Residual Platelet Reactivity and Dyslipidemia in Post-CABG Patients Undergoing Repeat Revascularization: Insights from Kazakhstan

1. Introduction

Coronary artery bypass grafting (CABG) remains a cornerstone in the management of advanced coronary artery disease (CAD), especially in patients with multivessel involvement. While surgical revascularization provides symptomatic relief and mortality benefit, a considerable proportion of patients continue to experience recurrent ischemic symptoms and adverse cardiovascular events during follow-up.

Platelets play a central role in the pathogenesis of atherosclerosis and arterial thrombosis. High residual platelet reactivity (HRPR), even under antiplatelet therapy, is a well-established predictor of major adverse cardiovascular events, including myocardial infarction (MI), stroke, and stent thrombosis [1,2]. Patients with multivessel CAD undergoing CABG have been shown to exhibit higher levels of HRPR compared to those with single-vessel disease. Several comorbidities—including dyslipidemia, anemia, chronic kidney disease (CKD), reduced left ventricular ejection fraction (LVEF), and overweight/obesity—are strongly associated both with HRPR and with the presence of extensive coronary disease, thereby amplifying the risk of recurrent ischemic events [3,4].

The prothrombotic role of platelets is particularly important in patients receiving long-term antiplatelet therapy aimed at reducing MI and stroke incidence. Anemia, common among patients with chronic heart failure (CHF), is linked to impaired response to clopidogrel, increased HRPR, higher hospitalization rates, and worse survival [5,6,7]. Renal dysfunction further diminishes antiplatelet efficacy and contributes to poor outcomes [8]. HRPR has consistently been recognized as a poor prognostic marker in acute coronary syndrome (ACS) [9]. Smoking, dyslipidemia, and elevated cholesterol levels additionally enhance platelet activation and thrombotic risk [4,5]. Moreover, obesity—particularly class I—has been associated with increased HRPR during antiplatelet therapy [10].

In the post-CABG setting, hemostatic alterations induced by cardiopulmonary bypass may further influence platelet function and predispose to enhanced platelet activation [11]. The pathophysiological mechanism linking HRPR to cardiovascular complications primarily involves exaggerated platelet aggregation and thrombus formation [12,13,14]. Consequently, HRPR is considered an independent risk factor for recurrent ischemic events, including MI, graft failure, stent thrombosis, and cardiovascular death [15,16].

Importantly, dyslipidemia represents a modifiable determinant of both platelet hyperreactivity and atherosclerotic progression. Failure to achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) targets—particularly <1.4 mmol/L in very-high-risk patients according to the 2019/2021 ESC guidelines—significantly increases the risk of recurrent ischemia and need for repeat revascularization. Thus, strict lipid control remains a cornerstone of secondary prevention in post-CABG patients and is crucial for improving long-term outcomes.

In this study, we analyzed 200 post-CABG patients from a tertiary cardiac center in Kazakhstan. Recurrent angina was observed in 94% (n=188), and 68% (n=136) required repeat percutaneous coronary intervention (PCI) after coronary angiography. Our aim was to identify the predominant clinical phenotypes associated with these outcomes, with particular emphasis on dyslipidemia and inadequate LDL-C control, residual platelet reactivity despite dual antiplatelet therapy, anemia, CKD, and heart failure (HF).

2. Materials and Methods

Study Design and Setting

This observational single-center cohort study was conducted from January 2023 to December 2024 at the Research Institute of Cardiology and Internal Medicine, a tertiary-level cardiovascular center in Almaty, Kazakhstan. The study aimed to evaluate residual platelet reactivity and dyslipidemia as risk factors for repeat revascularization in patients with established coronary artery disease (CAD) who previously underwent coronary artery bypass grafting (CABG).

Patient Population

Eligible participants were adult patients (≥18 years) with a documented history of coronary artery bypass grafting (CABG) and a diagnosis of stable coronary artery disease (CAD) who were admitted for repeat coronary angiography due to recurrent ischemic symptoms.

Inclusion Criteria:

Prior history of CABG

Documented stable CAD

Clinical and/or instrumental evidence of recurrent myocardial ischemia (e.g., angina, positive stress test, ischemic ECG changes)

Exclusion Criteria:

Presence of atrial fibrillation

Current use of oral anticoagulant therapy (e.g., rivaroxaban, apixaban, dabigatran)

Diagnosis of acute coronary syndrome (ACS) at the time of admission

A detailed flowchart of patient selection, including inclusion and exclusion criteria, is presented in Figure 1.

Residual Platelet Reactivity Assessment

Residual platelet reactivity (RPR) was evaluated using the VerifyNow P2Y12 assay (Instrumentation Laboratory, Bedford, MA, USA), a point-of-care system that quantifies platelet inhibition and reports results as P2Y12 Reaction Units (PRU). High residual platelet reactivity (HRPR) was defined as PRU ≥208, in accordance with current international consensus guidelines.

Clinical and Laboratory Data Collection

Baseline demographic, clinical, and pharmacological characteristics were extracted from electronic medical records. The following parameters were systematically evaluated:

Lipid profile: Total cholesterol, LDL-C, HDL-C, triglycerides

Renal function: Serum creatinine and estimated glomerular filtration rate (eGFR) to identify chronic kidney disease (CKD)

Hemoglobin level: Assessed for anemia according to WHO criteria

Left ventricular ejection fraction (LVEF): Measured via transthoracic echocardiography

Body mass index (BMI): Used to classify overweight and obesity

Cardiovascular complications: Including heart failure, diabetes mellitus, and prior myocardial infarction

All patients were treated with guideline-directed medical therapy in accordance with the 2024 European Society of Cardiology (ESC) recommendations for the management of chronic coronary syndromes.

Ethical Considerations

The study was conducted in accordance with the ethical principles of the Declaration of Helsinki. Ethical approval was obtained from the Local Ethics Committee of Asfendiyarov Kazakh National Medical University, Almaty, Republic of Kazakhstan (Protocol No. 11(134); Date: 04 November 2022). Written informed consent was obtained from all participants prior to enrollment.

Statistical Analysis

The data are presented as Median [Quartile 1; Quartile 3], as the majority of the quantitative variables do not follow a normal distribution. Between-group comparisons were performed using the Mann–Whitney U test for quantitative variables, or the chi-squared test (Fisher’s exact test when the number of observations was small) for qualitative variables. Categorical variables were expressed as frequencies and percentages. Normality of continuous variables, including PRU values, was assessed using the Shapiro–Wilk test. For comparisons of continuous variables between groups (e.g., HRPR vs. non-HRPR) Mann–Whitney U test was used as appropriate. Categorical variables were analyzed using the Chi-square test or Fisher’s exact test. A stepwise logistic regression analysis was performed to identify predictors associated with the risk of stenting after coronary artery bypass grafting (CABG). A p-value < 0.05 was considered statistically significant. All statistical tests were two-sided, and 95% confidence intervals (CIs) were reported when relevant.

3. Results

A total of 195 post-CABG patients were included in the final analysis. Among them, 136 patients (69.7%) underwent repeat percutaneous coronary intervention (PCI), whereas 59 patients (30.3%) did not require reintervention. Baseline demographic, clinical, laboratory, and instrumental characteristics were systematically compared between the two groups (Table 1).

Demographic and Clinical Characteristics

Patients requiring repeat PCI were significantly older than those without reintervention (median age: 71.0 [IQR 65.8–75.0] vs. 66.0 [61.5–73.0] years; p = 0.016). No significant difference in sex distribution was observed (p = 0.431). Current smoking was more frequent in the non-reintervention group (54.2% vs. 28.7%; p = 0.001), whereas alcohol consumption rates were low and comparable (p = 0.164). Systolic blood pressure was higher in the repeat PCI group (130 [120–140] vs. 120 [110–130] mmHg; p = 0.041), while diastolic pressure did not differ significantly.

Comorbidities and Medical History

The prevalence of hypertension, diabetes mellitus, prior myocardial infarction, stroke, chronic kidney disease (CKD), anemia, and obesity was similar between groups. However, a higher frequency of prior CABG was noted among patients undergoing reintervention (96.3% vs. 83.1%; p = 0.003).

Biochemical and Hematological Parameters

No significant group differences were found in lipid profile (total cholesterol, LDL-C, HDL-C, triglycerides), glycemic control (glucose, HbA1c), renal function (creatinine, eGFR), liver enzymes (ALT, AST), inflammatory markers (CRP), or thyroid function (TSH, T4). Interestingly, cardiac troponin levels were lower in the reintervention group (14.3 [10.3–32.8] vs. 20.0 [13.4–95.4] ng/L; p = 0.002), possibly reflecting differences in post-CABG myocardial injury dynamics.

Platelet Reactivity

Patients undergoing repeat PCI exhibited significantly higher platelet reactivity. Median PRU was 230 [200–274] versus 145 [140–155] (p < 0.001). Moreover, high residual platelet reactivity (HRPR) was present in 66.2% of the reintervention group compared to 0% in the control group (p < 0.001).

Echocardiographic Findings

End-diastolic volume (EDV) was lower in the reintervention group (136 [113–179] vs. 162 [129–206] mL; p = 0.038). Posterior wall thickness (PWT) was also higher (1.10 [1.00–1.20] vs. 1.05 [0.90–1.20] cm; p = 0.030). No significant differences were observed for LVEF, stroke volume, left atrial/ventricular dimensions, or pulmonary artery pressure.

Coronary Angiographic Findings

Patients with repeat PCI demonstrated more extensive coronary artery disease. Significant stenosis was more frequently detected in:

LAD: 52.9% vs. 27.1% (p = 0.002)

LCx: 37.5% vs. 13.6% (p = 0.002)

Diagonal branch: 30.9% vs. 8.5% (p = 0.001)

PDA: 16.9% vs. 1.7% (p = 0.006)

SVGs: 25.0% vs. 5.1% (p = 0.002)

The number of bypass grafts (3.00 [2.00–3.00] vs. 2.00 [2.00–3.00]; p < 0.001) and diseased vessels (4.00 [3.75–5.00] vs. 3.00 [2.00–3.00]; p < 0.001) was also higher in the reintervention group.

Medical Therapy

All patients received statin therapy. Ezetimibe was prescribed more frequently in the reintervention group (34.6% vs. 0%; p < 0.001), suggesting intensified lipid-lowering strategies in patients with progressive disease.

Symptoms and Outcomes

Persistent angina post-CABG was reported in all reintervention patients compared to 88.1% in the control group (p < 0.001). No significant difference in post-CABG mortality was observed.

Summary of Key Findings

High residual platelet reactivity was strongly associated with repeat revascularization.

Older age, greater coronary involvement, and higher number of bypass grafts predicted the need for reintervention.

Despite similar baseline lipid levels, patients requiring repeat PCI were more frequently prescribed ezetimibe.

The prevalence of anemia, CKD, and diabetes was similar between groups, suggesting HRPR and coronary disease burden play a more central role in post-CABG ischemic recurrence.

A total of 195 patients with a history of coronary artery bypass grafting (CABG) were included in the analysis. Based on platelet reactivity (PRU) and clinical criteria, patients were stratified into two groups: those who achieved the therapeutic window for antiplatelet therapy (n = 105) and those classified as having a high residual thrombotic risk (HRTR; n = 90). Comparative analyses of demographic, clinical, laboratory, and angiographic characteristics were performed (Table 2).

Demographic and Clinical Characteristics

No significant differences were observed between the groups regarding age (69.0 [62.0–74.0] vs. 70.5 [65.2–75.0] years; p = 0.147), sex distribution (p = 0.871), or body mass index (BMI; p = 0.096). Interestingly, the prevalence of current smoking was lower in the HRTR group compared with the therapeutic window group (27.8% vs. 43.8%; p = 0.030). Patients in the HRTR group exhibited significantly higher systolic blood pressure (130 [120–140] vs. 120 [115–130] mmHg; p = 0.031) and fasting glucose levels (5.90 [5.23–7.10] vs. 5.54 [5.00–6.20] mmol/L; p = 0.022). A prior history of stroke was also more frequent in the HRTR group (13.3% vs. 3.81%; p = 0.031).

Angiographic Findings

Patients with HRTR had more extensive coronary artery disease, with significantly higher rates of multivessel involvement. Severe stenoses were more prevalent in the proximal left anterior descending artery (57.8% vs. 34.3%; p = 0.002), left circumflex artery (42.2% vs. 20.0%; p = 0.001), diagonal branches (34.4% vs. 15.2%; p = 0.003), posterior descending artery (21.1% vs. 4.76%; p = 0.001), and venous bypass grafts (33.3% vs. 6.67%; p < 0.001). Furthermore, the HRTR group had a higher number of diseased vessels (4.00 [4.00–5.00] vs. 3.00 [2.00–3.00]; p < 0.001) and bypass grafts (3.00 [2.00–4.00] vs. 2.00 [2.00–3.00]; p = 0.001).

Platelet Reactivity and Clinical Outcomes

Platelet reactivity was markedly elevated in the HRTR group (PRU: 255 [230–280] vs. 170 [141–200]; p < 0.001), indicating a suboptimal response to dual antiplatelet therapy. Consistently, all patients in the HRTR group underwent post-CABG stenting (100% vs. 43.8%; p < 0.001) and experienced recurrent angina (100% vs. 93.3%; p = 0.016).

Medical Therapy

All patients were treated with statins; however, ezetimibe was prescribed significantly more often in the HRTR group (47.8% vs. 3.81%; p < 0.001), reflecting attempts at intensified lipid-lowering therapy.

Summary of Findings

Patients classified as HRTR exhibited:

More extensive and severe coronary atherosclerosis;

Higher platelet reactivity despite dual antiplatelet therapy;

Increased frequency of recurrent angina and need for repeat revascularization;

Greater use of adjunctive lipid-lowering therapy.

These findings emphasize the role of HRTR as a marker of poor outcomes in post-CABG patients and underscore the importance of individualized antiplatelet and lipid-lowering strategies in this high-risk population.

A stepwise logistic regression analysis was performed to identify predictors associated with the risk of stenting after coronary artery bypass grafting (CABG). Due to the relatively small sample size (n = 195) and a large number of potential covariates, a stepwise forward/backward selection algorithm was employed (Table 3, picture 1).

Figure 2. Stepwise logistic regression: predictors associated with the risk of developing stenting after CABG.

Figure 2. Stepwise logistic regression: predictors associated with the risk of developing stenting after CABG.

Among the variables included in the regression analysis, the number of affected vessels emerged as the strongest and statistically significant predictor of post-CABG stenting. Patients with more extensive coronary involvement had markedly higher odds of requiring stent implantation (Odds Ratio [OR] = 52.67; 95% CI: 17.33–213.77; p < 0.001).

Conversely, the use of ezetimibe was independently associated with a significantly lower risk of stenting (OR = 0.12; 95% CI: 0.02–0.75; p = 0.023), suggesting a potential protective effect of this lipid-lowering therapy in the postoperative setting.

Other factors, including thyroid-stimulating hormone (TSH) levels (OR = 0.87; 95% CI: 0.72–1.00; p = 0.116), serum potassium (OR = 2.53; 95% CI: 0.78–8.59; p = 0.127), and glycated hemoglobin (HbA1c) (OR = 1.18; 95% CI: 0.95–1.46; p = 0.138), did not reach statistical significance but were retained in the final model as clinically relevant covariates.

The regression model demonstrated good explanatory power, with a Tjur’s R² of 0.681, indicating that a substantial proportion of the variance in stenting risk was explained by the selected predictors.

Collectively, these findings emphasize the critical role of disease burden in determining the need for repeat revascularization, while also highlighting the potential benefit of ezetimibe as part of intensified secondary prevention strategies in post-CABG patients.