B-type natriuretic peptide predicts postoperative cardiac events and mortality after elective open abdominal aortic aneurysm repair Gavin J. Bryce, MD,a,b Christopher J. Payne, FRCS,a,b Simon C. Gibson, MD,a Dominique S. Byrne, MD,a Christian Delles, MD,b John McClure, PhD,b and David B. Kingsmore, MD,a Glasgow, United Kingdom Objective: The aim of this study was to determine if a single preoperative B-type natriuretic peptide (BNP) level correlated with perioperative cardiac events, cardiac death, and all-cause mortality in elective open abdominal aortic aneurysm (AAA) repair in the short term, intermediate term, and long term. Methods: A prospective, 2-year multicenter observational cohort study in the three vascular units in Glasgow was performed. All patients who were admitted for elective open AAA repair were recruited. Preoperative BNP levels were performed and batch analyzed at the end of the study. Postoperative screening for cardiac events (nonfatal myocardial infarction and cardiac death) was performed at 2, 5, and 30 days. Follow-up for all-cause mortality was sustained to a minimum of 3 years, where possible. Results: A total of 106 of 111 patients were recruited. Median BNP concentrations were higher in the 16 patients (15%) with immediate postoperative cardiac events (P ⴝ .001) and the five with cardiac death (P ⴝ .043). Area under the receiver-operating characteristic (AUC) curve analysis indicated BNP concentrations of 99.5 pg/mL best predicted cardiac events (AUC, 0.927), and 448 pg/mL predicted cardiac death (AUC, 0.963). BNP also predicted all-cause mortality in the short-term (P ⴝ .028), intermediate-term (P < .001), and long-term (P < .001) postoperative periods. Conclusions: Preoperative serum BNP concentration predicted postoperative cardiac events, cardiac death, and all-cause mortality in patients undergoing elective open AAA repair on short-term, intermediate-term, and long-term follow-up on an individual basis with greater accuracy than currently available risk prediction tools. ( J Vasc Surg 2013;57:345-53.)
Elective open surgical repair of an abdominal aortic aneurysm (AAA) is associated with a mortality of 5% to 6% in the United Kingtom.1,2 The UK Small Aneurysm Trial comparing surgical repair with observation of small AAAs demonstrated a greater risk of death from surgery than from rupture in the observation group for the first 3 years of follow-up.2 Most of the postoperative deaths in the operative group were related to cardiac complications such as myocardial infarction (MI). The desire to find a less-invasive treatment option with a reduced postoperative mortality and morbidity led to the development of endovascular aneurysm repair (EVAR). Trials of EVAR have shown that although perioperative mortality is lower, there is a constant level of device failure that requires regular surveillance and reintervention, with From the Department of Vascular Surgery, Western Infirmary,a and Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre,b University of Glasgow. Funding for B-type natriuretic peptide analysis was by the joint research funds of the Department of Cardiology and Department of Vascular Surgery, Western Infirmary, Glasgow. Author conflict of interest: none. Correspondence: Gavin J. Bryce, 116 Essex Dr, Jordanhill, Glasgow G14 9PD, UK (e-mail:
[email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214/$36.00 Copyright © 2013 by the Society for Vascular Surgery. http://dx.doi.org/10.1016/j.jvs.2012.07.053
consequent increased cost.3,4 Greater discrimination of those at risk of perioperative cardiac complications or with poorer short-term survival would improve management. Current strategies for cardiac-risk assessment are limited by subjectivity and poor accuracy, and imaging or functional assessment is limited by availability, expense, and the risk of an invasive procedure. B-type natriuretic peptide (BNP), originally identified in the porcine brain, is one of a family of cardiac peptides secreted almost exclusively by the myocardium in a nonspecific response to wall stress.5 A correlation has been demonstrated between the concentration of BNP and cardiac risk factors in the general population in the West of Scotland as well as with survival.6 A number of studies have evaluated preoperative BNP in noncardiac surgery as a method of predicting cardiac complications and demonstrated a direct association between increasing levels of BNP and the risk of postoperative cardiac events.7-16 Furthermore, a number of studies have demonstrated a greater risk of long-term major adverse cardiac events (MACE) and all-cause mortality after major noncardiac surgery with elevated preoperative BNP.10,13,16-18 The aim of the present study was to determine if a single preoperative BNP value can predict cardiac complications and all-cause mortality in the short term, intermediate term, and long term and thus aid selection and optimization of patients undergoing elective open AAA repair. 345
346 Bryce et al
METHODS Local Research and Development, and Central Ethics Committee approval was obtained for the study. All patients were provided with an information sheet and signed a study consent form. This study involved no additional risk to patients other than extra blood tests and noninvasive cardiac imaging. Study population and power. A prospective, observational, multicenter cohort study was performed involving the three vascular units within Glasgow (Gartnavel General Hospital, Glasgow Royal Infirmary, and the Southern General Hospital). Consecutive patients admitted for elective open AAA surgery between August 2005 and September 2007 were prospectively included in the study, with the aim of recruiting a minimum of 100 patients based on a power calculation using a cardiac event rate of 15% to 20% and a spread of BNP concentration with a cutoff level at 100 pg/mL selected through BNPs diagnostic capability for heart failure and its ability to predict MACE with higher BNP levels in noncardiac surgery.12,19 All patients were approached the evening before surgery, and informed consent was obtained. Patients were excluded if their operation was nonelective, if they were unable to give informed consent, or if they had preoperative evidence of acute cardiac ischemia measured by preoperative electrocardiogram (ECG), identified by ST changes or T-wave inversion, and cardiac troponin I (cTnI). Patients. Demographic data and factors relating to the risk of surgery were gathered for each patient by history and case-note review. Weight and height were recorded to allow calculation of body mass index (BMI). Chronic renal impairment, defined as preoperative serum creatinine ⬎130 mol/L or estimated glomerular filtration rate (eGFR) ⬍60 mL/min, was recorded. The eGFR was calculated from serum creatinine using the Modification of Diet in Renal Disease (MDRD) Study equation, which allowed patient categorization by chronic kidney disease (CKD) stage as derived from the National Institute for Health and Clinical Excellence (NICE), Scottish Intercollegiate Guidelines Network (SIGN), and Renal Association guidelines 2009.20-22 Preoperative assessment. The preoperative assessment and investigation was largely at the discretion of the surgical and anesthetic teams; however, preoperative venous blood samples were sent for all patients for urea and electrolytes, lipid screen, C-reactive protein, magnesium, full blood count, coagulation screen, and serum cTnI, which was measured using the ARCHITECT STAT Troponin I immunoassay (assay range, 0.02-50 ng/mL; sensitivity, ⱕ0.01 ng/mL; Abbott Diagnostics, Abbott Park, Ill). All patients also underwent preoperative ECG performed by a cardiac technician. Preoperative BNP samples were collected and analyzed in a standard fashion. An aliquot of venous blood was obtained from recumbent patients the evening before surgery. This was collected in chilled ethylenediaminetetraacetic acid and aprotinin (Trasylol; Bayer, Leverkusen,
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Germany; 50 U/mL) and immediately centrifuged at 3000 rpm for 10 minutes. The serum was removed from the tube and stored in a freezer at ⫺22°C. The minimum detectable quantity of human BNP was 2 pg/mL. The within-assay and between-assay coefficient of variation were ⬍5%. BNP was batch analyzed in lots of 100 samples at the end of the study period using a direct immunoradiometric assay kit (Shinoria BNP kit) supplied by Shinogi and Co, Ltd (Osaka, Japan). Intraoperative details. Intraoperative details were obtained from the postoperative anesthetic records. Hypotension was recorded if systolic blood pressure remained ⬍90 mm Hg for ⱖ5 minutes. Hypothermia was recorded if temperature was ⬍34.5°C. Aortic cross-clamp times and length of operation were recorded. Blood loss estimates were collected from intraoperative anesthetic records. Postoperative testing. Postoperative investigations were conducted at the discretion of the treating physician or surgeon. In addition, postoperative screening for cardiac events was performed by serial ECGs and cTnI measurement on the morning of the second and fifth postoperative days and when clinical suspicion required it. Tests for patients who were to be discharged before the fifth postoperative day were conducted on the morning of discharge instead of on day 5. Patients were reviewed at an outpatient clinic 30 days postprocedure. All ECGs were interpreted by two cardiologists of consultant or senior registrar grade who were blinded to all other data and patient details. Cardiology comments included the presence of abnormal findings on the preoperative ECG and ECG evidence of myocardial infarction. All patients were initially followed up through an areawide interhospital computer database for recording of mortality figures. If a patient had died, the date and cause of death were noted. If no cause of death was noted, then a death certificate review was performed. Where no recent contact was recorded, the patient’s general practice (GP) was contacted, and in the case of death, date and cause of death were noted and death certificates reviewed if necessary. End points. End points for the study were MACE (nonfatal MI and cardiac death), cardiac death, and allcause mortality. The definition of a nonfatal MI used was that of the Joint European Society of Cardiology/American College of Cardiology Committee requiring a typical rise and gradual fall in cTnI with at least one of ischemic symptoms, development of pathologic Q-waves on the ECG, ECG changes indicative of ischemia (ST segment elevation or depression), or coronary artery intervention. Cardiac death was defined as death secondary to MI, cardiogenic shock, or intractable dysrhythmia and was determined by a review of postoperative data by two cardiologists blinded to preoperative BNP levels. All-cause mortality was death from any cause. Statistical analysis. Statistical analysis was performed using SPSS software (SPSS Inc, Chicago, Ill). Continuous variables and BNP values are reported as median and interquartile ranges (IQR). Continuous variables were com-
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Table I. A, Preoperative risk factors, B-type natruretic peptide (BNP) levels, and cardiac events in elective open abdominal aortic aneurysm (AAA) patients Characteristic Sex Male Female Angina Present Absent Previous MI Present Absent Hypertension Present Absent Hyperlipidemia Present Absent Diabetes Present Absent Current smoker Present Absent Smoked ever Present Absent Cerebrovascular disease Present Absent Congestive heart failure Present Absent Chronic renal failure Present Absent Antiplatelet Present Absent Statin Present Absent -blocker Present Absent Antianginal drug Present Absent Diuretic Present Absent eGFR ⬍60 ⱖ60 Chronic kidney disease 1 2 3 4 5 C-reactive protein ⬍6 ⱖ6
No. (%) (n ⫽ 106)
BNP levela Median (IQR) pg/mL
P
MACE No. (%)
P
88 (83) 18 (17)
42 (26-74) 38.5 (17-99)
.433
13/88 (15) 3/18 (17)
.733
25 (24) 81 (76)
63 (31-154) 35 (17-81)
.007
4/25 (16) 12/81 (15)
23 (22) 83 (78)
70 (31-175) 35 (17-85)
.031
5/23 (22) 11/83 (13)
.332
72 (67) 34 (33)
14 (17-75) 39 (19-100)
.915
14/72 (19) 2/34 (6)
.085
15 (14) 91 (86)
30 (17-82) 40 (19-98)
3/15 (20) 13/91 (13)
.416
9 (8) 97 (92)
40 (18-93) 39 (32-105)
.139
3/9 (33) 13/97 (13)
.134
35 (33) 71 (67)
37 (18-85) 56 (21-98)
.713
5/35 (14) 11/71 (15)
90 (85) 16 (15)
62 (14-212) 40 (19-83)
.093
12/90 (13) 4/16 (25)
.258
22 (21) 84 (79)
47 (21-100) 30 (12-55)
.289
2/22 (9) 14/84 (17)
.515
13 (12) 93 (88)
184.5 (72-392) 35 (17-60)
.002
5/13 (38) 11/86 (12)
.026
8 (8) 98 (92)
39 (17-91) 50 (36-114)
.634
0/8 (0) 16/98 (16)
.604
63 (59) 43 (41)
35 (17-64) 52 (20-99)
.151
11/63 (17) 5/43 (12)
.582
66 (62) 40 (38)
37 (14-85) 43 (22-98)
.444
8/66 (12) 8/40 (20)
.280
43 (41) 63 (59)
34 (14-61) 60 (25-129)
.050
9/43 (21) 7/63 (11)
.180
23 (22) 83 (78)
39 (17-98) 61 (22-85)
.186
3/23 (13) 13/83 (16)
35 (33) 71 (67)
35 (17-73) 44 (21-110)
.213
7/35 (20) 9/71 (13)
.390
42 (40) 64 (60)
35 (17-81) 55 (27-100)
.461
9/42 (21) 7/64 (11)
.294
9 (8) 55 (52) 40 (38) 1 (1) 1 (1)
21 (11-108) 35 (17-82) 55 (26-100) 545 37
.386
1/9 (11) 6/55 (11) 8/40 (20) 1/1 (100) 0/1(0)
.184
62 (58) 44 (42)
35 (15-60) 55 (20-100)
.078
8/62 (13) 8/44 (18)
.121
1.0
1.0
1.0
1.0
eGFR, Estimated glomerular filtration rate; IQR, interquartile range; MACE, major adverse cardiac event; MI, myocardial infarction. a BNP analyses were determined using Mann-Whitney and Kruskal-Wallis for revised cardiac risk index and chronic kidney disease. Event analyses were determined using the Fisher exact test.
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348 Bryce et al
pared using Mann-Whitney U and Kruskal-Wallis analyses. The Fisher exact test was used to analyze the differences between independent categorical data. Receiver-operating characteristic (ROC) curves were plotted, and the area under the curve (AUC) was estimated. Multivariate logistic regression analysis was performed to determine independent factors associated with cardiac complications using factors with P ⬍ .150 on univariate analysis. A P value ⬍.05 was considered significant. RESULTS Patient characteristics and BNP levels. During the study period, 111 patients were admitted for elective open AAA repair and were invited to participate. Two refused consent, and three had elevated preoperative cTnI and were not included, resulting in 95% inclusion. The remaining 106 patients were a median age of 73 years (IQR, 66-77 years). The median preoperative BNP level was 39.5 pg/mL (IQR, 18.8-97.2 pg/mL). Further baseline characteristics are reported in Table I, A. The male-to-female ratio showed a male predominance of 5:1. Most patients (85%) had smoked at some point in their life. One-fifth of patients had experienced a previous MI, with similar numbers with cerebrovascular disease, and 13 patients (12%) suffered from congestive heart failure (CHF). Despite the known pathology of an AAA, only 59% patients were taking an antiplatelet agent and 62% were taking a statin. Median (IQR) BNP levels were significantly higher in those who had suffered a previous MI (70 [31-175] vs 35 [17-85] pg/mL; P ⫽ .031) or angina (63 [31-154] vs 35 [17-81] pg/mL; P ⫽ .007). Levels were also significantly higher in those who had CHF (184.5 [72-392] vs 35 [17-60] pg/mL; P ⫽ .002). Renal failure by chronic kidney disease stage did not show correlation with BNP levels. Two patients had an eGFR ⬍30 mL/min, one of whom had a BNP of 37 pg/mL and an uncomplicated postoperative recovery, and the second patient had a BNP of 545 pg/mL and died of cardiac death. As a further potential confounder, BMI was calculated in all, resulting in a median BMI of 28 kg/m2 (IQR, 24-31) and ranging from 20 to 35 kg/m2 in all patients. Immediate cardiac events and BNP. MACE occurred in 16 patients (15%) ⱕ30 days after their open AAA repair, of whom five died of cardiac death and 11 had a nonfatal MI. Of those with a nonfatal MI, three were of the non-ST elevation type, with three of the remaining eight patients presenting with asymptomatic ST-elevation MIs. MACE was significantly more likely to occur in patients with preoperative CHF (P ⫽ .026; Table I, A) and in those with preoperative hypertension (Table I, B), diabetes mellitus, or increasing grades of CKD, although this was not statistically significant. The median (IQR) preoperative BNP concentration was significantly higher in patients who had MACE than in those who did not (206 [118-454] vs 35 [17-61] pg/mL; P ⫽ .001; Fig 1, A) and was significantly higher in patients
Table I. B, Operative risk factors and cardiac events in elective open abdominal aortic aneurysm (AAA) patientsa Variable Hypotension Present Absent Hypothermia Present Absent Blood loss ⱕ750 mL ⬎750 mL Cross-clamp time ⱕ60 minutes ⬎60 minutes Operating times ⱕ3 hours 3 hours
No. (%) (n ⫽ 106)
MACE No. (%)
P
48 (45) 58 (55)
7/48 (15) 9/58 (16)
4 (4) 102 (96)
1/4 (25) 15/102 (15)
.486
39 (37) 67 (63)
6/39 (15) 10/67 (15)
.512
71 (67) 35 (33)
9/71 (13) 7/35 (20)
.430
58 (55) 48 (45)
4/58 (7) 12/48 (25)
.098
1.0
MACE, Major adverse cardiac event. a Event analyses were determined using the Fisher exact test.
with cardiac death alone than without (496 [280-881] vs 38 [18-84] pg/mL; P ⫽ .043; Fig 1, B). In a logistic regression model adjusting for hypertension, CHF, diabetes mellitus, and operating time (all P ⬍ .150 on univariate analysis), BNP remained a highly significant predictor of MACE (P ⬍ .001). The odds ratio (OR) for eLogBNP in this multivariate analysis was very large, with a wide 95% confidence interval (155.0 [6.463717.62]; P ⫽ .002), partly as a function of size of the ratio but also due to the small size of the data set. Logistic regression adjusting for CHF and operating time (P ⬍ .100 on univariate analysis) alone still revealed a large OR with again a wide 95% CI (81.94 [7.07-949.16]; P ⬍ .001). All-cause mortality and long-term outcome. Of the 106 patients who underwent elective open AAA repair, 97 survived the 30-day postoperative period. All patients were followed up to a minimum of 3 years after AAA repair. In five patients, there had been no recent contact with the hospital or GP at the 3-year follow-up. The last point of contact in these individual patients was at day 481, 780, 847, and 996, and 1052. Median BNP in this group (n ⫽ 5) was 58 pg/mL (IQR, 16-139 pg/mL). The 3-year all-cause mortality rate was 21% (n ⫽ 22), with 79 patients confirmed alive at 3 years. The cause of death in the 13 deaths that occurred between 30 days and 3 years was of cardiac origin in three patients. Other causes included respiratory disease (n ⫽ 3), cerebrovascular disease (n ⫽ 2), renal failure (n ⫽ 2), and cancer of different primary origins (n ⫽ 3). The survival rates at 6 months and at 1, 2, and 3 years were 89.6%, 89.6%, 83%, and 79.2%, respectively. Univariate analysis of patient characteristics at all stages of follow-up revealed that the presence of CHF was a significant predictor of outcome, with death more likely (late mortality, P ⬍ .001; 3-year mortality, P ⬍ .001). The presence of worsening renal function in relation to CKD stage also made death more likely at 3 years (P ⫽ .031). The
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Bryce et al 349
A
N=
90
16
B
N=
101
5
Fig 1. A, B-type natruretic peptide (BNP) concentration and major adverse cardiac events (MACE). B, BNP concentration and cardiac death. The horizontal line in the middle of each box indicates the median; the top and bottom borders of the box mark the 75th and 25th percentiles, respectively, and the whiskers mark the 90th and 10th percentiles. The dots represent outliers. The asterisks/stars represent extreme outliers where the level marked is less than three times the height of the boxes. N, Number of patients.
presence of a previous MI made 3-year mortality more likely but not significantly so (P ⫽ .063). Mortality and BNP. The median (IQR) preoperative BNP in those who survived ⬎30 days was significantly higher in those who died in the first year (late mortality) than in those who survived (201 [97-496] vs 35 [17-73] pg/mL; P ⬍ .001; Table II). The median (IQR) preoper-
ative BNP was significantly higher in those who died during the 3-year follow-up than in those who survived (98.5 [58-285] vs 32 [17-71.5] pg/mL; P ⬍ .001). The median (IQR) BNP was significantly higher in those who died of cardiac death than in those who died of another cause during the 3-year follow-up (342 [71-533] vs 65.5 [37134] pg/mL; P ⫽ .028). Although death was attributed to
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350 Bryce et al
Table II. Long-term outcomes by median B-type natruretic peptide (BNP) levela Mortality Peri-op all-cause Yes No Late (30 days-1 year) Yes No 1 year Yes No 2 years Yes No 3 years Yes No
No. (%) (n ⫽ 106)
BNP Median (IQR) pg/mL
P
9 (8.4) 97 (91.6)
100 (84-521) 35 (17-81)
.028
11 (10.4) 95 (89.6)
201 (97-496) 35 (17-73)
⬍.001
11 (10.4) 95 (89.6)
201 (97-496) 35 (17-73)
⬍.001
18 (17) 88 (83)
98.5 (42.25-291.25) 34.5 (17-77.5)
22 (20.%) 84 (79.2%)
98.5 (58-285) 32 (17-71.5)
.002 ⬍.001
IQR, Interquartile range; MACE, major adverse cardiac event. a Event analyses were determined using the Fisher exact test.
a cardiac cause in only three patients between 30 days and 3 years, those that died of cardiac death had a significantly higher median (IQR) preoperative BNP level than those who did not die (112 [46-435] vs 35 [17-75] pg/mL; P ⫽ .049). ROC curve analyses and BNP. To find the BNP concentration that would best predict MACE, an ROC curve analysis was performed (Fig 2). This revealed a cutoff value of 99.5 pg/mL and an AUC of 0.927. With this cutoff value, sensitivity was 88% and specificity 89%. The positive predictive value (PPV) was 61% and the negative predictive value (NPV) 98%. ROC analysis using BNP concentration to predict cardiac death revealed a cutoff value of 448 pg/mL with an AUC of 0.963. Sensitivity was 80% with a specificity of 100%. The PPV was 100% and NPV 99%. Results for ROC analysis in mortality outcomes are detailed in Table III. Best-performing BNP for prediction of MACE. BNP at a threshold level of 99.5 pg/mL, as identified from ROC curve analyses, predicted outcome independently of almost all preoperative risk factors or intraoperative factors. No MACE occurred in the presence of a BNP ⬍99.5 pg/mL with both a CRP ⬍6 and eGFR ⱖ60 mL/min. In the presence of a previous MI, diabetes mellitus, or current use of a diuretic therapy, MACE was more likely with higher BNP levels; however, this was not statistically significant (Table IV). Postoperative elevations in cTnI and long-term outcome. Postoperative elevations of cTnI were observed in 24 patients (23%), of which eight (33%) had neither chest pain nor ECG changes. The median preoperative BNP concentration was significantly higher in those that had postoperative elevations of serum cTnI compared with those that did not (median [IQR] BNP 75 [34-200] vs 35 [17-75] pg/mL; P ⫽ .002). All-cause mortality rates were
Fig 2. Receiver-operating characteristic (ROC) curve for B-type natruretic peptide concentration and major adverse cardiac events.
higher in those with immediate postoperative elevations in cTnI, regardless of clinical outcome or defined event, at all studied time intervals (1 year, 4 of 26 [15%] vs 7 of 80 [9%], P ⫽ .066; 2 years, 6 of 26 [23%] vs 12 of 80 [15%], P ⫽ .076; 3 years, 7 of 26 [27%] vs 15 of 80 [19%], P ⫽ .100), although this was not statistically significant. Survival analysis. The mean survival of patients with a BNP ⬎99.5 pg/mL was 1291 days (95% CI, 882-1701 days) compared with 1916 days (95% CI, 1774-2057 days) when BNP was ⬍99.5 pg/mL (P ⬍ .001; Fig 3). During the first 6 months, the rate of postoperative death in those with a BNP ⬎99.5 pg/mL was 8.6 times greater than in those with a BNP below this threshold (32% vs 3.7%; P ⬍ .001). At the minimum point of follow-up (3 postoperative years), the rate of death was 3.4 times greater in those with a BNP ⬎99.5 pg/mL (48% vs 14%; P ⬍ .001). In those who survived beyond the first 6 postoperative months, there was no significant difference in survival thereafter between those with a BNP ⬎99.5 pg/mL (1923 [95% CI, 1623-2334] days) and those with a BNP ⬍99.5 pg/mL (1988 [95% CI, 1866-2109] days; P ⫽ .442). DISCUSSION The prospective data from this elective open AAA cohort demonstrate that preoperative BNP levels predict both nonfatal MI and cardiac death in the 30-day postoperative period. A cutoff point of 99.5 pg/mL, similar to that seen in the diagnosis of heart failure,23 results in a sevenfold increased risk of cardiac events. With a sensitivity of 88% and specificity of 89%, preoperative BNP appears to outperform currently available noninvasive testing and su-
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Table III. Results of receiver-operating characteristic (ROC) curve analysis for B-type natruretic peptide according to outcomea AUC (95% CI)
Cutoff
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
P
0.927 (0.850-1.000) 0.963 (0.896-1.000) 0.860 (0.757-0.962)
99.5 448 93.0
88 80 78
89 100 79
61 100 30
98 99 99
⬍.001 ⬍.001 ⬍.001
0.885 (0.800-0.970) 0.733 (0.597-0.896) 0.761 (0.645-0.878)
93.0 68.5 60.5
81 61 68
82 74 73
35 33 41
97 90 90
⬍.001 .002 ⬍.001
Outcome MACE Cardiac death Perioperative death Mortality Late (30 days-1 year) At 2 years At 3 years
AUC, Area under the curve; CI, confidence interval; MACE, major adverse cardiac events; NPV, negative predictive value; PPV, positive predictive value. a Analyses were performed using Mann-Whitney U test.
Table IV. Major adverse cardiac events (MACE) by a B-type natruretic peptide (BNP) cutoff of 99.5 pg/mL and by risk factorsa Characteristic Previous MI Present Absent Diabetes Present Absent Diuretic Present Absent C-reactive protein ⬍6 ⱖ6 eGFR ⱖ60 ⬍60
BNP Level (pg/mL)
MACE No. (%)
⬍99.5 ⱖ99.5 ⬍99.5 ⱖ99.5
1/14 (7) 4/9 (44) 1/68 (1) 10/15 (67)
⬍99.5 ⱖ99.5 ⬍99.5 ⱖ99.5
1/6 (17) 2/3 (67) 1/76 (1) 12/21 (57)
⬍99.5 ⱖ99.5 ⬍99.5 ⱖ99.5
1/18 (6) 2/5 (40) 1/64 (2) 12/19 (63)
⬍99.5 ⱖ99.5 ⬍99.5 ⱖ99.5
0/49 (0) 8/16 (50) 2/33 (6) 6/8 (75)
⬍99.5 ⱖ99.5 ⬍99.5 ⱖ99.5
0/51 (0) 7/13 (54) 2/31 (6) 7/11 (64)
P
.056 ⬍.001 .226 ⬍.001 .107 ⬍.001 ⬍.001 .002 ⬍.001 .004
eGFR, Estimated glomerular filtration rate; MI, myocardial infarction. a Analyses were performed using the Fisher exact test.
persedes the current gold standard of dipyridamole stress echocardiography (sensitivity, ⬃74%; specificity, ⬃86%) or dobutamine stress echocardiography (sensitivity, ⬃85%; specificity, ⬃70%) as the objective cardiac risk stratification tool of choice.24 By using an upper limit of 99.5 pg/mL for BNP combined with a CRP ⬍6 mg/L and eGFR ⱖ60 mL/min, it is possible to identify a group of patients who are likely to have an uncomplicated perioperative period given that in these patients, no events were identified. Conversely, identifying patients at high risk of cardiac death can be done by BNP level alone, where this is found to exceed 448 pg/mL,
with an AUC of 0.963 and combined sensitivity of 80% and specificity of 100%. Given the 100% PPV for cardiac death with a BNP over this cutoff, delaying or canceling a prophylactic procedure might be preferable to the sizable risk of cardiac death. A single preoperative serum BNP level predicts not only perioperative outcome but also short-, intermediate-, and long-term all-cause mortality. At all follow-up points, BNP significantly predicted mortality. ROC curve analysis revealed lower cutoff values of serum BNP for predicting death over time. In addition, BNP became a less sensitive and specific predictor of death over time. The lowering cutoff level over time may be indicative that, at lower levels, BNP can predict long-term mortality in the general population, as previously demonstrated in Glasgow, where random population sampling in 1640 individuals revealed a significant difference in 4-year mortality of 14.9% for BNP ⱖ17.9 pg/mL vs 3.1% for BNP ⬍17.9 pg/mL (P ⬍ .001).6 Numerous studies have demonstrated that postoperative elevations in cTnI, whether associated with a defined cardiac event or asymptomatic and without evidence of a cardiac event, are a poor prognostic marker and are associated with increased short-term, intermediate-term, and long-term mortality.25-30 This study demonstrates that BNP has the ability to select patients who had postoperative elevations of cTnI. In patients with a very high serum BNP and a large AAA who are deemed not suitable for EVAR, the decision to proceed with elective open surgery would be difficult, and medical optimization or coronary revascularization would be the only remaining options. Preoperative -blockade has been widely considered, with reports differing in their conclusions. In this study, a greater proportion of events occurred in those on -blockade therapy. The reason for this is unclear but may be due to collation of data, because although the use of preoperative -blockade was noted, no consideration was given to the type or timing of -blockade. There is also evidence that aggressive medical management, in a similar manner to treating heart failure, can reduce a BNP level,31,32 but whether this would then change perioperative outcome is unknown. To date, no evidence has looked at the effect of preoperative lower-
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Patients at risk: 99.5 pg/ml 24
79 16
72 14
66 12
35 8
15 4
Fig 3. Kaplan-Meier curve of survival according to B-type natruretic peptide (BNP) level with a cutoff of 99.5 pg/mL. Censoring demonstrates loss of patient contact where relevant. The standard error for ⬎99.5 pg/mL exceeds 10% at 1032 days. The standard error for ⬍99.5 pg/mL does not exceed 10%.
ing of BNP on perioperative outcome in the elective AAA population. In those opting for operative repair, recent research has suggested that epidural anesthesia in addition to general anesthesia can reduce BNP levels and, potentially, cardiac risk.33 The present study has some limitations. The small sample size often made statistical analysis difficult, with only the most striking differences reaching statistical significance. However, the inclusion of consecutive patients makes this a representative sample of the patient population presenting for AAA repair in the West of Scotland and make the results relevant to current clinical practice. The incomplete 3-year follow-up data may affect the results; however, this was taken into account through censoring on KaplanMeier analyses, and after correction for this, a significant difference in survival persisted. The applicability of these results to populations outside Glasgow is unknown. CONCLUSIONS This report describes a prospective cohort study suitably powered for univariate analysis and that takes into account confounding biochemical issues, where BNP has been shown to hold important prognostic information. The BNP assessment outperforms all previous cardiac risk stratification tools and is both simple and objective. The use of this blood test in an outpatient clinic could prove vital in helping make the correct decision regarding the need for elective open AAA repair. Few studies have described the relation between long-term outcomes and BNP levels in
noncardiac surgery. The present study, according to the current published literature, is the first appropriately powered study to report on survival outcome after elective open AAA repair alone. The results highlight the importance of BNP in the perioperative period and reveal its value in predicting long-term survival. Its value as a basis on which to select patients who would be suitable for repair of their small asymptomatic AAA remains unknown; however, there is sufficient evidence to suggest that this question should now be addressed in a large prospective trial. AUTHOR CONTRIBUTIONS Conception and design: GB, DB, DK Analysis and interpretation: GB, DB, CD, JM Data collection: GB, CP, SG Writing the article: GB, DB, CD Critical revision of the article: GB, DB, CD, JM Final approval of the article: GB, CP, SG, DB, CD, JM, DK Statistical analysis: GB, JM Obtained funding: GB Overall responsibility: GB REFERENCES 1. Ernst CB. Abdominal aortic aneurysm. N Engl J Med 1993;328:116772. 2. Powell JT, Brady AR, Brown LC, Forbes JF, Fowkes FGR, Greenhalgh RM, et al. Mortality results for randomised controlled trial of early elective surgery or ultrasonographic surveillance for small abdominal aortic aneurysms. The UK Small Aneurysm Trial Participants. Lancet 1998;352:1649-55.
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