Background: Acute coronary syndrome (ACS) is one of the leading causes of cardiovascular mortality worldwide. Fibrinogen, a key mediator of coagulation and inflammation, remains controversial in its prognostic value. This meta-analysis aims to evaluate the predictive role of fibrinogen in ACS patient outcomes. 

Methods: Following PRISMA guidelines, we systematically searched PubMed, Embase, and other databases (from inception to November 2024) for cohort or case-control studies assessing the association between fibrinogen and ACS outcomes (all-cause mortality/major adverse cardiovascular events [1]). Study quality was evaluated using the Newcastle-Ottawa Scale (NOS), and pooled effect sizes were calculated using random- or fixed-effects models. Subgroup and sensitivity analyses were performed. 

Results: Nine studies (12,714 patients) were included. Elevated fibrinogen levels significantly increased the risk of all-cause mortality (HR = 1.51, 95% CI: 1.27-1.81, p < 0.001), but no significant association was found with MACE (HR = 3.00, 95% CI: 0.96-9.39, p > 0.05). Subgroup analysis suggested regional differences as a source of heterogeneity. Conclusion: Fibrinogen may serve as an independent predictor of all-cause mortality in ACS patients, but its prognostic value for MACE requires further investigation. Future studies should explore its potential in clinical risk stratification. 

Acute coronary syndrome (ACS) is a major global cause of cardiovascular Mmorbidity and mortality [1], particularly in high-risk populations such as patients with diabetes or dyslipidemia, where the risk of adverse outcomes is significantly elevated. Despite advances in percutaneous coronary intervention (PCI) and antithrombotic therapies, some patients still experience recurrent events and long-term cardiovascular mortality [2], highlighting the need for more precise prognostic tools. NF Zibrinogen, a critical mediator in both coagulation and inflammatory pathways [3], has garnered increasing attention for its role in ACS pathophysiology [4]. Elevated fibrinogen levels are associated with plaque instability and may directly influence clinical outcomes by promoting thrombosis and microvascular dysfunction [5]. Although existing studies have demonstrated the prognostic significance of fibrinogen, its role in ACS remains debated. For instance, a meta-analysis of acute myocardial infarction (AMI) patients found that elevated fibrinogen levels (HR = 1.218, 95% CI: 1.027-1.444, p= 0.02) independently predicted long-term cardiac mortality, with each 1 g/L increase associated with a 21.8% higher risk of death. The AUC for predicting AMI-related mortality was 0.684 (p< 0>

This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [17]. The protocol was registered on PROSPERO (CRD42024621282).

Search strategy

We conducted comprehensive searches in PubMed, Embase, Cochrane Library, and Web of Science databases. The search timeframe spanned from each database's inception to November 25, 2024, with results limited to English-language publications. Our search methodology employed a combination of Medical Subject Headings (MeSH) and free-text terms, with the primary search terms being "Fibrinogen" and "Acute Coronary Syndrome. "To ensure thorough literature coverage, we additionally: Manually examined reference lists of relevant articles; Searched grey literature sources; Performed backward citation tracking. The complete search strategy, including all specific search terms and syntax variations for each database, is provided in Appendix 1. Inclusion/Exclusion Criteria Studies were included if they: (1) enrolled ACS patients, (2) measured baseline fibrinogen levels, (3) were cohort or case-control designs, and (4) reported all-cause mortality. Exclusions: animal/cell studies, case reports, reviews, editorials, conference abstracts, duplicate publications, or studies with missing/unavailable data.

Two reviewers independently screened titles/abstracts and full texts using EndNote. Discrepancies were resolved via discussion or consultation with a third reviewer. Data on study characteristics, patient demographics, outcomes, and treatments were extracted using a standardized form. Quality Assessment NStudy quality was evaluated using the NOS (0-9 scale). Scores ≥6 indicated high quality. N Statistical Analysis STATA 15.1 was used to pool hazard ratios (HRs) with 95% CIs. I Heterogeniety was assessed via ²and Cochran's Qtests (I²> 50% or p< 0>

Study Selection From 12,670 records, 9 studies [4-6, 9-14] (12,714 patients) were included after screening (Figure 1).

                                                                                         Figure 1: PRISMA fowchart of literature search and study selection

Baseline Characteristics

The studies [4-6, 9-14] spanned three countries (China, Spain, Greece), with 8,219 male and 2,987 female patients (mean age: 61.3 ± 10.2 years). All studies had NOS scores ≥6 (Table 1).

                                        Table 1: Basic characteristics of included studies in this meta-analysis 

Meta- Analysis Findings

All-Cause Mortality

Nine studies involving 12,714 patients were included in the analysis of this outcome. Heterogeneity assessment revealed significant variation across studies (I² = 68%, P = 0.002), prompting the use of a random-effects model. The pooled results demonstrated that patients with elevated fibrinogen levels had significantly higher risk of all-cause mortality compared to controls (HR = 1.51, 95% CI: 1.27-1.81,  p less than 0.001).Forest plot visualization showed consistent direction of effect across most studies (Figure 2).

Figure 2: forest plots of association between all-cause mortality and fibrinogen in patients with acs 

Subgroup Analysis:

 Regional subgroup analysis revealed differential effects between Asian and European populations (Figure 3). The European subgroup showed more pronounced fibrinogen elevation (fibrinogen = 0.69, 95% CI: 0.39 to 0.99) compared to the Asian subgroup. Notably, within-group heterogeneity was reduced in both Asian (P = 0.044, I² = 59.1%) and European (P = 0.100, I² = 52.0%) subgroups, suggesting regional differences contribute substantially to overall heterogeneity.

Figure3: Forestplot of association between all-cause mortality and fibrinogen in patients with ACS.

Analysis by study design (cohort vs. case-control) showed no significant differences between groups (Figure 4). The case-control subgroup demonstrated an effect size of HR = 0.23 (95% CI: 0.06 to 0.39) while cohort studies showed HR = 0.24 (95% CI: 0.1 to 0.32), indicating study design was not a major source of heterogeneity.

Figure4: Forestplot of association between all-cause mortality and fibrinogen in patients with ACS

2、Sensitivity Analysis

To evaluate result robustness, we conducted leave-one-out sensitivity analysis (Figure 5). Sequentially excluding each study and recalculating the pooled effect size revealed stable estimates throughout, with all recalculated HRs remaining within the 95% CI of the primary analysis (range: 1.47-1.54). This consistency confirms our findings are not disproportionately influenced by any single study. 

                                                                                                      Figure 5: Sensitivity analysis.

3、Publication Bias

For outcomes with ≥9 studies (all-cause mortality), we assessed publication bias using funnel plot symmetry and Egger's test (Figure 6). Visual inspection of the funnel plot revealed mild asymmetry, with smaller studies showing more positive effects. This was confirmed quantitatively by Egger's test (p < 0>

Figure 6: Publication bias tests for OS and PFS
4 MACE Outcomes

Only two studies (n = 771 patients) reported data on major adverse cardiovascular events. Considerable heterogeneity was observed (I² = 89.6%, P = 0.002), necessitating a random-effects model. The pooled analysis showed no statistically significant association between fibrinogen levels and MACE risk (HR = 3.00, 95% CI: 0.96-9.39, p > 0.05) (Figure 7). The wide confidence interval reflects substantial uncertainty in this estimate.

5 Meta-Regression

For outcomes with significant heterogeneity (I² > 50%) and adequate study numbers (n ≥ 9), we performed meta-regression to explore potential moderators. Neither sample size (coefficient = 0.0001, p = 0.89) nor gender distribution (coefficient = -0.012, p = 0.76) showed significant associations with effect size magnitude, suggesting these factors do not explain the observed heterogeneity.

                                                                   Figure 7: Forest plot of association between MACE and fibrinogen in patients with ACS

This meta-analysis, incorporating 9 high-quality studies involving 12,714 patients, demonstrated a significant association between elevated fibrinogen levels and increased risk of all-cause mortality in ACS patients (HR=1.51, 95%CI: 1.27–1.81), supporting its role as an independent prognostic factor. However, the predictive value of fibrinogen for MACE did not reach statistical significance (HR=3.00, 95%CI: 0.96–9.39), which may be attributed to the limited number of included studies or heterogeneity in MACE definitions [18, 19]. The prognostic significance of fibrinogen likely stems from its dual pathophysiological mechanisms. As a key mediator in the coagulation cascade, elevated fibrinogen promotes platelet aggregation and thrombus formation [20-22], exacerbating coronary microcirculatory dysfunction. Additionally, through leukocyte and endothelial cell activation, fibrinogen contributes to plaque destabilization and myocardial reperfusion injury[23, 24]. Subgroup analysis further suggested potential regional variations (Europe vs. Asia) in the fibrinogen-outcome relationship, warranting further investigation into population-specific factors such as genetic background and treatment differences. Our findings provide evidence-based support for incorporating fibrinogen into ACS risk stratification. Baseline fibrinogen levels may serve as an early warning indicator for all-cause mortality, particularly offering supplementary value for intermediate-risk patients classified by traditional scoring systems [4-6]. Patients with elevated fibrinogen might benefit from intensified antithrombotic and anti-inflammatory therapies [25, 26], though optimal treatment strategies require validation through prospective studies. Several limitations should be acknowledged. First, the predominance of observational studies introduces potential residual confounding. Second, the lack of standardized fibrinogen assays and cutoff values may contribute to heterogeneity. Third, conclusions regarding MACE remain tentative due to the limited number of relevant studies. Finally, the analysis did not thoroughly explore potential effect modifications by ACS subtypes (e.g., STEMI vs. NSTEMI) or comorbidities (e.g., diabetes).

Future research should focus on multicenter prospective studies to clarify fibrinogen's role in MACE prediction. Investigating the dynamic changes in fibrinogen levels rather than relying solely on baseline measurements may yield additional prognostic insights. Furthermore, integrating fibrinogen with established risk scores (e.g., GRACE) could enhance the precision of risk prediction tools in ACS management.

• ACS Acute coronary syndrome
• PCI Percutaneous Coronary Intervention NOS      
• Newcastle-Ottawa Scale
• AMI acute myocardial infarction
• PRISMA  Preferred Reporting Items for Systematic Reviews and Meta-Analyses MACE  Major 
• Adverse Cardiovascular Events STEMI Stsegment Elevation Myocardial Infarction
• NSTEMI Non stsegment Elevation Myocardial Infarction

Funding

None