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.
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