The data summarized in this meta-analysis showed that elevated preoperative NP levels are associated with all-cause mortality ≥6 months after cardiac and noncardiac surgery and that preoperative NP values below the cutoff chosen in the individual studies were highly predictive of survival. Similarly, preoperative NP concentrations were associated with mortality at ≤90 days after noncardiac surgery.
Ventricular myocardium responds to stretching stress and to ischemia by the secretion of B-type NP.48,49 Both BNP and N-terminal prohormone BNP (NT-proBNP), a byproduct of BNP cleavage activation, were demonstrated to be useful biochemical markers for chronic systolic50 and diastolic51 heart failure, as well as for congestive systolic and diastolic heart failure.52 In addition, elevated B-type NP concentrations predict adverse cardiovascular events and death in patients with stable4,53,54 and unstable5,55 coronary artery disease, chronic6,56 and acute6–8 heart failure, and in patients at risk for cardiac events.9 The evidence summarized by this systematic review and meta-analysis broadens the clinical spectrum in which elevated NP levels are predictors of mortality by adding patients undergoing cardiac surgery.
Our meta-analysis showed a consistent association between elevated preoperative NP levels as defined by the individual cutoff used in the different studies, and mortality ≥6 months after cardiac surgery. According to the Bradford Hill criteria,57 evidence of a biological gradient or concentration-response relationship enforces the association between biomarker and outcome. However, no cardiac surgery studies that have reported on an association between NP and mortality used NP concentrations as continuous variables in logistic regression. Thus, whether there is a potential concentration-response of NP and mortality after cardiac surgery is unknown. Sodeck et al.32 demonstrated a concentration-dependent response for the association between preoperative NT-proBNP and postoperative outcome after repair of type A aortic dissection. These patients, however, represent a focused population of cardiac surgery patients and the observations cannot necessarily be extrapolated to other cardiac surgery patient populations.
Our analysis preserved the 2 components, i.e., sensitivity and specificity, of the NP diagnostic tests rather than computing only a single measure of association (dOR). We also estimated the PPV and NPV, a measure likely more clinically meaningful than the dOR, of preoperative NP concentrations for mortality. Preoperative NP had a low PPV and a high NPV for mortality ≥6 months after cardiac surgery. Thus, these results suggest that an elevated preoperative NP concentration may not accurately identify mortality with a high degree of certainty. In contrast, a nonelevated preoperative NP level is highly indicative of survival ≥6 months after cardiac surgery. This predictive pattern and its dimension parallel the prediction of NT-proNP in acute heart failure, where for short-term mortality a PPV of 19% and an NPV of 96% were reported.8 The low PPV and high NPV reflect the low number of true positives and the high number of true negatives, which is again mirrored by a higher specificity (0.75 [95% CI: 0.67–0.81]) than sensitivity (0.58 [95% CI: 0.43–0.72]). The validity of these results is enhanced by the fact that the between-study variance for specificity was lower than for sensitivity, indicating more homogeneous results in specificity than in sensitivity among the included studies. A possible explanation for this is that most studies calibrated their cutoff values for specificity, aiming at high specificity as for a rule-out test.
In addition to expanding the clinical settings in which NPs are predictive of mortality for patients undergoing cardiac surgery, our data confirm the results of recent meta-analyses of the diagnostic utility of preoperative NP levels for predicting mortality for patients undergoing noncardiac surgery.11,13 The estimates presented of the effect size for the association between preoperative NP concentration and mortality ≥6 months was similar to a previous meta-analysis addressing long-term all-cause mortality after noncardiac surgery.13 The association between preoperative NP and postoperative outcome after noncardiac surgery is supported by a concentration-effect response.37 The evidence of a concentration-effect response was reported for only short-term outcome after noncardiac surgery.
Because of a different statistical approach compared with previous meta-analyses on preoperative NP and mortality, our data maintained the 2 components of diagnostic tests, i.e., sensitivity and specificity, and thus allowed recognition that, in parallel to the cardiac surgery setting, preoperative NP had a low PPV and a high NPV mortality ≥6 months after noncardiac surgery. Thus, similar to our findings in cardiac surgery patients, the ability of elevated preoperative NPs to predict death after noncardiac surgery was limited, whereas nonelevated preoperative NPs were highly indicative of survival after noncardiac surgery.
Preoperative NP had a low PPV and a high NPV for ≤90-day mortality after noncardiac surgery. Thus, the ability of elevated preoperative NP concentrations to predict death after noncardiac surgery is limited, whereas nonelevated preoperative NP concentrations are highly indicative of an event-free course.
The sensitivity of NP tended to be higher than its specificity for ≤90-day mortality in noncardiac surgery patients. Moreover, specificity distribution among studies was larger than sensitivity in the studies addressing ≤90-day outcome. A possible interpretation is that most studies addressing ≤90-day outcome after noncardiac surgery calibrated their cutoff values in a way that resulted in high sensitivity, with the goal of using NP concentrations as a screening tool for patients in whom modification in clinical management was more immediately conceivable as the patients remained hospitalized.
Overall, as assessed by the heterogeneity of dOR, the noncardiac surgery studies evaluating preoperative NP levels and ≤90-day mortality strongly tended toward between-study variability (heterogeneity) without reaching statistical significance. Frequent sources of between-study variability in diagnostic or prognostic accuracy parameters include different threshold values used to determine individual study sensitivities and specificities. Caution in the appraisal of the pooled results is thus warranted, even when considering calculation from a random-effects model, because between-study variability may arise from differences in study populations as reflected by marked differences in mortality (ranging from 1% to >20%) and/or from the use of different assays, and the use of different NPs (NTproBNP and BNP).
Several limitations of our study require comment. First, even after contacting the authors for data on all-cause mortality, 2 cardiac surgery and 2 noncardiac surgery studies had to be excluded from the meta-analysis because not all data necessary to construct a 2 × 2 contingency table could be obtained. In this context, it is worth noting that one of the noncardiac surgery studies that was excluded did not show a significant difference in NP levels between survivors and deceased patients.39 However, this study suffered from a limited sample size (n = 40); as such, we do not expect these data to undermine the significant association between preoperative NP and mortality after noncardiac surgery.
A second limitation of our study is the reduced number of studies available despite using a sensitive search strategy without language restriction. Third, it should be noted that the presented dORs reflect unadjusted associations between preoperative NP and all-cause mortality after surgery. We opted against pooling the adjusted association measures as the different studies adjusted by different variables. However, the results of the multivariable analyses performed within the individual included studies support the independence of the association between preoperative NP and mortality at ≥6 months both in cardiac and noncardiac surgery. Furthermore, for the noncardiac surgery setting, Choi et al.37 presented data on the incremental effect on risk stratification by the addition of NT-proBNP to the Revised Cardiac Risk Index,1 a widely used risk stratification tool.
Fifth, in the meta-analysis, we pooled studies independent of the type of NP that was measured, i.e. if BNP or NT-proBNP was measured. In addition, individual studies used different assays that target different epitopes with different levels of precision.58–60 We did not find evidence for between-study variability; however, we cannot exclude the possibility of a different prognostic value of 2 markers or between assays.
Finally, the individual studies used different threshold values. Given that this was not an individual patients' data meta-analysis, it was not possible to calculate a cutoff value across studies and we listed the cutoff values used within the different studies as a source of information on which concentration can be considered nonelevated preoperatively.
Preoperative NP concentrations were associated with ≤90-day and ≥6-month mortality after both cardiac and noncardiac surgery. In both surgical settings and for both follow-up durations, NP concentrations had high NPVs suggesting that nonelevated preoperative NP concentrations were highly predictive of survival.
1. Lee TH, Marcantonio ER, Mangione CM, Thomas EJ, Polanczyk CA, Cook EF, Sugarbaker DJ, Donaldson MC, Poss R, Ho KK, Ludwig LE, Pedan A, Goldman L. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999;100:1043–9
2. Roques F, Nashef SA, Michel P, Gauducheau E, de Vincentiis C, Baudet E, Cortina J, David M, Faichney A, Gabrielle F, Gams E, Harjula A, Jones MT, Pintor PP, Salamon R, Thulin L. Risk factors and outcome in European cardiac surgery: analysis of the EuroSCORE multinational database of 19030 patients. Eur J Cardiothorac Surg 1999;15:816–22
3. Ford MK, Beattie WS, Wijeysundera DN. Systematic review: prediction of perioperative cardiac complications and mortality by the revised cardiac risk index. Ann Intern Med 2010;152:26–35
4. Kragelund C, Gronning B, Kober L, Hildebrandt P, Steffensen R. N-terminal pro-B-type natriuretic peptide and long-term mortality in stable coronary heart disease. N Engl J Med 2005;352:666–75
5. de Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, McCabe CH, Hall C, Cannon CP, Braunwald E. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001;345:1014–21
6. Doust JA, Pietrzak E, Dobson A, Glasziou P. How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review. BMJ 2005; 330:625
7. Fonarow GC, Peacock WF, Phillips CO, Givertz MM, Lopatin M. Admission B-type natriuretic peptide levels and in-hospital mortality in acute decompensated heart failure. J Am Coll Cardiol 2007;49:1943–50
8. Januzzi JL, van Kimmenade R, Lainchbury J, Bayes-Genis A, Ordonez-Llanos J, Santalo-Bel M, Pinto YM, Richards M. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients—the International Collaborative of NT-proBNP Study. Eur Heart J 2006;27:330–7
9. Bhalla MA, Chiang A, Epshteyn VA, Kazanegra R, Bhalla V, Clopton P, Krishnaswamy P, Morrison LK, Chiu A, Gardetto N, Mudaliar S, Edelman SV, Henry RR, Maisel AS. Prognostic role of B-type natriuretic peptide levels in patients with type 2 diabetes mellitus. J Am Coll Cardiol 2004;44:1047–52
10. Hlatky MA, Greenland P, Arnett DK, Ballantyne CM, Criqui MH, Elkind MS, Go AS, Harrell FE Jr, Hong Y, Howard BV, Howard VJ, Hsue PY, Kramer CM, McConnell JP, Normand SL, O'Donnell CJ, Smith SC Jr, Wilson PW. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation 2009;119:2408–16
11. Karthikeyan G, Moncur RA, Levine O, Heels-Ansdell D, Chan MT, Alonso-Coello P, Yusuf S, Sessler D, Villar JC, Berwanger O, McQueen M, Mathew A, Hill S, Gibson S, Berry C, Yeh HM, Devereaux PJ. Is a pre-operative brain natriuretic peptide or N-terminal pro-B-type natriuretic peptide measurement an independent predictor of adverse cardiovascular outcomes within 30 days of noncardiac surgery? A systematic review and meta-analysis of observational studies. J Am Coll Cardiol 2009;54:1599–606
12. Rodseth RN, Padayachee L, Biccard BM. A meta-analysis of the utility of pre-operative brain natriuretic peptide in predicting early and intermediate-term mortality and major adverse cardiac events in vascular surgical patients. Anaesthesia 2008;63:1226–33
13. Ryding AD, Kumar S, Worthington AM, Burgess D. Prognostic value of brain natriuretic peptide in noncardiac surgery: a meta-analysis. Anesthesiology 2009;111:311–9
14. Deeks JJ, Altman DG. Diagnostic tests 4: likelihood ratios. BMJ 2004;329:168–9
15. Wilczynski NL, Haynes RB. Developing optimal search strategies for detecting clinically sound prognostic studies in MEDLINE: an analytic survey. BMC Med 2004;2:23
16. Wilczynski NL, Haynes RB. Optimal search strategies for detecting clinically sound prognostic studies in EMBASE: an analytic survey. J Am Med Inform Assoc 2005;12:481–5
17. Haynes RB, Wilczynski NL. Optimal search strategies for retrieving scientifically strong studies of diagnosis from MEDLINE: analytical survey. BMJ 2004;328:1040
18. Wilczynski NL, Haynes RB. EMBASE search strategies for identifying methodologically sound diagnostic studies for use by clinicians and researchers. BMC Med 2005;3:7
19. Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol 2003;3:25
20. Arends LR, Hamza TH, van Houwelingen JC, Heijenbrok-Kal MH, Hunink MG, Stijnen T. Bivariate random effects meta-analysis of ROC curves. Med Decis Making 2008;28:621–38
21. Chu H, Cole SR. Bivariate meta-analysis of sensitivity and specificity with sparse data: a generalized linear mixed model approach. J Clin Epidemiol 2006;59:1331–2
22. Hamza TH, van Houwelingen HC, Heijenbrok-Kal MH, Stijnen T. Associating explanatory variables with summary receiver operating characteristic curves in diagnostic meta-analysis. J Clin Epidemiol 2009;62:1284–91
23. Reitsma JB, Glas AS, Rutjes AW, Scholten RJ, Bossuyt PM, Zwinderman AH. Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews. J Clin Epidemiol 2005;58:982–90
24. Van Houwelingen HC, Zwinderman KH, Stijnen T. A bivariate approach to meta-analysis. Stat Med 1993;12:2273–84
25. Berendes E, Schmidt C, Van Aken H, Hartlage MG, Rothenburger M, Wirtz S, Scheld HH, Brodner G, Walter M. A-type and B-type natriuretic peptides in cardiac surgical procedures. Anesth Analg 2004;98:11–9
26. Bergler-Klein J, Klaar U, Heger M, Rosenhek R, Mundigler G, Gabriel H, Binder T, Pacher R, Maurer G, Baumgartner H. Natriuretic peptides predict symptom-free survival and postoperative outcome in severe aortic stenosis. Circulation 2004;109:2302–8
27. Elíasdóttir SB, Klemenzson G, Torfason B, Valsson F. Brain natriuretic peptide is a good predictor for outcome in cardiac surgery. Acta Anaesthesiol Scand 2008;52:182–7
28. Fox AA, Shernan SK, Collard CD, Liu KY, Aranki SF, DeSantis SM, Jarolim P, Body SC. Preoperative B-type natriuretic peptide is an independent predictor of ventricular dysfunction and mortality after primary coronary artery bypass grafting. J Thorac Cardiovasc Surg 2008;136:452–61
29. Hutfless R, Kazanegra R, Madani M, Bhalla MA, Tulua-Tata A, Chen A, Clopton P, James C, Chiu A, Maisel AS. Utility of B-type natriuretic peptide in predicting postoperative complications and outcomes in patients undergoing heart surgery. J Am Coll Cardiol 2004;43:1873–9
30. Pedrazzini GB, Masson S, Latini R, Klersy C, Rossi MG, Pasotti E, Faletra FF, Siclari F, Minervini F, Moccetti T, Auricchio A. Comparison of brain natriuretic peptide plasma levels versus logistic EuroSCORE in predicting in-hospital and late postoperative mortality in patients undergoing aortic valve replacement for symptomatic aortic stenosis. Am J Cardiol 2008;102:749–54
31. Provenchère S, Berroeta C, Reynaud C, Baron G, Poirier I, Desmonts JM, Iung B, Dehoux M, Philip I, Bénessiano J. Plasma brain natriuretic peptide and cardiac troponin I concentrations after adult cardiac surgery: association with postoperative cardiac dysfunction and 1-year mortality. Crit Care Med 2006;34:995–1000
32. Sodeck G, Domanovits H, Schillinger M, Janata K, Thalmann M, Ehrlich MP, Endler G, Laggner A. Pre-operative N-terminal pro-brain natriuretic peptide predicts outcome in type A aortic dissection. J Am Coll Cardiol 2008;51:1092–7
33. Suntharalingam J, Goldsmith K, Toshner M, Doughty N, Sheares KK, Hughes R, Jenkins D, Pepke-Zaba J. Role of NT-proBNP and 6MWD in chronic thromboembolic pulmonary hypertension. Respir Med 2007;101:2254–62
34. Suttner S, Boldt J, Lang K, Rohm KD, Piper SN, Mayer J. Association of N-terminal pro-brain natriuretic peptide and cardiac troponin T with in-hospital cardiac events in elderly patients undergoing coronary artery surgery. Eur J Anaesthesiol 2008;25:834–41
35. Weber M, Hausen M, Arnold R, Nef H, Moellman H, Berkowitsch A, Elsaesser A, Brandt R, Mitrovic V, Hamm C. Prognostic value of N-terminal pro-B-type natriuretic peptide for conservatively and surgically treated patients with aortic valve stenosis. Heart 2006;92:1639–44
36. Bolliger D, Seeberger MD, Lurati Buse GA, Christen P, Rupinski B, Gurke L, Filipovic M. A preliminary report on the prognostic significance of preoperative brain natriuretic peptide and postoperative cardiac troponin in patients undergoing major vascular surgery. Anesth Analg 2009;108:1069–75
37. Choi JH, Cho DK, Song YB, Hahn JY, Choi S, Gwon HC, Kim DK, Lee SH, OH JK, Jeon ES. Preoperative NT-proBNP and CRP predict perioperative major cardiovascular events in noncardiac surgery. Heart 2010;96:56–62
38. Cuthbertson BH, Amiri AR, Croal BL, Rajagopalan S, Brittenden J, Hillis GS. Utility of B-type natriuretic peptide in predicting medium-term mortality in patients undergoing major non-cardiac surgery. Am J Cardiol 2007;100:1310–3
39. Cuthbertson BH, Card G, Croal BL, McNeilly J, Hillis GS. The utility of B-type natriuretic peptide in predicting postoperative cardiac events and mortality in patients undergoing major emergency non-cardiac surgery. Anaesthesia 2007;62:875–81
40. Dernellis J, Panaretou M. Assessment of cardiac risk before non-cardiac surgery: brain natriuretic peptide in 1590 patients. Heart 2006;92:1645–50
41. Feringa HH, Schouten O, Dunkelgrun M, Bax JJ, Boersma E, Elhendy A, de Jonge R, Karagiannis SE, Vidakovic R, Poldermans D. Plasma N-terminal pro-B-type natriuretic peptide as long-term prognostic marker after major vascular surgery. Heart 2007;93:226–31
42. Gibson SC, Payne CJ, Byrne DS, Berry C, Dargie HJ, Kingsmore DB. B-type natriuretic peptide predicts cardiac morbidity and mortality after major surgery. Br J Surg 2007;94:903–9
43. Goei D, Hoeks SE, Boersma E, Winkel TA, Dunkelgrun M, Flu WJ, Schouten O, Bax JJ, Poldermans D. Incremental value of high-sensitivity C-reactive protein and N-terminal pro-B-type natriuretic peptide for the prediction of postoperative cardiac events in noncardiac vascular surgery patients. Coron Artery Dis 2009;20:219–24
44. Leibowitz D, Planer D, Rott D, Elitzur Y, Chajek-Shaul T, Weiss AT. Brain natriuretic peptide levels predict perioperative events in cardiac patients undergoing noncardiac surgery: a prospective study. Cardiology 2008;110:266–70
45. Mahla E, Baumann A, Rehak P, Watzinger N, Vicenzi MN, Maier R, Tiesenhausen K, Metzler H, Toller W. N-terminal pro-brain natriuretic peptide identifies patients at high risk for adverse cardiac outcome after vascular surgery. Anesthesiology 2007;106:1088–95
46. Oscarsson A, Fredrikson M, Sorliden M, Anskar S, Gupta A, Swahn E, Eintrei C. Predictors of cardiac events in high-risk patients undergoing emergency surgery. Acta Anaesthesiol Scand 2009;53:986–94
47. Riemersma M, Dijkstra PU, van Veldhuisen DJ, Muskiet FA, van den Dungen JA, Geertzen JH. Mortality and preoperative cardiac function in vascular amputees: an N-terminal pro-brain natriuretic peptide (NT-proBNP) pilot study. Clin Rehabil 2008;22:56–9
48. Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med 1998;339:321–8
49. Ramos LW, Murad N, Goto E, Antonio EL, Silva JA Jr, Tucci PF, Carvalho AC. Ischemia/reperfusion is an independent trigger for increasing myocardial content of mRNA B-type natriuretic peptide. Heart Vessels 2009;24:454–9
50. Moertl D, Berger R, Struck J, Gleiss A, Hammer A, Morgenthaler NG, Bergmann A, Huelsmann M, Pacher R. Comparison of midregional pro-atrial and B-type natriuretic peptides in chronic heart failure: influencing factors, detection of left ventricular systolic dysfunction, and prediction of death. J Am Coll Cardiol 2009;53:1783–90
51. Lubien E, DeMaria A, Krishnaswamy P, Clopton P, Koon J, Kazanegra R, Gardetto N, Wanner E, Maisel AS. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation 2002;105:595–601
52. Maisel A, Hollander JE, Guss D, McCullough P, Nowak R, Green G, Saltzberg M, Ellison SR, Bhalla MA, Bhalla V, Clopton P, Jesse R. Primary results of the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT): a multicenter study of B-type natriuretic peptide levels, emergency department decision making, and outcomes in patients presenting with shortness of breath. J Am Coll Cardiol 2004;44:1328–33
53. Richards M, Nicholls MG, Espiner EA, Lainchbury JG, Troughton RW, Elliott J, Frampton CM, Crozier IG, Yandle TG, Doughty R, MacMahon S, Sharpe N. Comparison of B-type natriuretic peptides for assessment of cardiac function and prognosis in stable ischemic heart disease. J Am Coll Cardiol 2006;47:52–60
54. Schnabel R, Lubos E, Rupprecht HJ, Espinola-Klein C, Bickel C, Lackner KJ, Cambien F, Tiret L, Munzel T, Blankenberg S. B-type natriuretic peptide and the risk of cardiovascular events and death in patients with stable angina: results from the AtheroGene study. J Am Coll Cardiol 2006;47:552–8
55. Tapanainen JM, Lindgren KS, Makikallio TH, Vuolteenaho O, Leppaluoto J, Huikuri HV. Natriuretic peptides as predictors of non-sudden and sudden cardiac death after acute myocardial infarction in the beta-blocking era. J Am Coll Cardiol 2004;43:757–63
56. Berger R, Huelsman M, Strecker K, Bojic A, Moser P, Stanek B, Pacher R. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation 2002;105:2392–7
57. Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965;58:295–300
58. Rawlins ML, Owen WE, Roberts WL. Performance characteristics of four automated natriuretic peptide assays. Am J Clin Pathol 2005;123:439–45
59. Silver MA, Maisel A, Yancy CW, McCullough PA, Burnett JC Jr, Francis GS, Mehra MR, Peacock WF IV, Fonarow G, Gibler WB, Morrow DA, Hollander J. BNP Consensus Panel 2004: a clinical approach for the diagnostic, prognostic, screening, treatment monitoring, and therapeutic roles of natriuretic peptides in cardiovascular diseases. Congest Heart Fail 2004;10:1–30
60. Wu AH, Packer M, Smith A, Bijou R, Fink D, Mair J, Wallentin L, Johnston N, Feldcamp CS, Haverstick DM, Ahnadi CE, Grant A, Despres N, Bluestein B, Ghani F. Analytical and clinical evaluation of the Bayer ADVIA Centaur automated B-type natriuretic peptide assay in patients with heart failure: a multisite study. Clin Chem 2004;50:867–73