Anemia is an independent risk factor for worse 30-day outcomes in surgical aortic valve replacement: an insight from the ACS-NSQIP database from 2005 to 2022

Introduction

Aortic stenosis (AS) is a prevalent condition, especially in the elderly; in individuals aged over 75, the incidence of AS is 12.4%, with 3.4% suffering from severe AS that requires intervention (1). Surgical aortic valve replacement (SAVR) was traditionally the primary treatment for AS (2). While transcatheter aortic valve replacement (TAVR) has been playing an increasing role in aortic valve replacement (AVR) (3), there are ongoing concerns about the long-term durability of the stent used in TAVR, and it has been associated with increased long-term mortality (4). As a result, SAVR continues to be a crucial option for low-risk and/or younger patients, attributed to its durability and better long-term prognosis (5). This highlights the significance of continued research in SAVR.

Anemia is highly prevalent among patients with severe AS, affecting up to 40% of these patients, and the incidence of anemia increases with age (6,7). Anemia is associated with up to a 75% increase in long-term all-cause mortality, a 42% increase in sudden cardiac death, and various other morbidities among patients with severe AS (6,8). TAVR was initially offered to high-risk, elderly patients who are at significant surgical risk for SAVR. Previous studies have focused extensively on the impact of preoperative anemia on TAVR outcomes, revealing an association with higher short-term and long-term mortality and complications (9). However, the effect of baseline anemia on SAVR outcomes remains largely under-examined. Therefore, this study aimed to investigate the impact of preoperative anemia on 30-day outcomes following SAVR, which can contribute insights into the preoperative risk stratification and postoperative care of anemic patients. This study, therefore, was among the first to examine SAVR outcomes among patients with anemia using data from a large-scale national database.

Methods

Data source

This retrospective study used the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database from 2005 to 2022. The ACS-NSQIP database is a national quality control program for surgical outcomes, involving over 700 participating sites (10). All surgical outcomes are documented from patients’ medical records (10). Patients who underwent SAVR were identified by Current Procedural Terminology (CPT) codes 33400, 33401, 33402, 33403, 33404, 33405, 33406, 33407, 33408, 33409, 33410, 33411, and 33412. Exclusion criteria included age less than 18 years old, emergency presentation, concomitant coronary artery bypass grafting (CABG), and transfusion of greater or equal to one unit of whole or packed red blood cells (RBCs) within 72 hours prior to the surgery. Anemia was defined as having preoperative hematocrit less than 40% in males and 36% in females (11). Patients with and without preoperative anemia were stratified into two cohorts.

Preoperative factors

Demographics and baseline preoperative characteristics of patients with and without anemia were compared (Tables 1,2). The demographics examined included sex, age, as well as race and ethnicity. The baseline variables were defined by the ACS-NSQIP definitions (12).

Postoperative outcomes

Thirty-day postoperative outcomes following SAVR were assessed. This included mortality, cardiac complications, stroke, pulmonary complications, renal complications, sepsis, venous thromboembolism (VTE), wound complications, and bleeding requiring transfusion. In addition, unplanned reoperation, discharge not to home, 30-day readmission, and length of stay (LOS) were compared.

Major 30-day morbidities were reported as composite outcomes according to the ACS-NSQIP definitions (12). Cardiac complications were defined as myocardial infarction and cardiac arrest requiring cardio-pulmonary resuscitation. Pulmonary complications consisted of pneumonia, unplanned reintubation, and prolonged mechanical ventilation for >48 hours. Renal complications included progressive renal insufficiency (rise in serum creatinine by >2 mg/dL compared to the preoperative value) and acute renal failure requiring renal replacement therapy. Wound complications included superficial and deep surgical site infections, organ space infections, and wound dehiscence.

Statistical analysis

All preoperative factors were compared by Fisher’s exact tests. For binary postoperative outcomes, multivariable logistic regression was used, adjusting for all preoperative factors that showed adequate differences (P<0.10 in Fisher’s exact test in Tables 1,2). Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were reported. The hospital LOS (right-skewed) was compared using generalized linear models (GLMs) while adjusting for all preoperative factors in Tables 1,2.

All statistical analyses were performed by SAS (version 9.4). A P value less than 0.05 was considered statistically significant. The ACS-NSQIP dataset was accessed from The George Washington University and all statistical analyses were performed within the site. The authors had full access to the ACS-NSQIP dataset and took full responsibility for the accuracy of the analyses.

Ethical considerations

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was exempt from the IRB approval by The George Washington University as it analyzed a retrospective, deidentified ACS-NSQIP dataset. And individual consent for this retrospective analysis was waived.

Results

From 2005 to 2022, there were 3,349 (30.74%) patients with anemia who underwent SAVR.

Table 1 summarizes the demographics of patients with and without anemia who underwent SAVR. Patients who had anemia were more likely to be female (46.16% vs. 28.22%, P<0.01), age over 75 years (75–85 years, 32.13% vs. 25.94%, P<0.01; over 85 years, 7.17% vs. 4.03%, P<0.01). Table 2 summarizes the characteristics of the two study cohorts. Patients with anemia were more likely to have diabetes mellitus (DM; 34.37% vs. 21.50%, P<0.01), dyspnea (50.28% vs. 45.23%, P<0.01), partially dependent functional status (4.87% vs. 1.07%, P<0.01), fully dependent functional status (1.64% vs. 0.27%, P<0.01), chronic obstructive pulmonary disease (COPD; 9.61% vs. 7.12%, P<0.01), congestive heart failure (CHF; 27.32% vs. 13.84%, P<0.01), hypertension (78.47% vs. 70.67%, P<0.01), acute kidney injury (AKI; 1.64% vs. 0.28%, P<0.01), dialysis (5.40% vs. 0.64%, P<0.01), preoperative sepsis (7.44% vs. 1.67%, P<0.01), infection (2.30% vs. 0.52%, P<0.01), steroid use (5.55% vs. 2.72%, P<0.01), weight loss (1.82% vs. 0.45%, P<0.01), bleeding disorders (10.00% vs. 5.57%, P<0.01), estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² (43.71% vs. 21.63%, P<0.01), and American Society of Anesthesiology (ASA) score of 4 or 5 (83.85% vs. 77.77%, P<0.01). In contrast, patients with anemia were less likely to have body mass index (BMI) >30 kg/m² (40.43% vs. 43.85%, P<0.01) or international normalized ratio (INR) >2 (34.88% vs. 45.71%, P<0.01).

Table 3 summarizes the thirty-day postoperative outcomes of patients with and without anemia who underwent SAVR by multivariable analysis. Patients with anemia had higher risks of mortality (6.51% vs. 2.85%; aOR =1.243; 95% CI: 1.002–1.549; P=0.04), cardiac complications (4.54% vs. 2.74%; aOR =1.280; 95% CI 1.018–1.609; P=0.03), pulmonary events (17.59% vs. 9.23%; aOR =1.270; 95% CI 1.110–1.454; P<0.01), renal dysfunction (7.55% vs. 3.06%; aOR =1.721; 95% CI: 1.397–2.120; P<0.01), sepsis (6.27% vs. 2.31%; aOR =1.568; 95% CI: 1.233–1.993; P<0.01), VTE (2.39% vs. 1.18%; aOR =1.497; 95% CI: 1.065–2.103; P=0.02), bleeding requiring transfusion (66.83% vs. 47.53%; aOR =1.800; 95% CI: 1.638–1.978; P<0.01), discharge not to home (35.32% vs. 25.65%; aOR =1.316; 95% CI: 1.180–1.468; P<0.01), and 30-day readmission (7.88% vs. 6.47%; aOR =1.181; 95% CI: 1.004–1.390; P=0.04). In addition, anemic patients had a longer LOS (13.45±11.09 vs. 9.25±9.13 days; F=59.98; P<0.01).

Discussion

This study assessed the impact of preoperative anemia on the 30-day outcomes of patients who underwent SAVR in the ACS-NSQIP database. It was found that anemic patients had higher risks of 30-day mortality, cardiac complications, pulmonary events, renal dysfunction, sepsis, VTE, and bleeding requiring transfusion. Additionally, anemic patients were more likely to be discharged to a destination other than home, with higher rates of 30-day readmission, and extended LOS.

Anemia has a high prevalence that affects approximately 24.3% of the global population of all age (13). In this study, over 30% of patients undergoing SAVR were found to have anemia, which exceeds the prevalence observed in the general population (13). AS is the culmination of an inflammatory process initiated by endothelial damage from mechanical stress, lipid infiltration leading to fibrosis, thickening of the leaflet, and ultimately calcification (14). Therefore, the significant proportion of anemic patients in the SAVR cohort could be attributed to the interconnected inflammatory pathways shared between AS and anemia. This correlation underscores the importance of exploring the impact of preoperative anemia on the outcomes of SAVR.

In this study, patients with anemia were found to have a higher burden of comorbidities, including DM, hypertension, COPD, CHF, chronic kidney disease (CKD), dependent functional status, and bleeding disorders. While anemia has traditionally been considered a condition secondary to chronic diseases, recent research indicates that it can independently affect mortality, morbidity, and quality of life, especially in individuals with CHF and CKD (15). Across various surgeries, anemia has been associated with increased mortality and complications, including in vascular surgery (16-18), colorectal surgery (19,20), and transplant surgery (21). Despite this study using multivariable analysis to control for all comorbidities, the higher comorbidity burdens associated with anemia can further affect surgical outcomes and complicate postoperative recovery in clinical practice.

In cardiac surgery, preoperative anemia has been associated with increased mortality and morbidity (5,22). This aligns with the findings of this study on patients undergoing SAVR, where even after multivariable adjustment for comorbidities, preoperative anemia was independently linked to higher risks of mortality and organ system complications (including cardiac, pulmonary, and renal), sepsis, VTE, and bleeding. This increased risk may be attributed to inadequate oxygen delivery and hypoxia at the cellular level caused by the decreased hemoglobin concentration in anemic patients, which can lead to disturbed intracellular homeostasis, reduced adenosine trisphosphate levels, and eventually cell swelling and death (23). This hypothesis is further supported by observations from a previous study that identified a dose-response relationship between the severity of anemia and mortality in elective cardiac surgery (22).

Despite growing evidence emphasizing the importance of preoperative anemia in surgical outcomes, it often remains underrecognized by physicians, and comprehensive management guidelines are yet to be established (24). Various therapeutic strategies have been proposed to manage anemia prior to cardiac surgery, including prevalent approaches like intravenous administration of iron and erythropoietin (24,25). In addition, newer treatments. such as anti-hepcidin therapy (26) and erythropoiesis stimulation, have been proposed (25,27). However, the effectiveness of anemia treatment depends on its underlying cause, which calls for individualized interventions (27). Also, it remains unclear whether correcting preoperative anemia can reduce postoperative complications (16). Particularly in cases of anemia of chronic disease (ACD), addressing anemia preoperatively may not lead to improved postoperative outcomes, as the anemia could be a manifestation of an underlying decline in physiological reserve (18). Nonetheless, preoperative anemia in SAVR patients warrants increased attention, and the effectiveness of targeted therapies in these patients requires further investigation.

This study is subject to a number of limitations. First, the ACS-NSQIP data does not record the etiology of anemia, thus limiting our conclusion of how ACD might influence the outcomes in SAVR. Moreover, the hemoglobin levels of the patients were not recorded. Being a correlational study, it is also not possible to establish a direct cause-and-effect relationship between anemia and postoperative outcomes. Additionally, the ACS-NSQIP lacks specific details such as the degree of stenosis, and does not permit the calculation of the Society of Thoracic Surgeons (STS) score (28) or the European System for Cardiac Operative Risk Evaluation (EuroScore) II (29). Furthermore, patients with anemia, who often have a higher burden of comorbidities, may be deemed unsuitable for open heart surgery and instead be directed towards TAVR, which introduces a potential selection bias. The ACS-NSQIP’s follow-up period is limited to 30 days after discharge, which constrains the assessment of long-term SAVR outcomes in patients with preoperative anemia. The selective participation of hospitals in the ACS-NSQIP program might also affect the generalizability of the study’s findings. However, it is important to recognize that the ACS-NSQIP is a nationally recognized database with a comprehensive sample size tailored for quality control for surgical outcomes, which can provide valuable insights into the impact of baseline anemia on SAVR (30).

Conclusions

In conclusion, this study compared the 30-day outcomes of patients with and without preoperative anemia who underwent SAVR. Anemic patients faced higher risks of 30-day mortality, cardiac complications, pulmonary events, renal dysfunction, sepsis, VTE, and bleeding. Additionally, anemic patients were more likely to be discharged to a facility other than home, experienced higher rates of 30-day readmission, underwent longer operations, and had extended hospital stays. Implementing enhanced screening for preoperative anemia could prove beneficial in risk stratification for patients undergoing SAVR. Future research should focus on evaluating therapeutic interventions for anemic patients for potential improvement in postoperative outcomes.

Acknowledgments

The authors acknowledge Dr. Richard Amdur, PhD, for giving statistical support for this project.

Funding: None.

Footnote

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-23/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-23/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 study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was exempt from the IRB approval by The George Washington University as it analyzed a retrospective, deidentified ACS-NIQIP dataset. And individual consent for this retrospective analysis was waived.

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/.

References

1. Osnabrugge RL, Mylotte D, Head SJ, et al. Aortic stenosis in the elderly: disease prevalence and number of candidates for transcatheter aortic valve replacement: a meta-analysis and modeling study. J Am Coll Cardiol 2013;62:1002-12. [Crossref] [PubMed]
2. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187-98. [Crossref] [PubMed]
3. Carroll JD, Mack MJ, Vemulapalli S, et al. STS-ACC TVT Registry of Transcatheter Aortic Valve Replacement. J Am Coll Cardiol 2020;76:2492-516. [Crossref] [PubMed]
4. Zhang XL, Zhang XW, Lan RF, et al. Long-term and Temporal Outcomes of Transcatheter Versus Surgical Aortic-valve Replacement in Severe Aortic Stenosis: A Meta-analysis. Ann Surg 2021;273:459-66. [Crossref] [PubMed]
5. Yerasi C, Rogers T, Forrestal BJ, et al. Transcatheter Versus Surgical Aortic Valve Replacement in Young, Low-Risk Patients With Severe Aortic Stenosis. JACC Cardiovasc Interv 2021;14:1169-80. [Crossref] [PubMed]
6. Ducharme-Smith A, Chahal CAA, Sawatari H, et al. Relationship Between Anemia and Sudden Cardiac Death in Patients With Severe Aortic Stenosis. Am J Cardiol 2020;136:107-14. [Crossref] [PubMed]
7. Guralnik JM, Eisenstaedt RS, Ferrucci L, et al. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood 2004;104:2263-8. [Crossref] [PubMed]
8. Nagao K, Taniguchi T, Morimoto T, et al. Anemia in Patients with Severe Aortic Stenosis. Sci Rep 2019;9:1924. [Crossref] [PubMed]
9. Jiménez-Xarrié E, Asmarats L, Roqué-Figuls M, et al. Impact of Baseline Anemia in Patients Undergoing Transcatheter Aortic Valve Replacement: A Prognostic Systematic Review and Meta-Analysis. J Clin Med 2023;12:6025. [Crossref] [PubMed]
10. American College of Surgeons. History. Accessed August 25, 2024. Available online: https://www.facs.org/quality-programs/data-and-registries/acs-nsqip/history/
11. Billett HH. Hemoglobin and Hematocrit. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston: Butterworths; 1990: Chapter 151.
12. American College of Surgeons. ACS National Surgical Quality Improvement Program. Accessed August 26, 2024. Available online: https://www.facs.org/quality-programs/data-and-registries/acs-nsqip/
13. Prevalence, years lived with disability, and trends in anaemia burden by severity and cause, 1990-2021: findings from the Global Burden of Disease Study 2021. Lancet Haematol 2023;10:e713-34. [Crossref] [PubMed]
14. Dweck MR, Boon NA, Newby DE. Calcific aortic stenosis: a disease of the valve and the myocardium. J Am Coll Cardiol 2012;60:1854-63. [Crossref] [PubMed]
15. Nissenson AR, Goodnough LT, Dubois RW. Anemia: not just an innocent bystander? Arch Intern Med 2003;163:1400-4. [Crossref] [PubMed]
16. Dakour-Aridi H, Nejim B, Locham S, et al. Anemia and postoperative outcomes after open and endovascular repair of intact abdominal aortic aneurysms. J Vasc Surg 2019;69:738-751.e2. [Crossref] [PubMed]
17. Diehm N, Benenati JF, Becker GJ, et al. Anemia is associated with abdominal aortic aneurysm (AAA) size and decreased long-term survival after endovascular AAA repair. J Vasc Surg 2007;46:676-81. [Crossref] [PubMed]
18. Gupta PK, Sundaram A, Mactaggart JN, et al. Preoperative anemia is an independent predictor of postoperative mortality and adverse cardiac events in elderly patients undergoing elective vascular operations. Ann Surg 2013;258:1096-102. [Crossref] [PubMed]
19. Deng Y, Weng M, Zhang J. Preoperative anemia and long-term survival in patients undergoing colorectal cancer surgery: a retrospective cohort study. World J Surg Oncol 2023;21:122. [Crossref] [PubMed]
20. Quinn EM, Meland E, McGinn S, et al. Correction of iron-deficiency anaemia in colorectal surgery reduces perioperative transfusion rates: A before and after study. Int J Surg 2017;38:1-8. [Crossref] [PubMed]
21. Hernandez-Morgan M, Neelankavil J, Grogan T, et al. Preoperative Anemia as a Risk Factor for Postoperative Outcomes in Patients Undergoing Lung Transplantation. J Cardiothorac Vasc Anesth 2021;35:2311-8. [Crossref] [PubMed]
22. Hazen YJJM, Noordzij PG, Gerritse BM, et al. Preoperative anaemia and outcome after elective cardiac surgery: a Dutch national registry analysis. Br J Anaesth 2022;128:636-43. [Crossref] [PubMed]
23. Michiels C. Physiological and pathological responses to hypoxia. Am J Pathol 2004;164:1875-82. [Crossref] [PubMed]
24. Weiss G. Anemia of Chronic Disorders: New Diagnostic Tools and New Treatment Strategies. Semin Hematol 2015;52:313-20. [Crossref] [PubMed]
25. Kloeser R, Buser A, Bolliger D. Treatment Strategies in Anemic Patients Before Cardiac Surgery. J Cardiothorac Vasc Anesth 2023;37:266-75. [Crossref] [PubMed]
26. Nemeth E. Anti-hepcidin therapy for iron-restricted anemias. Blood 2013;122:2929-31. [Crossref] [PubMed]
27. Kidanewold A, Woldu B, Enawgaw B. Role of Erythropoiesis Stimulating Agents in the Treatment of Anemia: a Literature Review. Clin Lab 2021; [Crossref] [PubMed]
28. The Society of Thoracic Surgeons. ACSD Operative Risk Calculator. Accessed October 23, 2023. Available online: https://www.sts.org/resources/acsd-operative-risk-calculator
29. Nashef SA, Roques F, Sharples LD, et al. EuroSCORE II. Eur J Cardiothorac Surg 2012;41:734-44; discussion 744-5. [Crossref] [PubMed]
30. Li R, Sidawy A, Nguyen BN. Comparative assessment of racial disparity in 30-day outcomes for Asian Americans undergoing carotid endarterectomy. J Vasc Surg 2024;79:1132-41. [Crossref] [PubMed]