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Preoperative D-dimer level predicts adverse events after coronary endarterectomy combined with coronary artery bypass grafting: a retrospective cohort study

Journal of Cardiothoracic Surgery volume 19, Article number: 697 (2024) Cite this article

Abstract

Background

Little is known about the role of D-dimer (DD) on the prognosis of patients undergoing coronary endarterectomy (CE) combined with coronary artery bypass grafting (CABG).

Methods

A total of 371 patients undergoing CE with CABG between January 2018 and July 2022 were retrospectively enrolled. The primary endpoint was the perioperative major adverse cardiovascular and cerebrovascular events (MACCE). Univariate logistic regression was performed to detect the relationship between preoperative DD level and the occurrence of perioperative MACCE. Receiver operating characteristics method was applied to determine the optimal cut-off threshold, while the multivariable logistic regression analysis was used to adjust the potential confounders.

Results

Univariate logistic regression revealed that preoperative DD level was associated with increased risk of perioperative MACCE. The optimal cut-off for DD was 0.235 µg/ml. More patients in the high DD group suffered from perioperative MACCE than the low DD group (13.2% vs. 3.9%, P = 0.004), even after multiple adjustment (odds ratio [OR]: 2.93, 95% confidence interval [CI]: 1.07–8.04, P = 0.036) in the multivariable logistic analysis. The occurrence of perioperative myocardial infarction was also much higher in high DD group (3.1% vs. 11.2%, P = 0.013).

Conclusions

In conclusion, high preoperative DD levels might predict an increased risk of perioperative adverse events after CE with CABG.

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Background

Due to the increased comorbidity and usage of coronary stents, the complexity of coronary lesions is becoming more and more challenging, making surgical revascularization more difficult to perform [1,2,3]. Surgical techniques and perioperative management strategies for coronary endarterectomy (CE) combined with coronary artery bypass grafting (CABG) have been improved during the last two decades, resulting in its application in more patients than before [1, 4]. However, recent studies still show that CE with CABG is associated with higher surgical mortality and morbidity when compared to isolated CABG, especially in the early postoperative period [5, 6]. Therefore, exploring the potential predictors for the prognosis after CE with CABG is essential to the prevention of adverse events.

D-dimer (DD) is a soluble fibrin degradation product produced by the orderly breakdown of thrombus by the fibrinolytic system, and elevated DD levels can indicate hypercoagulative status [7, 8]. Studies report that elevated DD levels predict cardiovascular disease, such as atrial fibrillation [9], acute coronary events [10, 11] and the prognosis of percutaneous coronary intervention (PCI) [12, 13]. Researchers also observe that DD levels might indicate increased risk of major adverse cardiovascular and cerebrovascular events (MACEE) and graft patency after CABG [14, 15]. However, no studies report the impact of DD levels on the prognosis of patients undergoing CE with CABG.

This study aimed to assess the role of preoperative DD in predicting adverse events after CE with CABG.

Methods

Ethical statement

This was a retrospective study based on a single-center cohort. The study was performed in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of Fuwai Hospital (NO.: 2022 − 1849). Individual consent for this retrospective analysis was waived.

Patient selection and follow-up

The inclusion criteria included patients: (i) who underwent CE with CABG from January 2018 to July 2022, (ii) who were over the age of 18 years, and (iii) with baseline DD results available. Patients with concomitant valvular surgery, ventricular aneurysm surgery,  or myectomy were excluded.

The primary endpoint was the perioperative MACCE, which was defined as the composite endpoint of all-cause death, myocardial infarction and stroke within 30 days postoperatively. Perioperative clinical data was obtained from the electronic hospital records, while the follow-up data was obtained via outpatient visits and/or phone calls. Postoperative myocardial infarction (POMI) within 48 h after the surgery was defined previously [16]. Simply, POMI was diagnosed if the patient fulfilled all of the major criteria (cardiac biomarker) and one of the additional standards for CABG-related myocardial infarction. After 48 h postoperatively, POMI was diagnosed according to the general definition.

Sample collection and measurements of DD

Before the surgery, blood samples for DD tests were routinely collected via the peripheral vein. The plasma D-dimer levels were measured by the Stago-R Evolution (France) automatic coagulation analyzer.

Operative procedure

The surgical details have been described in previous studies [16].

Statistical methods

Continuous variables with a normal distribution were expressed as means ± standard deviations, while non-normally distributed continuous variables are presented as medians [Q1, Q3]. Continuous variables were tested by Student t-test or rank-sum test according to their distributions. Categorical variables were presented as numbers (%) and compared using the Chi-square test or Fisher exact test. Receiver operating characteristics (ROC) method was applied to find out the optimal cut-off thresholds of DD for predicting adverse events, and the specificity, sensitivity, as well as the area under curve (AUC) were calculated. Univariable logistic regression was performed to assess the relationship between DD and perioperative MACCE. Multi-variable logistic regression analysis was used for multiple adjustment. The actuarial between-group survival differences were compared using univariable Cox regression analysis, followed by multiple adjustments. Two tailed test was applied, and a P value < 0.05 was considered statistically significant. Statistical analyses were performed using R 4.0.2 (R Core Team, Vienna, Austria).

Results

Baseline and operative characteristics

A total of 371 patients were enrolled in the current study (Table 1). Of these patients, 291 (78.4%) were male, and the mean age was 61.4 ± 8.7 years. Overall, the level of preoperative DD was 0.29 [0.20, 0.43] µg/ml. Nearly two-thirds of patients (64.4%) had triple vessel disease, and the mean number of grafts for per patient was 3.5 ± 0.9. A total of 392 CEs were performed, most of which were operated on the LAD (43.6%) or right coronary artery (47.0%) territory.

Table 1 Baseline characteristics
Full size table

Univariable logistic regression showed that DD levels were associated with increased incidence of perioperative MACCE (odds ratio [OR]: 1.28, 95% confidence interval [CI]: 1.01–1.63, P = 0.039). ROC curve indicated that the optimal cut-off threshold for DD was 0.235 µg/ml (AUC: 0.645) (Fig. 1), according to which the patients were divided in to low (≤ 0.235 µg/ml) and high (> 0.235 µg/ml) DD level groups. Of all the patients, 242 (65.2%) had a higher DD level (Table 1). The high DD group acquired a lower prevalence for the history of smoking (64.3%vs. 48.8%, P = 0.006) and were at higher age (57.3 ± 8.2 vs. 63.6 ± 8.1, P < 0.001). No significant difference was detected regarding the other preoperative and operative characteristics between the two groups.

Fig. 1
figure 1

Receiver operating characteristics analysis for the optimal cut-off value for D-dimer (optimal cut-off value: 0.235 µg/ml). AUC, area under the curve

Full size image

Postoperative outcomes

High DD levels showed to be associated with an increased risk of POMI (3.1% vs. 11.2%, P = 0.013). In addition, patients with high DD levels had longer intubation time (14.0 [12.0, 17.0] hours vs. 16.0 [12.3, 20.0] hours, P = 0.003) and intensive care unit-stay (48.0 [24.0, 86.0] hours vs. 68.0 [25.0, 112.0] hours, P = 0.005). No significant differences were observed regarding the incidence of thoracotomy for bleeding (3.1% vs. 4.5%, P = 0.069), postoperative new-onset stroke (0.8% vs. 1.7%, P = 0.822), new-onset atrial fibrillation (19.4% vs. 21.9%, P = 0.664), and acute kidney injury (19.4% vs. 30.3%, P = 0.095), as well as the postoperative echocardiographic outcomes (Table 2).

Table 2 Postoperative outcomes
Full size table

More patients in the high DD group suffered from perioperative MACCE than the low DD group (13.2% vs. 3.9%, P = 0.004). Multivariable logistic regression analysis showed that after adjusting the potential confounders including age (OR: 1.04, 95% CI: 0.99–1.09, P = 0.083), sex (OR: 1.44, 95% CI: 0.56–3.66, P = 0.447), and smoking (OR: 0.76, 95% CI: 0.35–1.67, P = 0.498), high preoperative DD level was still associated with increased risk of perioperative MACCE (OR: 2.93, 95% CI: 1.07–8.04, P = 0.036).

Follow-up outcomes

Follow-up was completed among all patients in the cohort. The median follow-up time was 13.5 [5.6, 22.0] months. Cox regression analysis showed that high DD levels were associated with a significantly higher rate of MACCE (P = 0.011). After multiple adjustment using Cox regression, the high preoperative DD level was still associated with increased risk of MACCE (HR: 1.95, 95% CI: 0.95–4.03, P = 0.071), although did not reach a statistical difference.

Discussion

In this study, we evaluated the impact of DD on the postoperative outcomes after CE with CABG surgery, and compared the clinical outcomes between high and low DD level groups, which was classified according to the cut-off value determined by ROC analysis.

The potential mechanism for graft failure after CABG with CE

After CE with CABG, the absence of the endothelium exposes subendothelial tissue to the bloodstream, which can trigger coagulation cascade activation [1]. Initial histologic changes in a vessel are mixture of fibrin-platelet deposits on the denuded arterial surface [17, 18]. Therefore, prevention of thrombotic occlusion might play an important role in preventing graft failure after CABG with CE. Antiplatelet therapy is routinely used after CABG with CE, and dual antiplatelet therapy is more beneficial than single antiplatelet therapy in reducing the incidence of MACCE [19]. Anticoagulation has been evaluated in some studies [2, 20], but there is currently no standard anticoagulation protocol [6, 21]. The early postoperative period after heart surgery carries a high risk of both bleeding and thrombotic complications [22], so exploring the indications for postoperative anticoagulation after cardiac surgery are critical.

Potential role of preoperative DD in patients undergoing CE with CABG

DD is a biomarker of fibrin formation and degradation that serves as a valuable marker for activation of coagulation and fibrinolysis [7]. Increased DD level indicates hypercoagulative states and is associated with thrombotic events [7, 8]. Besides, DD is easily available through whole blood or in plasma test. One of the most serious complications after CE with CABG is acute thrombotic occlusion of the target coronary arteries, which can lead to acute myocardial infarction [23]. Therefore, preoperative DD levels may predict the occurrence of adverse events of thrombosis after CABG combined with CE. Furthermore, according to the DD level, a timely understanding of the risk of thrombosis and targeted anticoagulation therapy is of great significance to alleviating the hypercoagulability of patients and reducing the occurrence of adverse events [14]. However, studies on the effect of preoperative DD on CABG with CE are lacking.

Higher DD level might predict perioperative MACCE

Studies show that elevated DD levels are independently associated with an in-creased risk of recent cardiovascular events [8], and DD levels in older populations can predict future acute myocardial infarction [10]. Moreover, postmenopausal DD in women is observed to be associated with the occurrence of coronary events [11]. Others report that in patients treated with PCI, risk stratification for adverse outcomes can be performed based on DD levels [12, 13]. Researchers also evaluate the impact of DD in patients undergoing surgical coronary revascularization. Wang and colleagues report in their study that patients with higher levels of DD after CABG have a significantly higher incidence of angina, which is most pronounced in the first month after surgery [14]. Additionally, previous studies also show that high levels of DD before CABG predict postoperative graft occlusion at short-term follow-up [15]. Patients undergoing CE with CABG represent a population with high coagulative status [2]. However, few studies evaluate the impact of DD on the postoperative outcomes in this group of patients. In this study, we observed high preoperative DD level was associated with an increased risk of perioperative MACCE. Furthermore, the association between DD and outcomes remained stable after a follow-up of 13.5 months. Meanwhile, we noticed that this result was appropriate regarding POMI. POMI is one of the most serious problems during endarterectomy, occurring in 1.5-9% of patients after CABG with CE [1,2,3, 6, 24]. With the advancement of CE technology, the incidence of POMI has reduced, but it is still more prevalent than that of CABG alone [6, 24]. Previous studies have shown that postoperative thrombosis is the leading cause of POMI [3]. Our study showed that DD levels were associated with increased incidence of perioperative MACCE.

The possible explanation is that higher DD level might indicate thrombotic events. Because the balance between coagulation and fibrinolysis is significant, particularly in the perioperative setting, a state of hyper-coagulation can render a patient prone to bypass graft failure, myocardial infarction, stroke, or other venous or arterial thromboembolism [7, 25]. On the other hand, previous studies notice that levels of inflammatory factors are positively correlated with hypercoagulable states [26], and DD is a significant predictor of inflammatory states [27]. The present study demonstrated that higher preoperative DD level was more of a reflection of the postoperative state of hyper-coagulation, which therefore easy to causes MACCE and POMI. Therefore, anticoagulation might be necessary in patients with higher preoperative DD levels and undergoing CE with CABG, although other factors might also have impacted the elevation of DD.

Clinical implication

To our knowledge, this is the first available study to assess DD in patients undergoing CE with CABG. We observed that DD might be a complementary tool for assessing the risk of further thromboembolic and bleeding events. In the setting of elevated DD, careful consideration should be taken regarding the need for postoperative antithrombotic therapy to achieve a reduced incidence of MACCE and graft patency.

Limitations

Some general limitations of our study should be considered. Firstly, this was a retrospective cohort study from a single center. Hence, the bias caused by the study design is inevitable. Extrapolations of conclusions from the current study might require further validation. Secondly, there might be residual confounding factors in the measurement of DD, and the causal relationship between elevated DD and outcomes cannot be fully proven. For example, even though measurements from the last DD before surgery were used, the time of measurement and the time interval between the start of surgery was inconsistent. What’s more, the effect of DD on graft patency, particularly the early angiographic outcome, was not analyzed. Further research is needed on DD levels to guide individualized anticoagulation therapy in patients of CE with CABG.

Conclusions

In conclusion, high preoperative DD levels might predict an increased risk of perioperative adverse events after CE with CABG.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

AUC:

Area Under the Curve

CABG:

Coronary Artery Bypass Grafting

CE:

Coronary Endarterectomy

CI:

Confidence Interval

DD:

D-Dimer

MACCE:

Major Adverse Cardiovascular and Cerebrovascular Events

OR:

Odds Ratio

PCI:

Percutaneous Coronary Intervention

POMI:

Postoperative Myocardial Infarction

ROC:

Receiver Operating Characteristics

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Acknowledgements

Not applicable.

Funding

This research was funded by the National High Level Hospital Clinical Research Funding [2022-GSP-QN-11], Noncommunicable Chronic Diseases-National Science and Technology Major Project [2023ZD0504701] and the National Key Research and Development Program [2018YFC1311201] from the Ministry of Science and Technology of the People’s Republic of China.

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Author notes

  1. Lianxin Chen and Xieraili Tiemuerniyazi contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, National Clinical Research Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beilishi Road No. 167, Xicheng District, Beijing, 100037, China

    Lianxin Chen, Xieraili Tiemuerniyazi, Ziang Yang, Liaoming He, Yifeng Nan, Yangwu Song, Wei Zhao & Wei Feng

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Contributions

Conceptualization, L.C., and X.T.; methodology, L.C., and X.T.; validation, L.C., X.T., Z.Y., L.H., Y.N., Y.S., and W.Z; formal analysis, L.C., and X.T.; investigation, L.C., X.T., Z.Y., L.H., Y.N., Y.S., and W.Z; resources, W.F.; data curation, L.C., X.T., Z.Y., L.H., Y.N., Y.S., and W.Z; writing—original draft preparation, L.C., and X.T.; writing—review and editing, Z.Y., L.H., Y.N., Y.S., and W.Z; visualization, L.C. and X.T.; supervision, W.F.; project administration, L.C., X.T. and W.F.; funding acquisition, W.F. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Wei Feng.

Ethics declarations

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of Fuwai Hospital (NO.: 2022 − 1849).

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Individual consent for this retrospective analysis was waived.

Competing interests

The authors declare no competing interests.

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Chen, L., Tiemuerniyazi, X., Yang, Z. et al. Preoperative D-dimer level predicts adverse events after coronary endarterectomy combined with coronary artery bypass grafting: a retrospective cohort study. J Cardiothorac Surg 19, 697 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13019-024-03272-y

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Journal of Cardiothoracic Surgery

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