Impact of preoperative anemia in ischemic cardiomyopathy with or without coronary artery bypass grafting

Introduction

Ischemic cardiomyopathy (ICM), defined as heart failure with reduced ejection fraction caused by severe coronary artery disease, has resulted in substantial mortality and disability worldwide (1,2). For the management of patients with ICM, the Surgical Treatment of Ischemic Heart Failure (STICH) trial has demonstrated that, compared with medical therapy alone, coronary artery bypass grafting (CABG) provides additional survival benefits in patients with ICM at 10-year follow-up (3). Contemporary guidelines also strongly recommend CABG as the preferred myocardial revascularization strategy in ICM patients with acceptable surgical risk (class I of recommendation) (4-6). Therefore, CABG holds a crucial position in the treatment of patients with ICM.

Preoperative anemia is a clinically important and increasingly frequent comorbidity in patients undergoing CABG, and has been shown to be associated with increased perioperative adverse events and mortality in patients treated with CABG (7-10). Importantly, because ICM patients have extremely limited coronary reserve, they will be more sensitive to hypoxia or anemia when undergoing CABG (7,11). The original STICH and STICH extension study (STICHES) studies have thoroughly demonstrated that CABG is preferred over medical therapy alone in ICM patients (3,12). However, it remains unclear whether preoperative anemia, as a specific factor, affects the prognosis of ICM patients, as well as the therapeutic choice between CABG and medical therapy alone in these patients.

In practical clinical work, surgeons tend to choose conservative treatment in patients with concomitant ICM and anemia, missing out on the potential survival benefits associated with surgical revascularization (13,14). Here, we perform a post-hoc analysis of the STICH trial to compare the long-term outcomes between CABG and medical therapy alone in ICM patients with or without preoperative anemia. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1187/rc).

Methods

Data source

The present research is a retrospective post-hoc analysis of the prospective randomized controlled trials STICH (12) and the STICHES (http://www.ClinicalTrials.gov, registration number: NCT00023595) (3). The STICH and STICHES trial was approved by the institutional review committees at each multicentre and written informed consent was obtained from all participants. The de-identified dataset of STICH was obtained from the National Heart, Lung, and Blood Institute’s Biologic Specimen and Data Repository Information Coordinating Centre (BioLINCC) via an approved proposal by our institutional review board. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Study design and population

The study design of the STICH trial has been previously published (15). In brief, it was a prospective, multicenter, randomized controlled trial conducted at 127 clinical sites in 26 countries. Between July 2002 and May 2007, 1,212 patients from 22 countries and 99 sites with coronary artery disease and left ventricular ejection fraction (LVEF) ≤35% were enrolled in the STICH trial hypothesis 1 and randomized to CABG with optimal medical treatment (610 patients) versus medical treatment alone (602 patients). The median follow-up time was 9.8 years.

Patients categorized by anemia status

Among all 1,212 patients enrolled in hypothesis 1 of the STICH trial, patients with available preoperative hemoglobin (n=1,209) were included for the present study. The anemia status was assessed according to World Health Organization criteria (a preoperative hemoglobin less than 13 g/dL for men and less than 12 g/dL for women).

Outcomes of interest

Consistent with the STICH trial protocol, the primary endpoint of this study was long-term all-cause mortality. The secondary endpoint focused on cardiovascular mortality. All causes of death were determined by an independent, blinded committee following predefined criteria.

Statistical analyses

Our retrospective study adhered to the original group allocation as defined by the intention-to-treat principle in the STICH trial, ensuring consistency in the classification of patients. All statistical analyses were performed under the above grouping principle.

Baseline characteristics were summarized by anemia status. We tested the normal distribution of continuous variables by Kolmogorov-Smirnov test. Continuous variables were expressed as medians with interquartile ranges (25th and 75th percentiles) and compared using the Wilcoxon rank-sum test. Categorical variables were reported as counts with percentages and analyzed using Pearson’s Chi-square test or Fisher’s exact test, as applicable. The median follow-up time of 1,209 included patients was estimated using the reverse Kaplan-Meier method (16). Kaplan-Meier curves for time to all-cause and cardiovascular mortality were constructed to cumulative risk of long-term mortality and compared by log-rank test. The relationship between baseline preoperative anemia status and clinical outcomes was evaluated using a multivariable Cox proportional hazards model, with the proportional hazards assumption checked to confirm compliance. The model was adjusted for: (I) key demographics: age, sex and serum creatinine; (II) treatment assignment: CABG with optimal medical treatment or medical treatment alone; (III) baseline cardiac function and coronary anatomy: LVEF, New York Heart Association (NYHA) class ≥ grade 3 and left main coronary artery stenosis ≥50% or left anterior descending artery stenosis ≥75%; (IV) comorbidities at baseline: atrial fibrillation, diabetes mellitus, prior stroke and prior myocardial infarction. The findings were reported as adjusted hazard ratios (aHRs) with corresponding 95% confidence intervals (CIs). Interaction P values were calculated using the multivariable-adjusted Cox proportional hazards model. For sensitivity analyses, we performed as-treated analyses based on 10-year follow-up. All analyses were conducted as two-sided tests, with a P value below 0.05 regarded as statistically significant. Statistical computations were carried out using R software (version 3.6.3; R Foundation for Statistical Computing, http://www.R-project.org) and STATA software (version 15.0; StataCorp, College Station, TX, USA).

Results

Baseline characteristics of patients

We obtained the STICH dataset from the BioLINCC and retrospectively analyzed the data based on the objectives of the present study. The post-hoc analysis showed that of 1,212 patients enrolled in the STICH trial, a total of 1,209 patients were eligible for the present study. Table 1 shows the baseline characteristics of the overall 1,209 included patients as well as separated by preoperative anemia status. Of the 1,209 patients, 610 were randomized to CABG with optimal medical treatment and 599 to medical treatment alone. Among 1,209 included patients, 320 (26.5%) had preoperative anemia and 889 (73.5%) had preoperative non-anemia at baseline. Patients with preoperative anemia had the higher age and serum creatinine, the lower body mass index, and the lower proportion of atrial fibrillation, and were more likely to have diabetes mellitus, compared with patients without preoperative anemia. Comparing patients in the CABG arm with optimal medical treatment arm, there were no differences in the baseline characteristics between the two treatment arms in patients with or without preoperative anemia (Table S1).

Impact of anemia on long-term outcomes

After a median follow-up of 9.7 years (interquartile range, 9.0 to 10.8), compared with patients without anemia, patients with anemia had a higher risk of all-cause mortality (aHR: 1.15; 95% CI: 0.98 to 1.36; P=0.09) and cardiovascular mortality (aHR: 1.26; 95% CI: 1.04 to 1.53; P=0.02) (Figure 1). Kaplan-Meier curves also showed that patients with preoperative anemia had a significantly higher incidence of all-cause mortality and cardiovascular mortality compared with patients without anemia (Figure 1). In the CABG arm, there was no significant difference in all-cause mortality and cardiovascular mortality between patients with and without preoperative anemia (Figure S1). In medical therapy alone arm, patients with pre-existing anemia had a higher risk of all-cause mortality (aHR: 1.35; 95% CI: 1.07 to 1.69; P=0.01) and cardiovascular mortality (aHR: 1.47; 95% CI: 1.14 to 1.90; P=0.003), compared with patients without pre-existing anemia (Figure S2). Similar results were shown in the Kaplan-Meier curves (Figures S1,S2).

Figure 1 The impact of anemia on the long-term outcomes of patients with ischemic cardiomyopathy. (A) The association between anemia and long-term outcomes. The multivariable model was adjusted for age, sex, treatment assignment, NYHA class ≥ grade 3, LVEF, diabetes, prior stroke, prior myocardial infarction, LM stenosis ≥50% or LAD stenosis ≥75%, atrial fibrillation, and serum creatinine. (B) Kaplan-Meier estimated cumulative incidence of all-cause mortality and cardiovascular mortality based on preoperative anemia. HR, hazard ratio; CI, confidence interval; NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; LM, left main coronary artery; LAD, left anterior descending artery.

Impact of anemia on the therapeutic effect of CABG

Among patients with anemia, patients in the CABG arm had a significantly lower risk of all-cause mortality (aHR: 0.64; 95% CI: 0.48 to 0.85; P=0.002) (Figure 2) and cardiovascular mortality (aHR: 0.54; 95% CI: 0.39 to 0.76; P<0.001) (Figure 3), compared with medical treatment alone. Though with borderline statistical significance, CABG also provided additional survival benefits among patients without anemia (all-cause mortality: aHR: 0.87; 95% CI: 0.73 to 1.03; P=0.11; cardiovascular mortality: aHR: 0.83; 95% CI: 0.68 to 1.01; P=0.06) (Figures 2,3). Similar results were shown in the Kaplan-Meier curves (Figures 2,3). Furthermore, a significant interaction was shown between the anemia status and treatment allocation on all-cause mortality (interaction P=0.047) and cardiovascular mortality (interaction P=0.04) (Figures 2,3). Sensitivity analyses under the as-treated principle also were performed, and the results were robust and consistent with the current allocation principle (Figures S3,S4).

Figure 2 The impact of anemia on all-cause mortality following CABG or medical therapy alone. (A) Impact of anemia on the therapeutic effect of CABG, compared with medical therapy alone. The multivariable model was adjusted for age, sex, treatment assignment, NYHA class ≥ grade 3, LVEF, diabetes, prior stroke, prior myocardial infarction, LM stenosis ≥50% or LAD stenosis ≥75%, atrial fibrillation, and serum creatinine. (B) Kaplan-Meier estimated cumulative incidence of all-cause mortality by treatment group, in patients with and without preoperative anemia (left: non-anemia; right: anemia). CABG, coronary artery bypass grafting; MED, medical therapy alone; HR, hazard ratio; CI, confidence interval; NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; LM, left main coronary artery; LAD, left anterior descending artery.

Figure 3 The impact of anemia on cardiovascular mortality following CABG or medical therapy alone. (A) Impact of anemia on the therapeutic effect of CABG, compared with medical therapy alone. The multivariable model was adjusted for age, sex, treatment assignment, NYHA class ≥ grade 3, LVEF, diabetes, prior stroke, prior myocardial infarction, LM stenosis ≥50% or LAD stenosis ≥75%, atrial fibrillation, and serum creatinine. (B) Kaplan-Meier estimated cumulative incidence of cardiovascular mortality by treatment group, in patients with and without preoperative anemia (left: non-anemia; right: anemia). CABG, coronary artery bypass grafting; MED, medical therapy alone; HR, hazard ratio; CI, confidence interval; NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; LM, left main coronary artery; LAD, left anterior descending artery.

Discussion

In the present post-hoc analysis of the STICH trial, we demonstrate that preoperative anemia is an independent risk factor for mortality in patients with ICM. Nevertheless, preoperative anemia does not appear to influence the long-term treatment effect of CABG. Furthermore, among ICM patients with pre-existing anemia, CABG provided a more significant additional survival benefit, compared with medical therapy alone (Figure 4). Building on the original STICH study, our research specifically investigates the impact of preoperative anemia on the long-term prognosis of CABG. This provides new insights into evaluating the effectiveness of CABG in special, heterogeneous populations.

Figure 4 Impact of anemia in ischemic cardiomyopathy patients undergoing CABG or medical treatment. The figure was created with BioRender.com. HR, hazard ratio; CI, confidence interval; MED, medical therapy alone; CABG, coronary artery bypass grafting; ICM, ischemic cardiomyopathy; NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; LM, left main coronary artery; LAD, left anterior descending artery.

Currently, many studies have established preoperative anemia as an independent risk factor for patients undergoing CABG (7-10). This present study also found the similar results in patients with ICM. However, our results indicated that preoperative anemia was not associated with a higher risk of long-term mortality in the CABG arm. That might be attributed to preoperative anemia primarily augmenting early postoperative cardiac stress, retarding wound healing, escalating infection risk, and heightening blood transfusion necessity, which predominantly influence short-term mortality and adverse events in patients undergoing CABG (7-9). As these immediate surgical stressors and risks diminish over time, their impact on long-term mortality lessens (17,18). Similarly, the study performed by Schwann et al. showed that perioperative anemia was only marginally associated with 7-year mortality in patients undergoing CABG (19). Conversely, our results showed pre-existing anemia significantly increased the risk of 10-year mortality in the medical therapy alone arm. Owing to the fact that preoperative anemia may serve as a potential harbinger of underlying conditions such as chronic kidney disease or malnutrition, it carries the independent capacity to accentuate the risk of long-term mortality (20). Besides, preoperative anemia could adjust the effectiveness of ICM treatments like beta-blockers and ACE inhibitors (21). While these drugs intend to lighten the cardiac workload, preoperative anemia might incite a counteraction in the body, bolstering cardiac output and oxygen delivery, thus diminishing the therapeutic impact of these medications (21). Hence, it is plausible to believe that pre-existing anemia is an independent risk factor of long-term mortality in ICM patients treated with medical therapy alone.

At present, it is not clear whether the increased operative risk potentially limits the therapy effect of CABG. The STICH trial previously reported that CABG was associated with triple the risk of death within initial 30 days after randomization compared with medical therapy alone (3,12). Hence, we suspect that preoperative anemia, as a risk factor for CABG, could impact its therapeutic efficacy, thereby diminishing the survival advantage conferred by revascularization. Nevertheless, our results showed that CABG provided a significant survival benefit in patients with anemia, and while the survival benefit in patients without anemia did not reach statistical significance, there was a trend toward improved outcomes. These findings are generally consistent with the main conclusions of the STICH trial (3). Due to poor coronary hemodynamics and myocardial energetics in ICM patients, surgical revascularization via CABG could improve oxygen delivery and mediate repair of myocardial and other organ damage (2,22), while preoperative anemia can exacerbate coronary artery disease and increase the risk of myocardial infarction (23). Notably, Doenst et al. found that CABG may differ from percutaneous coronary intervention or medical therapy alone by providing “surgical collateralization” prolonging additional survival benefit by preventing myocardial infarctions (24). Besides, although preoperative anemia can further complicate existing cardiac conditions, there is growing evidence regarding that CABG may provide the greatest benefit to the patients who have the most extensive coronary disease, and severe left ventricular dysfunction and remodeling (4,25). Similarly, Doenst and his colleagues reported that chronic kidney disease, which predisposes anemia, does not appear to influence the long-term treatment effects of CABG in ICM patients (26). In summary, it is reasonable to believe that preoperative anemia does not affect the survival benefit of CABG in ICM patients.

It is worth noting that our study found that CABG provided a more significant survival benefit in patients with anemia. Although the presence of preoperative anemia has a wide range of clinically important consequences, currently barely no evidence has demonstrated that correcting preoperative anemia could modify the risk associated with preoperative anemia, except for transfusion-related complications (27). In ischemic heart failure, diminished coronary blood flow culminates in cardiac contractile dysfunction. However, for ICM patients undergoing CABG, preoperative anemia may paradoxically mitigate surgical risk, serving as a catalyst to augment coronary blood flow while accelerating the recruitment and activation of immune cells and cytokines at the injury site (28,29). Additionally, preoperative anemia partially alleviates blood viscosity, offering an antithrombotic effect that could mitigate microcirculation resistance and myocardial embolism complications, thus potentially promoting a favorable prognosis (28,29). Furthermore, since CABG and preoperative anemia are associated with upfront perioperative surgical risks, and the survival benefits of CABG are emerged merely after a long-term follow-up. Therefore, the advantages of preoperative anemia will also be more pronounced in the long-term survival benefit.

In our study, it can be seen that the benefit of CABG does not seem to be limited to the presence of preoperative anemia. Notably, in real-world clinical work, it remains complicated for surgeons to determine whether CABG should be performed when facing patients with ICM, with only 1.3% of ICM patients undergoing CABG within 90 days of their hospitalization (30). Obviously, surgeons are more likely to choose conservative treatment or to mitigate anemia before CABG (such as transfusion) in patients with concomitant ICM and anemia (30,31). However, there is growing evidence that transfusion itself is associated with increased adverse outcomes and may not reduce the risk of anemia (8,32,33). Currently, many studies have found that even single-unit red blood cell (RBC)-transfusion is associated with worse short-term and long-term outcomes among CABG patients (19,34-36). The study performed by Schwann et al. showed that transfusion was strongly associated with increased late mortality among CABG patients, regardless of the degree of anemia (19). Intraoperative tolerance to anemia is more beneficial to the prognosis of patients with CABG than transfusion (19,36). Similarly, recent studies have shown that the impact of preoperative anemia on mortality in patients undergoing CABG is mainly due to intraoperative transfusion (37,38). Based on existing studies, we could observe that intraoperative transfusion has a significantly adverse effect on the survival benefit of CABG in ICM patients. Consequently, this implies that although a substantial number of patients with preoperative anemia before undergoing CABG do not have mitigated anemia, yet this lack of anemia correction does not contribute to additional mortality.

Although our study found that preoperative anemia does not affect the long-term survival benefits of CABG in ICM patients, it is unlikely to give a blanket treatment recommendation for all ICM patients with preoperative anemia. After all, preoperative anemia is just one of many factors that influence CABG outcomes. The most appropriate personalized treatment strategy in ICM patients should be determined following a comprehensive evaluation of anemia severity, comorbidities, frailty, left ventricular function and the overall clinical condition (39-41). For ICM patients with mild anemia and good health conditions, CABG may be preferred due to its long-term benefits. However, in ICM patients with severe anemia or significant comorbidities, the decision to undergo CABG should be made with greater caution. It requires a thorough evaluation by cardiac surgeons to determine an individualized treatment strategy (39,42). Regardless of the treatment choice, careful management of anemia through perioperative strategies such as iron supplementation and medicated blood replenishments is essential to improve outcomes in ICM patients (43).

Study limitations

Our study should be interpreted within the context of its limitations. Firstly, the STICH dataset remains the only available randomized controlled trial comparing the long-term outcomes of CABG versus medical therapy alone in patients with ICM. Although the retrospective design and non-randomized sample may introduce potential selection bias, our study benefits from the intrinsic advantages of randomized trials, such as multicentricity, homogenous population, comprehensive data records, and longer follow-up, which might provide reasonable evidence for the current investigation. Secondly, we were unable to completely rule out the type I and type II errors due to the relatively small sample size and restricted test power. Thirdly, the status of intraoperative transfusion was not recorded in the STICH trial. Hence, further analyses on the association between preoperative anemia, intraoperative transfusion and clinical outcomes of CABG treatment were unlikely to be performed in this study. Fourth, due to the limited sample size of the moderate and severe anemic patients, our study classified patients solely based on the presence or absence of preoperative anemia, without further stratification by the severity of anemia. Finally, our findings stemming from the STICH trial were based on relatively outdated medical therapy and surgical techniques. It is crucial to note that the therapeutic landscape for ICM patients, particularly concerning medical therapy and revascularization, has evolved considerably in recent years. Therefore, the direct applicability of our conclusions to the current clinical setting may be somewhat limited. However, the latest results from the REVIVED-BCIS2 trial indicated that percutaneous coronary intervention (PCI) did not provide better survival benefits compared to optimal medical therapy alone in patients with ICM (44), which underscores that CABG remains the treatment of choice for ICM patients. Given this, the fundamental insights gained from the STICH trial regarding the impact of preoperative anemia on CABG outcomes remain valuable, particularly considering that these conclusions are derived from the randomized controlled trial cohort with long-term follow-up. Additionally, we look forward to the ongoing STICH3C trial, which aims to compare the clinical outcomes and safety of contemporary PCI versus CABG in patients with ICM (45). This trial is expected to provide the latest guidance for therapeutic decisions in ICM patients in the near future.

While our findings should be treated with caution and considered only as exploratory and hypothesis-inducing, our study offers a comprehensive portrayal of the impact of preoperative anemia on CABG therapy. This insight aids in clinical decision-making and could influence the planning of subsequent research endeavors. Besides, these issues could be factored into the design of future studies and highlight the need for further well-designed investigations (such as detailed data on anemia management and updated medical strategies, etc.) with larger sample sizes to evaluate the impact of preoperative anemia on CABG therapy in patients with ICM.

Conclusions

Preoperative anemia is an independent risk factor for mortality in patients with ICM. However, preoperative anemia does not affect the long-term survival benefits associated with CABG, which might help surgeons make rational therapeutic decisions in clinical practice.

Acknowledgments

We thank the investigators of the STICH trial and the staff of the BioLINCC for their contributions. We appreciate NHLBI for establishing BioLINCC to share the data for analysis. This study was presented as a poster at the 103rd Annual Meeting of the American Association for Thoracic Surgery (AATS) in Los Angeles from May 6 to 9, 2023. Figure 4 was created with materials from Biorender.com.

Funding: This work was supported by the National Key R&D Program of China (No. 2023YFC2706200); National Natural Science Foundation of China (Nos. 82370271; 82070297); National Key Research and Development Program of Guangzhou (No. 202103000014).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1187/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1187/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1187/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The de-identified dataset was obtained from the National Heart, Lung, and Blood Institute’s Biologic Specimen and Data Repository Information Coordinating Centre (BioLINCC) via an approved proposal by the institutional review board. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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