The role of troponin and albumin to assess myocardial dysfunction after cardiac surgery and
in the critically ill
van Beek, Dianne E.C.
DOI:
10.33612/diss.101333600
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van Beek, D. E. C. (2019). The role of troponin and albumin to assess myocardial dysfunction after cardiac
surgery and in the critically ill. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.101333600
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Chapter
Dianne van Beek, Fred de Geus, Pim van der Harst, Massimo Mariani, Iwan van der Horst, Thomas Scheeren.
Improving the use
of troponin to assess
the risk for mortality
after cardiac surgery:
a retrospective cohort study
Abstract
Background: Cardiac troponin (cTn) elevations after cardiac surgery have been shown to be associated with mortality. However, which Tn measurement has the strongest association remains to be determined.
Methods: This study in patients undergoing cardiac surgery, consisted of a derivation cohort of two years and a subsequent validation cohort. The evaluated Tn modalities included: (A) the pre-operative cTn, (B) the operative delta cTn, (C) the maximum delta cTn, (D) the post-operative peak level of cTn, (E) the timing of the peak level. The area under the receiver operating curve (AUROC) for 30-day all-cause mortality was determined. Subsequently we tested the performance of three thresholds for cTn: I. an elevated pre-operative cTn, II. cTn >10 times the 99th percentile, III: a late peak of cTn, using log
binominal regression analysis.
Results: A total of 1466 patients were included in the derivation cohort and 1467 patients in the validation cohort. The postoperative peak cTn level (C) showed the strongest association with mortality in both the derivation (AUROC 0.73, [95%CI 0.65-0.81], p<0.005) and the validation cohort (AUROC 0.79, [95%CI 0.70-0.87], p<0.005). The postoperative peak cTn level above 10 times the 99th percentile (II.) increases the odds the most for
mortality (OR 4.77 [95% CI 2.33-9.75], p=<0.005 in derivation cohort and OR 9.03 [95%CI 3.13-26.10], p<0.005 in validation cohort).
Conclusions: Postoperative peak cTn level and a cTn level >10 times the 99th percentile
showed the strongest association with 30-day all-cause mortality in patients undergoing cardiac surgery.
4
Introduction
Cardiac troponin (cTn) is part of the myocardial contractile apparatus and its presence in plasma is used as a biomarker for myocardial injury. With the new high-sensitive cTn tests, even small amounts of myocardial injury (which do not necessarily result in electrocardiographic [ECG] or ventricular wall motion abnormalities or clinical symptoms) can be detected. The observed elevations of cTn are therefore more difficult to interpret.1 Since
the development of the high-sensitive cTn assays the diagnostic criteria for spontaneous MI have been focused on the changes (delta) rather than on the absolute values of cTn.2,3
Depending on the cTn value on the first postoperative day after cardiac surgery, the delta between the first and second post-operative day was found to be associated with mortality and adverse outcome.4 Even more so, the delta from pre-operative to post-operative cTn
levels seems to be relevant in assessing the cardiac risk after non-cardiac surgery.5
During cardiac surgery there is inevitably direct surgical trauma to the heart, but diffuse myocardial ischemia or early graft failure might also occur. Accordingly, cTn elevation is found in all patients after cardiac surgery performed with cardiopulmonary bypass6;7, which
makes interpretation of a postoperative cTn elevation and recognizing significant myocardial injury even more challenging. In one study only 255 (64%) of the 399 patients who underwent emergent coronary angiography for the suspicion of a postoperative MI after coronary artery bypass grafting (CABG) actually had graft failure or incomplete revascularization.8
While postoperative cTn elevations have been well established as a prognostic marker for mortality after cardiac surgery9;10;11, the preoperative cTn level has also been shown
to be prognostic for adverse outcomes and mortality12;13. In addition, the timing of cTn
measurements seems to be relevant as well, with measurements in the time window between 18 to 24 hours after cardiac surgery having the highest association with adverse outcomes14.
Although these studies show that a higher absolute cTn level increases the likelihood of adverse outcome, it is unknown which cTn level best characterizes an individual`s risk. Identifying the patients most at risk at an early stage could probably be beneficial for patient outcome.
Currently, the recommended threshold for cTn after CABG to diagnose excessive myocardial damage is >10 times the 99th percentile of the normal range of the laboratory
reference range.15 However, there is no clear recommendation on which cTn threshold
is best for other types of cardiac surgery (e.g. off-pump coronary artery bypass grafting [OPCABG], valve surgery or a combination of valve and coronary surgery).
60
Chapter 4
The aim of this study was to determine the optimal cTn measurement to predict mortality after cardiac surgery in general and for the different types of cardiac surgery in particular. For this purpose, we evaluated pre- and postoperative cTn levels in one cohort and subsequently validated the results in a second cohort of patients undergoing cardiac surgery.
Methods
This observational retrospective cohort study included two subsequent cohorts. The first cohort, ‘derivation cohort’ included all adult patients undergoing CABG (performed both on-pump and off-pump [OPCABG]) and/or heart valve surgery in the University Medical Center Groningen (UMCG) between 01-01-2012 and 31-12-2013. The second cohort, termed ‘validation cohort’, consisted of all adult patients undergoing coronary and/or heart valve surgery in the UMCG between 01-01-2014 and 31-12-2015.
The primary outcome was 30-day all-cause mortality. Data was collected from the local Board Heart interventions Netherlands (BHN) registry18, the hospital electronic patient
record system and the anesthesia patient data management system (PDMS). Considering the nature of this retrospective study the local medical ethical review board waived the need for obtaining written informed consent or further approval (METc 2015/070). The UMCG has implemented an opt-out system, in which patients can object against using their medical data for research purposes.
Laboratory measures
Laboratory cTn measures were obtained from 72 hours before surgery until 72 hours after surgery. The cTn-T levels were determined in all patients using the highly sensitive fifth generation Roche Modular (Roche diagnostics) with an upper reference limit (99th
percentile) of 50 ng/L. Values between 14-50 ng/L are considered above normal and a sign for potentially ongoing myocardial damage. However, 50 ng/L is the cut-off value above which cTn is considered pathologically elevated. Postoperative cTn measurements were standard care and ordered in general at an interval of 4 to 6 hours, although the exact timing and the frequency of cTn measurements were not protocolized.
The different cTn measurement modalities
We evaluated four different cTn measurements. In addition, we evaluated the timing of the peak level after surgery. These four measurements were chosen to evaluate whether it is more optimal to look at the pre-operative cTn level, the change in cTn, the peak level of cTn or the timing of the peak level of cTn.
4
The five continuous variables for analysis were: ▪
▪ Variable A: Pre-operative cTn, defined as the last measured pre-operative cTn.
▪
▪ Variable B: Operative delta cTn, defined as the difference between the first measured
postoperative cTn level – the last measured pre-operative cTn level. ▪
▪ Variable C: Maximum delta cTn, defined as the difference between the highest
measured cTn level in the first 72 hours after surgery – the first measured post-operative cTn level.
▪
▪ Variable D: Postoperative peak cTn, defined as the highest measured cTn level in the
72 hours after surgery. ▪
▪ Variable E: Timing of the peak cTn level, defined as the time of the peak of level of
cTn after surgery measured in time since end of surgery.
We also evaluated the early postoperative delta between the first and second measured cTn (see supplementary materials).
The different thresholds for cTn
We subsequently evaluated three binary cTn thresholds to determine which one can be used to identify the patients most at risk.
The three binary variables analyzed were: ▪
▪ Variable I: an elevated pre-operative cTn level, defined as a pre-operative cTn level
>50 ng/L. ▪
▪ Variable II: >10 times the 99th percentile, defined as the occurrence of a cTn level
postoperatively above the currently recommended cut-off point 10 times the 99th
percentile (>500 ng/l). ▪
▪ Variable III: Late peak, defined as the occurrence of the highest measured cTn level
more than 24 hours after the end of surgery.
We also conducted two sensitivity analysis. Since cTn levels >14 ng/L are already considered above normal, we evaluated whether 10 times the 99th percentile based on the 14 ng/L
threshold would change the results. In addition, we evaluated whether patients with an early peak of cTn could be considered as having a lower risk. For both sensitivity analysis we refer to the supplementary materials.
Subgroup analysis
We also conducted a subgroup analyses based on the different types of cardiac surgery. The cardiac surgeries were grouped into isolated on-pump CABG, OPCABG, isolated heart valve surgery, and combined CABG and heart valve surgery. For the subgroup analysis the patients in the two cohorts were combined.
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Chapter 4
Statistical analysis
The baseline characteristics for both cohorts were presented in strata of the different cohorts. For these groups the number and proportions or the mean with the standard deviation (SD) or the median with interquartile ranges (IQR) were presented where appropriate.
First all analyses were conducted in the derivation cohort. The area under the receiver operating curve (AUROC) with the 95% confidence intervals were calculated for the different cTn measurements. For the cTn thresholds the odds ratio (OR) with 95% CI were calculated using log binominal regression. Subsequently the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated.
The analyses were repeated in the validation cohort, to assess the reproducibility of the results. To prove the usefulness of a prognostic model, it is essential that the results of the study are validated in a different cohort of patients than that in which the model was developed.16,17
For the subgroup analysis based on type of surgery the two cohorts were combined, because the limited number of outcomes. For all analyses a complete case analysis was conducted and a two-sided p-value below 0.05 was considered statistically significant to.
Results
In total 1466 patients were included in the derivation cohort and subsequently 1467 patients in the validation cohort. The baseline pre-operative condition (e.g. critical condition, left ventricular ejection fraction, recent MI, EuroSCORE) differed slightly between the cohorts (table 1). The total number of available cTn measures in the 72 hours after surgery was 13,889, with a median of 4 measurements (IQR 4-6) per patient. The peak cTn level was reached on average 8.2 hours after surgery in the derivation cohort and 9.8 hours after surgery in the validation cohort. In the derivation cohort, for 392 (27%) patients a pre-operative cTn was available and for all patients postoperative cTn measures were available. In the validation cohort, pre-operative cTn was available for 465 patients (32%) and post-operative cTn was unavailable in 37 patients (3%).
30-day all-cause mortality
The 30-day all-cause mortality was 43 (3%) in the derivation cohort and 30 (2%) in the validation cohort. In the derivation cohort the pre-operative cTn level (A), the maximum delta cTn (C), the postoperative peak troponin level (D) and the timing of peak level of cTn (E) were all significantly associated with 30-day all-cause mortality (table 2).
4
Table 1. Baseline characteristics.
Derivation cohort 1466 Validation cohort 1467 P value Men 1055 (72%) 1001 (68%) 0.07 Age [years] 68 [59-75] 67 [59-74] 0.482 BMI [kg/m2] 27 (SD 4) 27 (SD 4) 0.897
Pre-operative creatinine level [µmol/l] 81 (SD 41) 93 (SD 60) 0.282
Pre-operative critical condition 77 (5%) 37 (3%) <0.005*
LVEF >50% 987 (67%) 814 (55%) <0.005*
Pre-operative unstable angina pectoris 150 (10%) 162 (11%) 0.488
Myocardial infarction <90 days before surgery 318 (22%) 444 (30%) <0.005*
EuroSCORE 1 3.2 [1.7-6.8] 4.1 [2.2-8.4] 0.007*
Preoperative cTn available 392 (27%) 465 (32%) 0.001*
Mean (SD: standard deviation), Median [IQR: interquartile ranges], Number (percentage)
BMI: body mass index, cTn: cardiac troponin, LVEF: left ventricular ejection fraction. * indicates a significant result
Table 2. The area under the receiver operating characteristic (AUROC) with the 95% confidence interval for
30-day all-cause mortality for the different troponin measurements.
Derivation cohort Validation cohort AUROC P AUROC P A. pre-operative cTn level 0.62 (0.50-0.74) 0.070* 0.71 (0.57-0.85) 0.012*
B. operative delta cTn level 0.55 (0.44-0.65) 0.319 0.48 (0.27-0.70) 0.857
C. maximum delta cTn level 0.62 (0.52-0.72) 0.009* 0.63 (0.55-0.70) 0.012*
D. postoperative peak cTn level 0.73 (0.65-0.81) <0.005* 0.79 (0.70-0.87) <0.005*
E. timing postoperative peak cTn level 0.61 (0.51-0.72) 0.013* 0.62 (0.50-0.75) 0.031*
* indicates a significant result
The post-operative peak cTn level (D) showed the strongest association with mortality (AUROC 0.73, [95%CI 0.65-0.81], p<0.005). This association was confirmed in the validation cohort (AUROC 0.79, [95%CI 0.70-0.87], p<0.005).
We subsequently evaluated the clinically applicable cut-off points for cTn: I. elevated pre-operative cTn level, II. cTn >10 times 99th percentile, III. late peak of cTn. Both the
postoperative peak cTn elevation >10 times the 99th percentile (II.) and a late peak of cTn
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Chapter 4
Table 3. The Odds ratio (OR) with the 95% confidence interval for 30-day all-cause mortality the derivation and
the validation cohort.
Derivation cohort Validation cohort OR (95%CI) P OR (95%CI) P I. elevated pre-operative cTn level 1.37 (0.38-4.88) 0.630 4.98 (1.08-22.98) 0.040*
II. Postoperative peak cTn elevation >10
times 99th percentile
4.77 (2.33-9.75) <0.005* 9.03 (3.13-26.10) <0.005*
II. late peak of cTn 3.31 (1.34-8.15) 0.009* 3.59 (1.69-7.63) 0.001*
* indicates a significant result
The postoperative peak cTn level above 10 times the 99th percentile (II.) increases the
odds more (OR 4.77 [95% CI 2.33-9.75, p=<0.005 in derivation cohort and OR 9.03 [95%CI 3.13-26.10], p<0.005 in validation cohort) than a late peak of cTn (III.) (OR 3.31 [95% CI 1.34-8.15], p=0.009 in the derivation cohort and OR 3.59 [95% CI 1.69-7.63], p=0.001 in the validation cohort). The cut-off points preformed differently on sensitivity and specificity but were all characterized by a high NPV and a low PPV (figure 1 and 2).
Subgroup analysis
For on-pump CABG surgery the pre-operative cTn level (A) and the postoperative cTn level (D) had the highest AUROC (0.66, [95%CI 0.49-0.84], p=0.089 and 0.66, [95%CI 0.49-0.82], p=0.054 respectively) (table 4).
Figure 1. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) for the different
thresholds for cTn in the derivation cohort plotted in a radar plot. Variable I: an elevated pre-operative cTn level. Variable II: >10 times the 99th percentile. Variable III: Late peak of cTn.
0% 20% 40% 60% 80% 100%sensitivity specificity PPV NPV I. II. III
4
Figure 2. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) for the different
thresholds for cTn in the validation cohort plotted in a radar plot. Variable I: an elevated pre-operative cTn level. Variable II: >10 times the 99th percentile. Variable III: Late peak of cTn.
0% 20% 40% 60% 80% 100%sensitivity specificity PPV NPV I. II. III
Table 4. The area under the receiver operating characteristic (AUROC) with the 95% confidence interval for
30-day all-cause mortality for the different troponin measurements per category of surgery. A. pre-operative cTn level. B. operative delta cTn level. C. maximum delta cTn level. D. postoperative peak cTn level. E. timing postoperative peak cTn level.
CABG OPCAB Valve Combination
AUROC (95% CI) p AUROC (95% CI) p AUROC (95% CI) p AUROC (95% CI) p A. 0.66 (0.49-0.84) 0.089 0.60 (0.45-0.75) 0.075 0.65 (0.42-0.89) 0.119 0.76 (0.54-0.97) 0.109 B. 0.41 (0.18-0.63) 0.347 0.53 (0.37-0.70) 0.666 0.55 (0.37-0.73) 0.500 0.55 (0.37-0.72) 0.564 C. 0.54 (0.35-0.72) 0.629 0.75 (0.60-0.90) <0.0005 0.63 (0.50-0.76) 0.051 0.63 (0.49-0.77) 0.044* D. 0.66 (0.49-0.82) 0.054 0.73 (0.57-0.89) 0.001* 0.71 (0.62-0.80) 0.001* 0.71 (0.59-0.84) 0.001* E. 0.53 (0.37-0.70) 0.687 0.70 (0.54-0.86) 0.007* 0.64 (0.52-0.77) 0.031* 0.61 (0.46-0.76) 0.099
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Chapter 4
For OPCABG surgery the maximum delta cTn (C) showed the strongest association with mortality with an AUROC of 0.75, [95 % CI 0.60-0.90], p<0.005. Valve surgery and combined surgery both showed the highest AUROC with the peak cTn level (D) (AUROC 0.71, [95%CI 0.62-0.80], p=0.001 and AUROC 0.71, [95%CI 0.59-0.84], p=0.001 respectively).
When evaluating the different thresholds per type of surgery the highest OR was found for the peak level of cTn >10 times the 99th percentile (II.), namely OR 2.06, [95%CI 0.54-7.88],
p=0.060 for on pump CABG surgery, OR 6.25, [95%CI 2.29-17.05], p<0.0005 for OPCABG surgery and OR 3.72, [95%CI 1.24-11.17], p=0.019 for valve surgery (table 5).
Table 5. The Odds ratio (OR) with the 95% confidence interval for 30-day all-cause mortality for the entire
cohort subdivided per type of surgery. Variable I: elevated pre-operative cTn level. Variable II: cTn >10 times 99th
percentile. Variable III: late peak of cTn.
I. II. III. CABG OR (95% CI) 2.06 (0.54-7.88) 4.30 (0.94-19.60) 1.38 (0.30-6.39) p 0.292 0.060 0.682 OPCAB OR (95% CI) 1.13 (0.28-4.58) 6.25 (2.29-17.05) 4.47 (1.54-13.56) p 0.864 <0.0005* 0.006* Valve OR (95% CI) 1.33 (0.28-6.39) 3.72 (1.24-11.17) 1.44 (0.41-5.01) p 0.724 0.019* 0.571 Combination OR (95% CI) 1.21 (0.20-7.40) 3.88 (0.89-17.00) 4.29 (1.66-11.14) p 0.833 0.072 0.003*
* indicates a significant result
Yet, in on-pump CABG surgery the association did not reach the level of statistical significance in contrast to OPCABG and valve surgery. Only in a combined coronary and valve surgery the OR was the highest for the late peak level of cTn (III.) (OR 4.29, [95% CI 1.66-11.14], p=0.003).
4
Discussion
The pre-operative cTn level, the maximum delta cTn, the peak cTn level and the timing of the peak level were all significantly associated with 30-day all-cause mortality, of which the peak level of cTn showed the strongest association. The results of the analyses were all reproduced in the validation cohort. In addition, we found that the currently recommended cut-off level for cTn (>10 times the 99th percentile) was the best predictor for 30-day all-cause
mortality in both OPCABG and valve surgery. Only for combined coronary and valve surgery a peak level of cTn >24 hours after surgery performed better in our study. None of the studied thresholds were significantly associated with mortality in isolated on-pump CABG surgery. Since, the use of cardiopulmonary bypass per se is related to cTn release6;7, it is not
surprising that previous studies have shown that OPCABG results in lower postoperative levels of cTn compared to on-pump CABG19;20. In addition, different types of cardiac surgery
(e.g. mitral valve surgery compared to CABG) will result in different typical postoperative cTn release patterns.21 One mechanism that contributes to the myocardial damage
after cardiac surgery is the systemic inflammatory response syndrome (SIRS), which is partially caused by the body`s response to the foreign material of the CPB and the ischemia and subsequent reperfusion injury resulting from the aortic cross clamping..19;20
We hypothesized that the different thresholds for per type of cardiac surgery (i.e. valve surgery, on-pump CABG, and off-pump coronary artery bypass grafting [OPCABG]) might improve the use of cTn as a prognostic marker. However, we found that the general cut-off threshold >10 times 99th percentile performed better in OPCABG and valve surgery,
as compared to isolated on-pump CABG surgery.
We did not find a significant association between pre-operative cTn level and 30-day all-cause mortality. Pre-operative cTn levels have previously been shown to be a prognostic factor for the occurrence of adverse outcomes and mortality.12;13 A possible explanation
for this finding could be cTn that our study lacked the power for this.
Our results are in line with a study reporting that the recommended cut-off level was useful to predict mortality if combined with specific ECG changes or new ventricular wall motion abnormalities observed by echocrdiography.24 Although in that study 93% (n=522)
of the patients had a post-operative cTn level above 10 times the 99th percentile24, in our
derivation cohort 42% (n=615) of the patients had a cTn level above 10 times the 99th
percentile. This suggests that a cut-off level of 500 ng/L potentially is less discriminative and explains the low PPV that we found. In support of this proposal, it was likewise suggested in another study with patients undergoing coronary revascularization that the 10 times the 99th percentile cut-off level needs to be increased.25
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Chapter 4
This study has several limitations. First, not for all patients a pre-operative cTn measurement was available. It is therefore possible that the patients who showed clinical symptoms (e.g. patients with a preoperative MI) were more likely to undergo pre-operative cTn measurements. This could have potentially resulted in selection bias for both the operative delta cTn and for the pre-operative cTn measurement. Second, although cTn was measured in all patients post-operatively in the derivation cohort, the timing and the frequency of measurements were not standardized. Third, we only evaluated cTnT. While in the general population it has been shown that cTnI shows a stronger correlation with cardiovascular disease and cTnT with all-cause mortality26, and that cTnT and cTnI provide
complementary information27.
Fourth, we validated the results of our study internally with a different cohort, but not externally. We expect that the results are generalizable since we used two large independent cohorts of cardiac surgery patients and it is not expected that the cardiac surgery population in our academic hospital markedly differs from that of other tertiary hospitals. Finally, this was a retrospective study, increasing the risk for several types of bias. Interpreting cTn levels after cardiac surgery confronts clinicians with an extreme challenge. On the one hand, cTn elevation is inherent and common after cardiac surgery6;7, and can
therefore seem irrelevant information. On the other hand it has been shown that early revascularization with ongoing myocardial ischemia after cardiac surgery is beneficial.28,29
Even conservative treatment (e.g. pain control, beta-blocker therapy, antiplatelet therapy, intravenous heparin, combined with hemodynamic support) can be beneficial in acute post-operative graft failure.34 Sufficient effort should be made to identify the patients
most at risk. This study is a first step to evaluate new ways in evaluating cTn levels in patients undergoing cardiac surgery, and to find the most clinically relevant interpretation for this biomarker. The results of this study should be externally validated. Therewith, a consensus for evaluating cTn after cardiac surgery could be established and reporting and benchmarking on myocardial injury could be optimized. Future studies could focus on preventive and early interventions to determine if the optimized use of this biomarker can be used to improve patient outcome.
Conclusions
In conclusion, we found that the postoperative peak cTn level and a cTn level >10 times the 99th percentile were most suitable to identify the patients at risk for 30-day all-cause
4
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