elevated NT-proBNP.31 An early indication of the proven benefit in the routine measurement of pre-operative NT-proBNP levels cannot be ignored. Although risk stratification through the use of NT-proBNP testing is being utilized in intensive care, it is crucial to assess the impact of preventive strategies in the pre-operative setting for NCVS.37 At present, those with vascular morbidity are not offered routine NT-proBNP measurement.38 However, its utility in selective patients is unquestionable, including those with high CV risk scheduled for NCVS. Therefore, we recommend a more extensive controlled comparative study to establish the impact of routinely assessing NT-proBNP on the outcomes of vascular surgery for validating its prognostic utility on the CV outcomes.
This study has several limitations. We only included a small proportion of all the elective AAA repairs (14.7%) in our center based on the retrospective nature of the study and the inclusion criteria, which relied upon clinically driven NT-pro-BNP determination rather than performing determinations in the overall population. Several of our patients did not have pre-operative NT-proBNP levels; therefore, they could not be included in this study. We acknowledge that the relative small sample size could potentially cause selection bias. Also, we considered all the procedures as aortic surgeries, regardless of being endovascular or open interventions. As evident, in open repair, high pressures caused by clamping, as well as increased myocardial wall stress can elevate NT-proBNP levels, directly contributing to the adverse CV events.39,40 Furthermore, the duration between NT-proBNP measurement and surgical interventions also varied between participants. Some of them had the measurements on the day of the procedure while others had measurements taken a few weeks or months before their procedure, probably leading to the differences in a quantitative measure of the NT-pro BNP levels. An arbitrary analysis did not demonstrate a clear correlation between the timing of proBNP measurement and cardiovascular outcome, but we had insufficient numbers to draw meaningful conclusions. Intuitively, proBNP measured nearer to surgery is a lot more informative than more remote measurements, and that timing needs to be standardized in controlled studies going forward.
Pre-operative NT-proBNP was higher in patients with adverse surgical outcomes after AAA repairs, highlighting a significant association between pre-operative NT-proBNP and the postoperative outcomes. We suggest implementing routine pre-operative measurement of NT-proBNP levels in high-risk NCVS to enhance perioperative CV risk stratification for optimal surgical outcomes and overall health. This study can serve as a nidus to conduct a similar study with procedural stratifications (endovascular vs open repair) in the future. n
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. They report no conflicts of interest regarding the content herein.
Address for correspondence:
Sherif Sultan, MCh, MD, FRCS, FACS, PhD
Department of Vascular and Endovascular Surgery
Western Vascular Institute
National University of Ireland
Telephone: +35 39 172 0122
Fax: +35 39 172 0121
Email: email@example.com; firstname.lastname@example.org,
Prof Sherif Sultan ORCID ID: 0000-0001-8767-4929
1. Augoustides J, Fleisher LA. Advancing perioperative prediction of cardiac risk after vascular surgery: Does post-operative N-terminal pro-brain natriuretic peptide do the trick? Anesthesiology. 2007;106(6):1080-1082.
2. Hoeks SE, Bax JJ, Poldermans D. Should the ACC/AHA guidelines be changed in patients undergoing vascular surgery? Eur Heart J. 2005;26(22):2358-2360.
3. Bursi F, Babuin L, Barbieri A, et al. Vascular surgery patients: perioperative and long-term risk according to the ACC/AHA guidelines, the additive role of post-operative troponin elevation. Eur Heart J. 2005;26(22):2448-2456.
4. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2006 guideline update on perioperative cardiovascular evaluation for non-cardiac surgery: Focused update on perioperative beta-blocker therapy—a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to update the 2002 Guidelines on Perioperative Evaluation for Noncardiac Surgery). Anesth Analg. 2007;104(1):15-26.
5. Rothenbacher D, Koenig W, Brenner H. Comparison of N-terminal pro-B-natriuretic peptide, C-reactive protein, and creatinine clearance for prognosis in patients with known coronary artery disease. Arch Intern Med. 2006;166(22):2455-2460.
6. Kim H, Yang DH, Park Y, et al. Incremental prognostic value of C-reactive protein and N-terminal pro-B-type natriuretic peptide in acute coronary syndrome. Circ J. 2006;70(11):1379-1384.
7. Yeh HM, Lau HP, Lin JM, Sun WZ, Wang MJ, Lai LP. Pre-operative plasma N-terminal pro-brain natriuretic peptide as a marker of cardiac risk in patients undergoing elective non-cardiac surgery. Br J Surg. 2005;92(8):1041-1045.
8. Feringa HH, Bax JJ, Elhendy A, et al. Association of plasma N-terminal pro-B-type natriuretic peptide with postoperative cardiac events in patients undergoing surgery for abdominal aortic aneurysm or leg bypass. Am J Cardiol. 2006;98(1):111-115.
9. Hall C. Essential biochemistry and physiology of (NT-pro)BNP. Eur J Heart Fail. 2004;6(3):257-260.
10. Causey MW, Singh N. Clinical implications of B-type natriuretic peptide and N-terminal pro--B-type natriuretic peptide in the care of the vascular surgery patient. Semin Vasc Surg. 2014;27(3-4):143-147.
11. Daniels LB, Maisel AS. Natriuretic peptides. J Am Coll Cardiol. 2007;50(25):2357-2368.
12. Cantinotti M, Walters HL, Crocetti M, Marotta M, Murzi B, Clerico A. BNP in children with congenital cardiac disease: Is there now sufficient evidence for its routine use? Cardiol Young. 2015;25(3):424-437.
13. Attaran S, Sherwood R, Desai J, et al. Brain natriuretic peptide a predictive marker in cardiac surgery. Interact Cardiovasc Thorac Surg. 2009;9(4):662-666.
14. Stone PA, Schlarb H, Campbell JE, et al. C-reactive protein and brain natriuretic peptide as predictors of adverse events after lower extremity endovascular revascularization. J Vasc Surg. 2014;60(3):652-660.
15. Jin QH, Ye WL, Chen HH, et al. Levels of brain natriuretic peptide are associated with peripheral arterial disease in subjects with type-2 diabetes mellitus. BMC Endocr Disord. 2014;14:27.
16. Svennberg E, Lindahl B, Berglund L, et al. NT-proBNP is a powerful predictor for incident atrial fibrillation — Validation of a multimarker approach. Int J Cardiol. 2016;223:74-81.
17. Taylor CJ, Roalfe AK, Iles R, Hobbs FDR. The potential role of NT-proBNP in screening for and predicting prognosis in heart failure: a survival analysis. BMJ Open. 2014;4(4):e004675.
18. Crilley JG, Farrer M. Left ventricular remodelling and brain natriuretic peptide after first myocardial infarction. Heart. 2001;86(6):638-642.
19. Bay M, Kirk V, Parner J, et al. NT-proBNP: A new diagnostic screening tool to differentiate between patients with normal and reduced left ventricular systolic function. Heart. 2003;89(2):150-154.
20. Hobbs FDR, Davis RC, Roalfe AK, Hare R, Davies MK. Reliability of N-terminal proBNP assay in diagnosis of left ventricular systolic dysfunction within representative and high risk populations. Heart. 2004;90(8):866-870.
21. Fleisher LA. Preoperative assessment of the patient with cardiac disease undergoing noncardiac surgery. Anesthesiol Clin. 2016;34(1):59-70.
22. Rutherford RB, Baker JD, Ernst C, et al. Recommended standards for reports dealing with lower extremity ischemia: Revised version. J Vasc Surg. 1997;26(3):517-538.
23. Chaikof EL, Blankensteijn JD, Harris PL, et al. Reporting standards for endovascular aortic aneurysm repair. J Vasc Surg. 2002;35(5):1048-1060.
24. Grassi P, Calderan C, Vassallo MC, et al. B-type natriuretic peptide as a predictor of outcome in a general intensive care unit. HSR Proc Intensive Care Cardiovasc Anesth. 2011;3(1):59-66.
25. Hutfless R, Kazanegra R, Madani M, et al. Utility of B-type natriuretic peptide in predicting postoperative complications and outcomes in patients undergoing heart surgery. J Am Coll Cardiol. 2004;43(10):1873-1879.
26. Liu H, Wang C, Liu L, Zhuang Y, Yang X, Zhang Y. Perioperative application of N-terminal pro-brain natriuretic peptide in patients undergoing cardiac surgery. J Cardiothorac Surg. 2013;8:1.
27. Panagopoulou V, Deftereos S, Kossyvakis C, et al. NTproBNP: An important biomarker in cardiac diseases. Curr Top Med Chem. 2013;13(2):82-94.
28. Reyes G, Forés G, Rodríguez-Abella RH, et al. NT-proBNP in cardiac surgery: A new tool for the management of our patients? Interact Cardiovasc Thorac Surg. 2005;4(3):242-247.
29. Ferrandis MJ, Ryden I, Lindahl TL, Larsson A. Ruling out cardiac failure: Cost-benefit analysis of a sequential testing strategy with NT-proBNP before echocardiography. Ups J Med Sci. 2013;118(2):75-79.
30. Malhotra AK, Ramakrishna H. N-terminal pro B type natriuretic peptide in high cardiovascular-risk patients for noncardiac surgery: What is the current prognostic evidence? Ann Card Anaesth. 2016;19(2):314-320.
31. Mahla E, Baumann A, Rehak P, et al. N-terminal pro-brain natriuretic peptide identifies patients at high risk for adverse cardiac outcome after vascular surgery. Anesthesiology. 2007;106(6):1088-1095.
32. Heart Protection Study Collaborative Group, Emberson JR, Ng LL, Armitage J, Bowman L, Parish S, Collins R. N-terminal pro-B-type natriuretic peptide, vascular disease risk, and cholesterol reduction among 20,536 patients in the MRC/BHF heart protection study. J Am Coll Cardiol. 2007;49(3): 311-319.
33. Feringa HH, Schouten O, Dunkelgrun M, et al. Plasma N-terminal pro-B-type natriuretic peptide as long-term prognostic marker after major vascular surgery. Heart. 2007;93(2):226-231.
34. Zhang LJ, Li N, Li Y, Zeng XT, Liu MY. Cardiac biomarkers predicting MACE in patients undergoing noncardiac surgery: A meta-analysis. Front Physiol. 2019;9:1923.
35. Ryding ADS, Kumar S, Worthington AM, Burgess D. Prognostic value of brain natriuretic peptide in noncardiac surgery: a meta-analysis. Anesthesiology. 2009;111(2):311-319.
36. Murphy JJ, Fuat A. Natriuretic peptide testing in primary care. Circulation. 2006;113(9):f35-36.
37. Hoffmann U, Borggrefe M, Brueckmann M. New horizons: NT-proBNP for risk stratification of patients with shock in the intensive care unit. Crit Care. 2006;10(2):134.
38. Poldermans D, Bax JJ, Boersma E, et al. Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery: the Task Force for Preoperative Cardiac Risk Assessment and Perioperative Cardiac Management in Non-cardiac Surgery of the European Society of Cardiology (ESC) and endorsed by the European Society of Anaesthesiology (ESA). Eur J Anaesthesiol. 2010;27(2):92-137.
39. Vetrugno L, Costa MG, Pompei L, et al. Prognostic power of pre- and postoperative B-type natriuretic peptide levels in patients undergoing abdominal aortic surgery. J Cardiothorac Vasc Anesth. 2012;26(4):637-642.
40. Sako H, Hadama T, Miyamoto S, et al. Limb ischemia and reperfusion during abdominal aortic aneurysm surgery. Surg Today. 2004;34(10):832-836.