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The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis
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Heart, Lung and Circulation (2019) -, -–1443-9506/19/$36.00 https://doi.org/10.1016/j.hlc.2019.11.021
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REVIEW
The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis Zhengyang Liu a,b, Jacqueline Nguyen Khuong a,b, Carla Borg Caruana a, Sarah M. Jackson a,b, Ryan Campbell c, Dhruvesh M. Ramson d, Jahan C. Penny-Dimri d, Michael Kluger a, Reny Segal a, Luke A. Perry a,* a
Department of Anaesthesia, Royal Melbourne Hospital, Melbourne, Vic, Australia Melbourne Medical School, University of Melbourne, Melbourne, Vic, Australia c Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia d Department of Surgery, Monash University, Melbourne, Vic, Australia b
Received 16 September 2019; received in revised form 20 November 2019; accepted 28 November 2019; online published-ahead-of-print xxx
Background
The neutrophil-lymphocyte ratio (NLR) is an emerging inflammatory perioperative biomarker which has been studied to predict the incidence of postoperative atrial fibrillation (POAF) after cardiac surgery. This systematic review and meta-analysis aimed to evaluate the prognostic accuracy of elevated perioperative NLR in predicting POAF after cardiac surgery.
Methods
Multiple databases were searched from inception to May 2019 for prognostic studies on perioperative NLR and POAF following cardiac surgery. Maximally adjusted odds ratios (OR) with associated confidence intervals were obtained from each included study and pooled using random effects inverse variance modelling for preoperative NLR measurements, while standardised mean differences were pooled for postoperative NLR values. The significance of inter- and intra-study heterogeneity was explored using meta-regression.
Results
1,799 unique studies satisfied selection criteria, from which 12 studies incorporating 9,262 participants were included. Elevated preoperative NLR significantly predicted POAF, with a pooled OR of 1.42 (95% CI 1.16–1.72). Multiple predefined covariates contributed to inter-study heterogeneity; however, only prevalence of hypertension (p=0.0055), history of congestive cardiac failure (p=0.0282) and average ejection fraction (p=0.0359) were significant effect modifiers. Elevated postoperative NLR was not a significant predictor of POAF (standardised mean difference 1.60 [95% CI -0.56–3.77] between POAF1 and POAFgroups).
Conclusions
Elevated preoperative NLR is a promising prognostic biomarker for POAF, but residual sources of heterogeneity remain. Larger scale validation studies are required to justify the integration of preoperative NLR testing into routine clinical practice.
Keywords
Neutrophil-lymphocyte ratio Postoperative atrial fibrillation Cardiac surgery Prognostic biomarker
*Corresponding author at: 300 Grattan Street, Parkville, Victoria 3050. Australia. Tel.: 1613 9342 7000., Email: [email protected] Ó 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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Introduction Postoperative atrial fibrillation (POAF) is one of the most common complications after cardiac surgery, with a reported incidence varying between 15–40% after coronary artery bypass grafting (CABG), 33–49% after valve surgery and 33–67% after combined valve surgery and CABG [1–6]. Multiple studies have investigated and confirmed an association between POAF and adverse postoperative outcomes including myocardial infarction, ventricular arrhythmias, congestive cardiac failure, renal failure, respiratory failure, stroke, increased infection risk, prolonged hospital stay, decreased quality of life, and increased early and late morbidity and mortality [1,4,7–10]. Atrial fibrillation has also been linked to inflammation, and the perioperative level of systemic inflammation before and after cardiac surgery seems to be related to POAF [2,9,11,12]. Neutrophil-lymphocyte ratio (NLR) is an emerging inflammatory biomarker that has been widely analysed in recent years across multiple surgical disciplines [13–17], and in particular, it has been evaluated in the prediction of POAF after cardiac surgery [12]. Given that a full blood examination is routine in the perioperative workup of cardiac surgical patients, NLR exhibits potential as a novel, cost effective, and readily accessible indicator of POAF likelihood and, in turn, patients’ postoperative trajectory. However, the differential prognostic values of elevated NLR when measured preoperatively and postoperatively are currently unclear. We therefore conducted a systematic review and meta-analysis to evaluate the prognostic value of preoperative and postoperative NLRs in predicting POAF after cardiac surgery.
Methods Study Design and Registration This systematic review and meta-analysis of prognostic performance was reported in compliance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) Statement and designed according to the latest methodological guidance [18,19]. Study protocol details were prospectively registered with PROSPERO. There were no major protocol deviations. Eligibility criteria We included original research studies—randomised controlled trials and cohort studies—that reported associations between perioperative NLR and the development of POAF after cardiac surgery. Our definition of cardiac surgery was restricted to patients undergoing CABG, open heart valve surgery, or combined procedures, and excluded transcatheter procedures. We excluded abstracts, case reports, case series, conference presentations, editorials, expert opinions, publications with incompletely reported data, and non-human studies. Search strategy We searched the following electronic bibliographic databases from inception to May 2019: Medline (Ovid), EMBASE (Ovid),
Z. Liu et al.
and the Cochrane Library. Our search strategy included a comprehensive set of search terms for NLR and cardiac surgery (see Supplementary data) [20]. We placed no restrictions on language or publication period. The reference lists of included studies were searched for additional potentially relevant citations, and the articles citing included studies were reviewed for further relevant studies. Study selection Two review authors (Z.L. and L.A.P.) independently screened the titles and abstracts of each search result for potentially relevant studies. The full texts of potentially relevant studies were independently assessed for eligibility by both authors, with a third author adjudicating any disagreements (J.N.). We also screened the reference lists of included studies, as well as studies citing these works, for additional potentially relevant publications. Data extraction and management Two review authors (Z.L. and L.A.P.) used standardised spreadsheets to independently extract data from included studies. We recorded the following: the study design, population attributes and operation details, follow-up time, preoperative history of comorbidities, time (preoperative vs postoperative) and number of NLR measurements, the threshold of raised NLR where relevant, and the method of arrhythmia detection. Where studies compared mean perioperative NLR measurements between POAF1 and POAFgroups, we standardised reported data into mean and standard deviation and calculated the log odds ratio from the standardised mean difference [21,22]. Where studies stratified participants into more than two groups based on NLR (e.g. tertiles or quartiles), we dichotomised the results into standardised upper quantile and cumulative lower quantiles to compare POAF incidences, and calculate odds ratios and log odds ratios. Assessment of methodological quality Two review authors (L.A.P. and Z.L.) independently assessed the risk of bias in included studies using the Prediction model Risk Of Bias ASsessment (PROBAST) tool [23,24], with discrepancies resolved by a third author (J.N.) (Figure 1). Statistical Analysis and Data Synthesis We tabulated the maximally adjusted reported odds ratios with associated confidence intervals for each included study and generated summary estimates using random effects inverse variance modelling. Separate analyses were conducted for preoperative NLR measurements compared with postoperative measurements. To explore potential sources of heterogeneity, we conducted a meta-regression by inputting several predefined covariates into the random effects model. The metaregression generates a regression coefficient that describes how the covariate modifies the effect size of NLR on POAF, as well as a measure of statistical significance which describes whether there is a linear relationship between the covariate and the effect size (in this case, the prognostic value of NLR to predict POAF). Moreover, the percentage
Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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Figure 1 Risk of Bias Graph.
heterogeneity which could be accounted for by each covariate was also generated. Pre-specified covariates were: study characteristics such as the study design (retrospective vs prospective), level of bias as determined by the PROBLAST tool, year of publication, number of covariates accounted for, and NLR positivity threshold; clinical characteristics such as
cross-clamp time, percentage off pump percentage CABG, and percentage male; patient characteristics such as average age, ejection fraction, European System for Cardiac Operative Risk Evaluation score (EuroSCORE), and body mass index (BMI); and patient comorbidities such as prevalence of smoking, hypertension, history of congestive cardiac failure,
Figure 2 PRISMA Flow Chart.
Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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Table 1 Characteristics of Included Studies. Study ID
Study design: Sample size Case mix
% Male and age NLR measurement (mean (SD)) and positivity threshold:
NLR reporting:
Azab 2013
Prospective
57.5% Male
Preoperative
Patients split into tertiles based on
64.7 (10.9) years
Threshold: NLR 3.4
NLR, POAF incidence reported
1,126
(single centre) CABG (91% off pump) Cerit 2016
Retrospective
106
(single centre) CABG (0% off Durukan 2013
Prospective
pump) 523
(single centre) CABG (0% off
(upper tertile) 89.6% Male
Preoperative
Reported NLR mean6SD for
64.6 (9.6) years
Threshold NR
POAF1 vs POAF- patients
75.9% Male
Preoperative
Reported NLR mean6SD for
61.6 (9.6) years
Postoperative
POAF1 vs POAF- patients
pump) Erdem 2014
Retrospective
165
(single centre) CABG (0% off
Threshold NR 78.2% Male
Preoperative
Reported NLR mean6SD for
65.4 (9.2) years
Threshold NR
POAF1 vs POAF- patients
pump)
Multivariate logistic regression of preop NLR for AF: reported as OR
Gibson 2007
Prospective 1,938 (single centre) CABG (11% off
Gibson 2010
Prospective
77% Male 65 (9) years
pump) 275
(single centre) CABG (11.3% off
(Upper Quartile) Preoperative
Patients split into quartiles based
64.5 (8.3) years
Postoperative
on NLR, POAF incidence reported
Threshold NLR = 3.46
Reported NLR mean6SD for
(Upper Quartile)
POAF1 vs POAF- patients Reported NLR median (IQR) for POAF1 vs POAF- patients Multivariate logistic regression of
Prospective
657
70.2% Male
Preoperative
(multi centre)
CABG (47.3%) (0% off pump)
65.0 (11.4) years
Postoperative Threshold NR
Katlandur 2017 Retrospective
Patients split into quartiles based on NLR, POAF incidence reported
83.6% Male
pump) Jacob 2017
Preoperative Threshold NLR=3.36
Valve Surgery
preop NLR and DNLR for AF:
(52.7%) 346
reported as OR
(single centre) CABG (14.7% off
89.2% Male
Preoperative
Reported NLR mean6SD for
62.4 (9.2) years
Postoperative
POAF1 vs POAF- patients
Threshold NR
Univariate logistic regression of
pump)
preoperative and postoperative Ozer 2018
Retrospective
59
(single centre) CABG (0% off
62.7% Male
Preoperative
NLR for AF: reported as OR Patients split into two groups
61.4 (8.4) years
Postoperative
above and below the cut-off of
Threshold NLR = 4
NLR = 4, POAF incidence
pump)
(justification not reported) reported. Ozyurtlu 2018
Retrospective
124
83.9% Male
Preoperative
Reported NLR mean6SD for
61.3 (9.4) years
Postoperative
POAF1 vs POAF- patients
pump)
Threshold NLR = 8.5
Univariate logistic regression of
916
80.0% Male
(ROC Analysis) Preoperative
preop NLR for AF: reported as OR Multivariate regression of
60.8 (8.3) years
Threshold NR
preoperative NLR for AF:
68.9% Male
Preoperative
Patients split into two groups
64.3 (11.7) years
Threshold NLR = 2.6
above and below the cut-off of
(single centre) CABG (0% off
Saskin 2015
Retrospective
(single centre) CABG (0% off pump) Silberman 2017 Retrospective
3,027
(single centre) CABG (42.7%) (0% off pump) Valve surgery and
reported as OR
(justification not reported) NLR = 2.6, POAF incidence reported.
mixed surgery (57.3%) Abbreviations: CABG, coronary artery bypass grafting; NLR, neutrophil-Lymphocyte Ratio; NR, not reported; OR, odds ratio; POAF, postoperative atrial fibrillation; ROC, receiver-operating characteristic analysis.
Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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Figure 3 Funnel plot for estimation of publication bias.
previous myocardial infarction, diabetes mellitus, and chronic kidney disease. Publication bias was assessed by generating a funnel plot with the horizontal axis of log odds ratio and vertical axis of standard error. Visual testing of skew was performed, and regression statistics with p values were generated to analyse potential funnel plot asymmetry [25,26]. All analyses were performed using the R statistical package ‘metafor’ [26] and figures were generated using ‘ggplot2’ [27] and Review Manager 5.3 [28].
Results Search Results The search returned 1,633 results, and an additional 249 potentially relevant citations were found from other sources. These were reduced to 1,799 unique studies after duplicate results were removed. After title and abstract screening, 84 studies underwent full-text review, from which 12 studies were included in this review (Figure 2).
Description of Included Studies The 12 studies included 9,262 participants and were published between 2007 and 2018 [29–40]. Six (6) studies involving 7,278 participants reported preoperative NLR
measurements [29,30,32,33,39,40], and the other six studies involving 1,984 participants reported both preoperative and postoperative NLR measurements. Four (4) studies were prospective [29,31,33,34], and eight were retrospective. The mean age ranged from 61 to 65 years, and there was a high proportion of males overall. The selection of threshold for elevated NLR varied substantially. The minimum duration of what constituted POAF were varied from 10 seconds to 20 minutes, and the POAF capture strategy was variable and inconsistently reported (Table 1). We calculated standardised mean differences and log odds ratio for two studies reporting preoperative NLR means according to whether or not individuals developed POAF [30,31], and calculated standardised mean differences for three studies reporting postoperative NLR means according to POAF status [31,34,38]. One study reported the association of change in NLR from preoperative to postoperative (DNLR) with POAF, and reported a statistically significant between-group difference in DNLR (p=0.002), however the effect lost significance in multivariable analysis (adjusted odds ratio of 1.65 [95% CI 0.94–2.9]) [35]. Publication bias was deemed non-significant by a regression test for funnel plot asymmetry (p=0.4017). Visual inspection of asymmetry was consistent, with individual reported odds ratios seemingly evenly distributed both above and below the pooled effect size (Figure 3).
Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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Figure 4 Forest plot for Preoperative NLR odds ratios in predicting POAF.
Methodological Quality
Meta-Analyses
The overall methodological quality of included studies was variable, and is delineated in Figure 1. Three studies were identified as having a high risk of bias due to a reliance on univariable analytical techniques in predictor selection which does not account for complexities in data to the same degree as multivariable analyses [36–38]. Three (3) studies possessed unclear risks of bias as the cut-off NLR values used for odds ratio calculation were not reported [32,35,39]. The remaining studies had low risks of bias. Receiver operating characteristic (ROC) analysis is commonly employed in determining biomarker cut-offs where there is no widely accepted positivity threshold [41]; this was performed by one study to identify the maximally predictive NLR threshold [38].
Preoperative NLR We combined 12 studies involving 9,262 participants investigating preoperative elevated NLR to predict POAF, and found a moderate positive association between elevated NLR and the development of POAF that reached statistical significance (Figure 4). The pooled odds ratio was 1.42 (95% CI 1.16–1.72). There was a considerable degree of interstudy heterogeneity (I2 statistic 99.05%). Statistical heterogeneity was further investigated through meta-regression of prespecified covariates, identifying whether or not they accounted for observed heterogeneity, and to what extent if they did. If they were substantial contributors to heterogeneity, whether or not they were significant effect modifiers (how much they
Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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Table 2 Results of meta-regression of elevated preoperative NLR’s ability to predict POAF. Covariate
Multivariable analysis of
k
6
Regression coefficient – magnitude of effect size modification
P-value
95% CI (lb, ub)
Heterogeneity accounted for
Residual heterogeneity present
-
-
-
57.30%
p,0.0001
hypertension and congestive cardiac failure Hypertension
11
1.8118
0.0055
0.5338 3.0898
50.09%
p,0.0001
6
-0.9592
0.0282
-1.8158 -0.1027
53.33%
p,0.0001
Average EF
8
-0.0396
0.0359
-0.0765 -0.0026
35.10%
p,0.0001
Average age
12
0.0897
0.0911
-0.0143 0.1937
22.95%
p,0.0001
Level of bias
12
0.3151
0.1036
-0.0643 0.6945
15.47%
p,0.0001
NLR threshold
6
-0.0546
0.2466
-0.1470 0.0378
7.03%
p,0.0001
Cross-clamp time BMI
9 6
-0.0075 0.1501
0.2474 0.4397
-0.0201 0.0052 -0.2306 0.5307
7.08% 3.96%
p,0.0001 p,0.0001
Congestive cardiac failure
%male Smoking status EuroSCORE
12 8
0.0086 -0.432
0.4455
-0.0134 0.0305
0.00%
p,0.0001
0.4905
-1.6599 0.7958
0.00%
p,0.0001
5
-0.0312
0.5175
-0.1258 0.0633
0.00%
p,0.0001
Year of publication
12
-0.0154
0.6148
-0.0756 0.0447
0.00%
p,0.0001
% off-pump
12
0.1704
0.6485
-0.5621 0.9028
0.00%
p,0.0001
Study design (retrospective vs
12
-0.0905
0.6645
-0.4994 0.3184
0.00%
p,0.0001
prospective % CABG
12
0.1675
0.7396
-0.8203 1.1554
0.00%
p,0.0001
Diabetes mellitus
11
0.2001
0.8269
-1.5927 1.9928
0.00%
p,0.0001
Number of covariates in study
12
-0.0031
0.8774
-0.0421 0.0360
0.00%
p,0.0001
Abbreviations: POAF, postoperative atrial fibrillation; CABG, coronary artery bypass graft; EuroSCORE, European System for Cardiac Operative Risk Evaluation score; BMI, body mass index; EF, ejection fraction; CI, confidence interval.
influenced the pooled odds ratio above) was identified. Of the 19 prespecified covariates outlined in the Methods section, only 17 could be included in the meta-regression due to inconsistent reporting between studies (prevalence of past myocardial infarction and chronic kidney disease were excluded), and of those, prevalence of hypertension, prevalence of congestive cardiac failure history, and average ejection fraction were determined to be significant modifiers of NLR’s predictive ability, in other words, of the pooled odds ratio (Table 2). In univariable meta-regressions, hypertension was a positive modifier (regression coefficient 1.81, p=0.0055), and congestive cardiac failure and average ejection fraction were negative modifiers (regression coefficients -0.96 and -0.04, p=0.0282 and 0.0359 respectively). A multivariable meta-regression was unfortunately not possible with all three significant modifiers due to insufficient reporting of data, so the two most significant modifiers were chosen (hypertension and congestive cardiac failure). Together, they accounted for 57.30% of heterogeneity. Additional sources of heterogeneity in the univariable metaregression which could not be included in the multivariable analysis were non-significant effect modifiers, and included the prespecified covariates: average age, level of bias, NLR threshold, cross-clamp time, and BMI. Prespecified
covariates not already mentioned neither accounted for heterogeneity nor were significant effect modifiers. Postoperative NLR From three studies involving 922 participants reporting the association between postoperative NLR and POAF, the POAF1 group had a higher post-operative NLR, but the result was not statistically significant (standardised mean difference 1.60 [95% CI -0.56–3.77]) (Figure 5). There was a moderate degree of statistical heterogeneity (I2 statistic 51.20%).
Discussion This systematic review and meta-analysis of prognostic studies found that elevated preoperative NLR was a promising prognostic biomarker for POAF. The odds of developing POAF was 42% higher in individuals with an elevated preoperative NLR compared to those without, whereas elevated postoperative NLR was not a statistically significant predictor. The overall methodological quality was variable, and studies were considerably heterogenous. We found that the prevalence of hypertension, prevalence of congestive cardiac failure history, and average ejection fraction
Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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Figure 5 Forest plot for Postoperative NLR mean differences between POAF1 and POAF- groups.
significantly modified the ability of elevated preoperative NLR to predict POAF, while average age, level of bias, NLR threshold, cross clamp time, BMI, percentage male, smoking status, EuroSCORE, year of publication, percentage off pump, study design, percentage CABG, diabetes mellitis, and number of covariates adjusted for by studies did not. We were unable to detect an effect-modifier relationship between NLR threshold and the pooled odds ratio. This is possibly explained by the meta-regression not being powered to detect small associations in the setting of incomplete reporting of NLR thresholds in the included studies. Other conceivable sources of inter study heterogeneity which were considered include possible inconsistencies in the definition of significant modifier covariates such as hypertension and congestive cardiac failure. Further research should include clear definitions of variables and work towards defining a standardised threshold for NLR elevation in the cardiac surgical cohort. It is curious to note that both increased prevalence of congestive cardiac failure and increased average ejection
fraction exerted significant negative influences on NLR’s predictive ability of POAF. While it may seem counterintuitive at first that heart failure and increased ejection fraction could result in effects of identical direction, we hypothesise that the presence of heart failure with preserved ejection fraction may be the underlying mechanism behind these two significant effect modifiers. Unfortunately, the specific type of cardiac failure (preserved vs reduced ejection fraction) was not specified in any of our included studies, presenting an interesting opportunity for further investigation. Haematological biomarkers other than single NLR measurements were beyond the scope of this meta-analysis. Of note however, preoperative to postoperative DNLR has been found to be of prognostic significance in other operative cohorts, at times independently of single preoperative or postoperative NLR readings [42–45]. While Jacob et al. (2017) found DNLR to be non-significant in predicting POAF, to our knowledge no other study has investigated the independent prognostic value of DNLR in predicting POAF to date with multivariable analysis. Further investigation in alternate
Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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cohorts may be worthwhile to validate this negative finding. Similarly, other blood predictors of POAF such as white blood cell count, platelet count, platelet distribution width, mean platelet volume, C-reactive protein, and red cell distribution width have also been investigated and confirmed as perioperative biomarkers of POAF in other studies and metaanalyses [32,36,38,46]. The addition of DNLR and other potentially independently prognostic haematological indices to NLR-based predictive models may therefore enhance POAF prediction. The following limitations should be considered when interpreting our results. First, while we were able to explore 17 predefined covariates in our meta-regression, and identified three important effect modifiers (hypertension, congestive cardiac failure, and average ejection fraction) and five other contributors of heterogeneity which were non-significant effect modifiers, there remain unexplained sources of heterogeneity as demonstrated by the tests for residual heterogeneity. Further work is required to identify additional factors significantly associated with the prognostic value of NLR, and should consider the addition of other haematological parameters and biochemical markers of inflammation along with operative factors and population factors such as ethnicity and additional echocardiographic data. Second, due to the fact that there is no universally accepted cut-off positivity threshold for NLR, no two studies in our meta-analysis utilised the same cut-off when defining elevated NLR. Although our meta-regression showed the variability in precise NLR thresholds did not affect the predictive performance of elevated NLR in predicting POAF to any significant degree, consistency in this regard in future trials would lead to more robust results. Third, due to inconsistent reporting of patient baseline characteristics between studies, we were unable to meta-regress important predefined covariates (chronic kidney disease and past myocardial infarction) and statistically analyse whether they exerted any confounding effects on NLR’s predictive capacity of POAF. These factors could be further investigated in the future given they are risk factors for development of atrial fibrillation themselves. Several opportunities for future research and practice may be identified from this systematic review and meta-analysis. The clinical utility of a preoperative, low-cost, and widely available haematological biomarker for POAF is substantial. At risk patients could be identified and stratified preoperatively based on test results to guide subsequent testing, prehabilitation to increase cardiopulmonary reserve, and appropriate postoperative monitoring, medications, and interventions could be implemented to minimise modifiable risk factors as well as the incidence of adverse postoperative outcomes related to POAF which are varied and significant. However, to warrant the integration of preoperative NLR testing into routine clinical practice, larger scale validation studies are required to corroborate our findings. Further explorations of DNLR and postoperative NLR would be required, as well as combined multivariable analysis of these NLR values with other haematological inflammatory biomarkers to establish whether the prognostic value of the different NLR measurements are independent of those other
factors. There would be an additional need to generate a generalisable NLR positivity threshold from high quality ROC studies to facilitate cross-centre consistency and clinical execution more broadly. Finally, although this may be difficult to study, additional investigation into the effect of perioperative NLR screening on patient outcomes would be needed [47].
Acknowledgements No other Acknowledgments.
Funding statement The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest Statement None declared.
Appendix A. Supplementary Data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j. hlc.2019.11.021.
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The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis Zhengyang Liu a,b, Jacqueline Nguyen Khuong a,b, Carla Borg Caruana a, Sarah M. Jackson a,b, Ryan Campbell c, Dhruvesh M. Ramson d, Jahan C. Penny-Dimri d, Michael Kluger a, Reny Segal a, Luke A. Perry a,* a
Department of Anaesthesia, Royal Melbourne Hospital, Melbourne, Vic, Australia Melbourne Medical School, University of Melbourne, Melbourne, Vic, Australia c Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia d Department of Surgery, Monash University, Melbourne, Vic, Australia b
Received 16 September 2019; received in revised form 20 November 2019; accepted 28 November 2019; online published-ahead-of-print xxx
Background
The neutrophil-lymphocyte ratio (NLR) is an emerging inflammatory perioperative biomarker which has been studied to predict the incidence of postoperative atrial fibrillation (POAF) after cardiac surgery. This systematic review and meta-analysis aimed to evaluate the prognostic accuracy of elevated perioperative NLR in predicting POAF after cardiac surgery.
Methods
Multiple databases were searched from inception to May 2019 for prognostic studies on perioperative NLR and POAF following cardiac surgery. Maximally adjusted odds ratios (OR) with associated confidence intervals were obtained from each included study and pooled using random effects inverse variance modelling for preoperative NLR measurements, while standardised mean differences were pooled for postoperative NLR values. The significance of inter- and intra-study heterogeneity was explored using meta-regression.
Results
1,799 unique studies satisfied selection criteria, from which 12 studies incorporating 9,262 participants were included. Elevated preoperative NLR significantly predicted POAF, with a pooled OR of 1.42 (95% CI 1.16–1.72). Multiple predefined covariates contributed to inter-study heterogeneity; however, only prevalence of hypertension (p=0.0055), history of congestive cardiac failure (p=0.0282) and average ejection fraction (p=0.0359) were significant effect modifiers. Elevated postoperative NLR was not a significant predictor of POAF (standardised mean difference 1.60 [95% CI -0.56–3.77] between POAF1 and POAFgroups).
Conclusions
Elevated preoperative NLR is a promising prognostic biomarker for POAF, but residual sources of heterogeneity remain. Larger scale validation studies are required to justify the integration of preoperative NLR testing into routine clinical practice.
Keywords
Neutrophil-lymphocyte ratio Postoperative atrial fibrillation Cardiac surgery Prognostic biomarker
*Corresponding author at: 300 Grattan Street, Parkville, Victoria 3050. Australia. Tel.: 1613 9342 7000., Email: [email protected] Ó 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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Introduction Postoperative atrial fibrillation (POAF) is one of the most common complications after cardiac surgery, with a reported incidence varying between 15–40% after coronary artery bypass grafting (CABG), 33–49% after valve surgery and 33–67% after combined valve surgery and CABG [1–6]. Multiple studies have investigated and confirmed an association between POAF and adverse postoperative outcomes including myocardial infarction, ventricular arrhythmias, congestive cardiac failure, renal failure, respiratory failure, stroke, increased infection risk, prolonged hospital stay, decreased quality of life, and increased early and late morbidity and mortality [1,4,7–10]. Atrial fibrillation has also been linked to inflammation, and the perioperative level of systemic inflammation before and after cardiac surgery seems to be related to POAF [2,9,11,12]. Neutrophil-lymphocyte ratio (NLR) is an emerging inflammatory biomarker that has been widely analysed in recent years across multiple surgical disciplines [13–17], and in particular, it has been evaluated in the prediction of POAF after cardiac surgery [12]. Given that a full blood examination is routine in the perioperative workup of cardiac surgical patients, NLR exhibits potential as a novel, cost effective, and readily accessible indicator of POAF likelihood and, in turn, patients’ postoperative trajectory. However, the differential prognostic values of elevated NLR when measured preoperatively and postoperatively are currently unclear. We therefore conducted a systematic review and meta-analysis to evaluate the prognostic value of preoperative and postoperative NLRs in predicting POAF after cardiac surgery.
Methods Study Design and Registration This systematic review and meta-analysis of prognostic performance was reported in compliance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) Statement and designed according to the latest methodological guidance [18,19]. Study protocol details were prospectively registered with PROSPERO. There were no major protocol deviations. Eligibility criteria We included original research studies—randomised controlled trials and cohort studies—that reported associations between perioperative NLR and the development of POAF after cardiac surgery. Our definition of cardiac surgery was restricted to patients undergoing CABG, open heart valve surgery, or combined procedures, and excluded transcatheter procedures. We excluded abstracts, case reports, case series, conference presentations, editorials, expert opinions, publications with incompletely reported data, and non-human studies. Search strategy We searched the following electronic bibliographic databases from inception to May 2019: Medline (Ovid), EMBASE (Ovid),
Z. Liu et al.
and the Cochrane Library. Our search strategy included a comprehensive set of search terms for NLR and cardiac surgery (see Supplementary data) [20]. We placed no restrictions on language or publication period. The reference lists of included studies were searched for additional potentially relevant citations, and the articles citing included studies were reviewed for further relevant studies. Study selection Two review authors (Z.L. and L.A.P.) independently screened the titles and abstracts of each search result for potentially relevant studies. The full texts of potentially relevant studies were independently assessed for eligibility by both authors, with a third author adjudicating any disagreements (J.N.). We also screened the reference lists of included studies, as well as studies citing these works, for additional potentially relevant publications. Data extraction and management Two review authors (Z.L. and L.A.P.) used standardised spreadsheets to independently extract data from included studies. We recorded the following: the study design, population attributes and operation details, follow-up time, preoperative history of comorbidities, time (preoperative vs postoperative) and number of NLR measurements, the threshold of raised NLR where relevant, and the method of arrhythmia detection. Where studies compared mean perioperative NLR measurements between POAF1 and POAFgroups, we standardised reported data into mean and standard deviation and calculated the log odds ratio from the standardised mean difference [21,22]. Where studies stratified participants into more than two groups based on NLR (e.g. tertiles or quartiles), we dichotomised the results into standardised upper quantile and cumulative lower quantiles to compare POAF incidences, and calculate odds ratios and log odds ratios. Assessment of methodological quality Two review authors (L.A.P. and Z.L.) independently assessed the risk of bias in included studies using the Prediction model Risk Of Bias ASsessment (PROBAST) tool [23,24], with discrepancies resolved by a third author (J.N.) (Figure 1). Statistical Analysis and Data Synthesis We tabulated the maximally adjusted reported odds ratios with associated confidence intervals for each included study and generated summary estimates using random effects inverse variance modelling. Separate analyses were conducted for preoperative NLR measurements compared with postoperative measurements. To explore potential sources of heterogeneity, we conducted a meta-regression by inputting several predefined covariates into the random effects model. The metaregression generates a regression coefficient that describes how the covariate modifies the effect size of NLR on POAF, as well as a measure of statistical significance which describes whether there is a linear relationship between the covariate and the effect size (in this case, the prognostic value of NLR to predict POAF). Moreover, the percentage
Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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Figure 1 Risk of Bias Graph.
heterogeneity which could be accounted for by each covariate was also generated. Pre-specified covariates were: study characteristics such as the study design (retrospective vs prospective), level of bias as determined by the PROBLAST tool, year of publication, number of covariates accounted for, and NLR positivity threshold; clinical characteristics such as
cross-clamp time, percentage off pump percentage CABG, and percentage male; patient characteristics such as average age, ejection fraction, European System for Cardiac Operative Risk Evaluation score (EuroSCORE), and body mass index (BMI); and patient comorbidities such as prevalence of smoking, hypertension, history of congestive cardiac failure,
Figure 2 PRISMA Flow Chart.
Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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Table 1 Characteristics of Included Studies. Study ID
Study design: Sample size Case mix
% Male and age NLR measurement (mean (SD)) and positivity threshold:
NLR reporting:
Azab 2013
Prospective
57.5% Male
Preoperative
Patients split into tertiles based on
64.7 (10.9) years
Threshold: NLR 3.4
NLR, POAF incidence reported
1,126
(single centre) CABG (91% off pump) Cerit 2016
Retrospective
106
(single centre) CABG (0% off Durukan 2013
Prospective
pump) 523
(single centre) CABG (0% off
(upper tertile) 89.6% Male
Preoperative
Reported NLR mean6SD for
64.6 (9.6) years
Threshold NR
POAF1 vs POAF- patients
75.9% Male
Preoperative
Reported NLR mean6SD for
61.6 (9.6) years
Postoperative
POAF1 vs POAF- patients
pump) Erdem 2014
Retrospective
165
(single centre) CABG (0% off
Threshold NR 78.2% Male
Preoperative
Reported NLR mean6SD for
65.4 (9.2) years
Threshold NR
POAF1 vs POAF- patients
pump)
Multivariate logistic regression of preop NLR for AF: reported as OR
Gibson 2007
Prospective 1,938 (single centre) CABG (11% off
Gibson 2010
Prospective
77% Male 65 (9) years
pump) 275
(single centre) CABG (11.3% off
(Upper Quartile) Preoperative
Patients split into quartiles based
64.5 (8.3) years
Postoperative
on NLR, POAF incidence reported
Threshold NLR = 3.46
Reported NLR mean6SD for
(Upper Quartile)
POAF1 vs POAF- patients Reported NLR median (IQR) for POAF1 vs POAF- patients Multivariate logistic regression of
Prospective
657
70.2% Male
Preoperative
(multi centre)
CABG (47.3%) (0% off pump)
65.0 (11.4) years
Postoperative Threshold NR
Katlandur 2017 Retrospective
Patients split into quartiles based on NLR, POAF incidence reported
83.6% Male
pump) Jacob 2017
Preoperative Threshold NLR=3.36
Valve Surgery
preop NLR and DNLR for AF:
(52.7%) 346
reported as OR
(single centre) CABG (14.7% off
89.2% Male
Preoperative
Reported NLR mean6SD for
62.4 (9.2) years
Postoperative
POAF1 vs POAF- patients
Threshold NR
Univariate logistic regression of
pump)
preoperative and postoperative Ozer 2018
Retrospective
59
(single centre) CABG (0% off
62.7% Male
Preoperative
NLR for AF: reported as OR Patients split into two groups
61.4 (8.4) years
Postoperative
above and below the cut-off of
Threshold NLR = 4
NLR = 4, POAF incidence
pump)
(justification not reported) reported. Ozyurtlu 2018
Retrospective
124
83.9% Male
Preoperative
Reported NLR mean6SD for
61.3 (9.4) years
Postoperative
POAF1 vs POAF- patients
pump)
Threshold NLR = 8.5
Univariate logistic regression of
916
80.0% Male
(ROC Analysis) Preoperative
preop NLR for AF: reported as OR Multivariate regression of
60.8 (8.3) years
Threshold NR
preoperative NLR for AF:
68.9% Male
Preoperative
Patients split into two groups
64.3 (11.7) years
Threshold NLR = 2.6
above and below the cut-off of
(single centre) CABG (0% off
Saskin 2015
Retrospective
(single centre) CABG (0% off pump) Silberman 2017 Retrospective
3,027
(single centre) CABG (42.7%) (0% off pump) Valve surgery and
reported as OR
(justification not reported) NLR = 2.6, POAF incidence reported.
mixed surgery (57.3%) Abbreviations: CABG, coronary artery bypass grafting; NLR, neutrophil-Lymphocyte Ratio; NR, not reported; OR, odds ratio; POAF, postoperative atrial fibrillation; ROC, receiver-operating characteristic analysis.
Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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5
Figure 3 Funnel plot for estimation of publication bias.
previous myocardial infarction, diabetes mellitus, and chronic kidney disease. Publication bias was assessed by generating a funnel plot with the horizontal axis of log odds ratio and vertical axis of standard error. Visual testing of skew was performed, and regression statistics with p values were generated to analyse potential funnel plot asymmetry [25,26]. All analyses were performed using the R statistical package ‘metafor’ [26] and figures were generated using ‘ggplot2’ [27] and Review Manager 5.3 [28].
Results Search Results The search returned 1,633 results, and an additional 249 potentially relevant citations were found from other sources. These were reduced to 1,799 unique studies after duplicate results were removed. After title and abstract screening, 84 studies underwent full-text review, from which 12 studies were included in this review (Figure 2).
Description of Included Studies The 12 studies included 9,262 participants and were published between 2007 and 2018 [29–40]. Six (6) studies involving 7,278 participants reported preoperative NLR
measurements [29,30,32,33,39,40], and the other six studies involving 1,984 participants reported both preoperative and postoperative NLR measurements. Four (4) studies were prospective [29,31,33,34], and eight were retrospective. The mean age ranged from 61 to 65 years, and there was a high proportion of males overall. The selection of threshold for elevated NLR varied substantially. The minimum duration of what constituted POAF were varied from 10 seconds to 20 minutes, and the POAF capture strategy was variable and inconsistently reported (Table 1). We calculated standardised mean differences and log odds ratio for two studies reporting preoperative NLR means according to whether or not individuals developed POAF [30,31], and calculated standardised mean differences for three studies reporting postoperative NLR means according to POAF status [31,34,38]. One study reported the association of change in NLR from preoperative to postoperative (DNLR) with POAF, and reported a statistically significant between-group difference in DNLR (p=0.002), however the effect lost significance in multivariable analysis (adjusted odds ratio of 1.65 [95% CI 0.94–2.9]) [35]. Publication bias was deemed non-significant by a regression test for funnel plot asymmetry (p=0.4017). Visual inspection of asymmetry was consistent, with individual reported odds ratios seemingly evenly distributed both above and below the pooled effect size (Figure 3).
Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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Z. Liu et al.
Figure 4 Forest plot for Preoperative NLR odds ratios in predicting POAF.
Methodological Quality
Meta-Analyses
The overall methodological quality of included studies was variable, and is delineated in Figure 1. Three studies were identified as having a high risk of bias due to a reliance on univariable analytical techniques in predictor selection which does not account for complexities in data to the same degree as multivariable analyses [36–38]. Three (3) studies possessed unclear risks of bias as the cut-off NLR values used for odds ratio calculation were not reported [32,35,39]. The remaining studies had low risks of bias. Receiver operating characteristic (ROC) analysis is commonly employed in determining biomarker cut-offs where there is no widely accepted positivity threshold [41]; this was performed by one study to identify the maximally predictive NLR threshold [38].
Preoperative NLR We combined 12 studies involving 9,262 participants investigating preoperative elevated NLR to predict POAF, and found a moderate positive association between elevated NLR and the development of POAF that reached statistical significance (Figure 4). The pooled odds ratio was 1.42 (95% CI 1.16–1.72). There was a considerable degree of interstudy heterogeneity (I2 statistic 99.05%). Statistical heterogeneity was further investigated through meta-regression of prespecified covariates, identifying whether or not they accounted for observed heterogeneity, and to what extent if they did. If they were substantial contributors to heterogeneity, whether or not they were significant effect modifiers (how much they
Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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Table 2 Results of meta-regression of elevated preoperative NLR’s ability to predict POAF. Covariate
Multivariable analysis of
k
6
Regression coefficient – magnitude of effect size modification
P-value
95% CI (lb, ub)
Heterogeneity accounted for
Residual heterogeneity present
-
-
-
57.30%
p,0.0001
hypertension and congestive cardiac failure Hypertension
11
1.8118
0.0055
0.5338 3.0898
50.09%
p,0.0001
6
-0.9592
0.0282
-1.8158 -0.1027
53.33%
p,0.0001
Average EF
8
-0.0396
0.0359
-0.0765 -0.0026
35.10%
p,0.0001
Average age
12
0.0897
0.0911
-0.0143 0.1937
22.95%
p,0.0001
Level of bias
12
0.3151
0.1036
-0.0643 0.6945
15.47%
p,0.0001
NLR threshold
6
-0.0546
0.2466
-0.1470 0.0378
7.03%
p,0.0001
Cross-clamp time BMI
9 6
-0.0075 0.1501
0.2474 0.4397
-0.0201 0.0052 -0.2306 0.5307
7.08% 3.96%
p,0.0001 p,0.0001
Congestive cardiac failure
%male Smoking status EuroSCORE
12 8
0.0086 -0.432
0.4455
-0.0134 0.0305
0.00%
p,0.0001
0.4905
-1.6599 0.7958
0.00%
p,0.0001
5
-0.0312
0.5175
-0.1258 0.0633
0.00%
p,0.0001
Year of publication
12
-0.0154
0.6148
-0.0756 0.0447
0.00%
p,0.0001
% off-pump
12
0.1704
0.6485
-0.5621 0.9028
0.00%
p,0.0001
Study design (retrospective vs
12
-0.0905
0.6645
-0.4994 0.3184
0.00%
p,0.0001
prospective % CABG
12
0.1675
0.7396
-0.8203 1.1554
0.00%
p,0.0001
Diabetes mellitus
11
0.2001
0.8269
-1.5927 1.9928
0.00%
p,0.0001
Number of covariates in study
12
-0.0031
0.8774
-0.0421 0.0360
0.00%
p,0.0001
Abbreviations: POAF, postoperative atrial fibrillation; CABG, coronary artery bypass graft; EuroSCORE, European System for Cardiac Operative Risk Evaluation score; BMI, body mass index; EF, ejection fraction; CI, confidence interval.
influenced the pooled odds ratio above) was identified. Of the 19 prespecified covariates outlined in the Methods section, only 17 could be included in the meta-regression due to inconsistent reporting between studies (prevalence of past myocardial infarction and chronic kidney disease were excluded), and of those, prevalence of hypertension, prevalence of congestive cardiac failure history, and average ejection fraction were determined to be significant modifiers of NLR’s predictive ability, in other words, of the pooled odds ratio (Table 2). In univariable meta-regressions, hypertension was a positive modifier (regression coefficient 1.81, p=0.0055), and congestive cardiac failure and average ejection fraction were negative modifiers (regression coefficients -0.96 and -0.04, p=0.0282 and 0.0359 respectively). A multivariable meta-regression was unfortunately not possible with all three significant modifiers due to insufficient reporting of data, so the two most significant modifiers were chosen (hypertension and congestive cardiac failure). Together, they accounted for 57.30% of heterogeneity. Additional sources of heterogeneity in the univariable metaregression which could not be included in the multivariable analysis were non-significant effect modifiers, and included the prespecified covariates: average age, level of bias, NLR threshold, cross-clamp time, and BMI. Prespecified
covariates not already mentioned neither accounted for heterogeneity nor were significant effect modifiers. Postoperative NLR From three studies involving 922 participants reporting the association between postoperative NLR and POAF, the POAF1 group had a higher post-operative NLR, but the result was not statistically significant (standardised mean difference 1.60 [95% CI -0.56–3.77]) (Figure 5). There was a moderate degree of statistical heterogeneity (I2 statistic 51.20%).
Discussion This systematic review and meta-analysis of prognostic studies found that elevated preoperative NLR was a promising prognostic biomarker for POAF. The odds of developing POAF was 42% higher in individuals with an elevated preoperative NLR compared to those without, whereas elevated postoperative NLR was not a statistically significant predictor. The overall methodological quality was variable, and studies were considerably heterogenous. We found that the prevalence of hypertension, prevalence of congestive cardiac failure history, and average ejection fraction
Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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Figure 5 Forest plot for Postoperative NLR mean differences between POAF1 and POAF- groups.
significantly modified the ability of elevated preoperative NLR to predict POAF, while average age, level of bias, NLR threshold, cross clamp time, BMI, percentage male, smoking status, EuroSCORE, year of publication, percentage off pump, study design, percentage CABG, diabetes mellitis, and number of covariates adjusted for by studies did not. We were unable to detect an effect-modifier relationship between NLR threshold and the pooled odds ratio. This is possibly explained by the meta-regression not being powered to detect small associations in the setting of incomplete reporting of NLR thresholds in the included studies. Other conceivable sources of inter study heterogeneity which were considered include possible inconsistencies in the definition of significant modifier covariates such as hypertension and congestive cardiac failure. Further research should include clear definitions of variables and work towards defining a standardised threshold for NLR elevation in the cardiac surgical cohort. It is curious to note that both increased prevalence of congestive cardiac failure and increased average ejection
fraction exerted significant negative influences on NLR’s predictive ability of POAF. While it may seem counterintuitive at first that heart failure and increased ejection fraction could result in effects of identical direction, we hypothesise that the presence of heart failure with preserved ejection fraction may be the underlying mechanism behind these two significant effect modifiers. Unfortunately, the specific type of cardiac failure (preserved vs reduced ejection fraction) was not specified in any of our included studies, presenting an interesting opportunity for further investigation. Haematological biomarkers other than single NLR measurements were beyond the scope of this meta-analysis. Of note however, preoperative to postoperative DNLR has been found to be of prognostic significance in other operative cohorts, at times independently of single preoperative or postoperative NLR readings [42–45]. While Jacob et al. (2017) found DNLR to be non-significant in predicting POAF, to our knowledge no other study has investigated the independent prognostic value of DNLR in predicting POAF to date with multivariable analysis. Further investigation in alternate
Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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cohorts may be worthwhile to validate this negative finding. Similarly, other blood predictors of POAF such as white blood cell count, platelet count, platelet distribution width, mean platelet volume, C-reactive protein, and red cell distribution width have also been investigated and confirmed as perioperative biomarkers of POAF in other studies and metaanalyses [32,36,38,46]. The addition of DNLR and other potentially independently prognostic haematological indices to NLR-based predictive models may therefore enhance POAF prediction. The following limitations should be considered when interpreting our results. First, while we were able to explore 17 predefined covariates in our meta-regression, and identified three important effect modifiers (hypertension, congestive cardiac failure, and average ejection fraction) and five other contributors of heterogeneity which were non-significant effect modifiers, there remain unexplained sources of heterogeneity as demonstrated by the tests for residual heterogeneity. Further work is required to identify additional factors significantly associated with the prognostic value of NLR, and should consider the addition of other haematological parameters and biochemical markers of inflammation along with operative factors and population factors such as ethnicity and additional echocardiographic data. Second, due to the fact that there is no universally accepted cut-off positivity threshold for NLR, no two studies in our meta-analysis utilised the same cut-off when defining elevated NLR. Although our meta-regression showed the variability in precise NLR thresholds did not affect the predictive performance of elevated NLR in predicting POAF to any significant degree, consistency in this regard in future trials would lead to more robust results. Third, due to inconsistent reporting of patient baseline characteristics between studies, we were unable to meta-regress important predefined covariates (chronic kidney disease and past myocardial infarction) and statistically analyse whether they exerted any confounding effects on NLR’s predictive capacity of POAF. These factors could be further investigated in the future given they are risk factors for development of atrial fibrillation themselves. Several opportunities for future research and practice may be identified from this systematic review and meta-analysis. The clinical utility of a preoperative, low-cost, and widely available haematological biomarker for POAF is substantial. At risk patients could be identified and stratified preoperatively based on test results to guide subsequent testing, prehabilitation to increase cardiopulmonary reserve, and appropriate postoperative monitoring, medications, and interventions could be implemented to minimise modifiable risk factors as well as the incidence of adverse postoperative outcomes related to POAF which are varied and significant. However, to warrant the integration of preoperative NLR testing into routine clinical practice, larger scale validation studies are required to corroborate our findings. Further explorations of DNLR and postoperative NLR would be required, as well as combined multivariable analysis of these NLR values with other haematological inflammatory biomarkers to establish whether the prognostic value of the different NLR measurements are independent of those other
factors. There would be an additional need to generate a generalisable NLR positivity threshold from high quality ROC studies to facilitate cross-centre consistency and clinical execution more broadly. Finally, although this may be difficult to study, additional investigation into the effect of perioperative NLR screening on patient outcomes would be needed [47].
Acknowledgements No other Acknowledgments.
Funding statement The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest Statement None declared.
Appendix A. Supplementary Data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j. hlc.2019.11.021.
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Please cite this article in press as: Liu Z, et al. The Prognostic Value of Elevated Perioperative Neutrophil-Lymphocyte Ratio in Predicting Postoperative Atrial Fibrillation After Cardiac Surgery: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.11.021
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