Predictive Value of the COP-INH Score for Adverse Cardiovascular Events After PCI in ACS Patients

Introduction

Dual antiplatelet therapy (DAPT), which includes aspirin and a P2Y12 receptor antagonist, is recommended for at least 1 year post percutaneous coronary intervention (PCI) with drug-eluting stents. This regimen aims to reduce the incidence of stent thrombosis and major adverse cardiac events (MACE).^1,2 However, variations in aspirin tolerance and clopidogrel reactivity, along with a strong association between high residual platelet reactivity (HRPR) post-clopidogrel treatment and increased risk of clinical adverse events after PCI,^3,4 necessitate regular monitoring of platelet function. The VerifyNow P2Y12 assay, a common method for assessing platelet aggregation function.^5,6 However, as a whole blood assay, VerifyNow can be influenced by variables such as platelet or leukocyte counts, as well as haemoglobin or haematocrit.⁷ To address this question, we took the opportunity of VerifyNow P2Y12 system to measure P2Y12 reactivity and platelet inhibition rate, calculating the combination of P2Y12 reaction unit (PRU) and percentage of platelet inhibition (%INH) score (combination of PRU and %INH COP-INH), and to investigate the correlation between COP-INH scores and adverse cardiovascular events in patients with acute coronary syndrome (ACS) undergoing PCI. To facilitate the early identification of the patients with high aspirin tolerance or high residual platelet reactivity to clopidogrel, and reducing the risk of adverse clinical events post-PCI.

Materials and Methods

The study was conducted in accordance with the Declaration of Helsinki and the Institutional Review Board of Jinggangshan University approved the study protocol. Written informed consent was obtained from each participant before any sample or data collection.

Study Design and Patients

This study analyzed 337 patients with ACS who underwent PCI at the Ji’an Central People’s Hospital affiliated Jinggangshan University, from November 2017 to December 2023.

After excluding participants with factors such as stable coronary artery disease, current use of anticoagulant or antiplatelet medications, contraindications to aspirin or clopidogrel, severe liver or kidney dysfunction (serum creatinine >2 mg/dL or alanine transaminase levels >3 times the normal limit), thrombocytopenia (less than 100×10⁹/L), recent stroke or transient ischemic attack within the last 3 months, and in-hospital death, 226 participants were included in the study. The participant selection process is depicted in Figure 1.

Figure 1 Patient inclusion flowchart.

Coronary Angiography and Drug Treatment

Coronary angiography and PCI procedures were performed according to standard protocols.^8,9 All patients received a loading dose of 300 mg clopidogrel and 300 mg aspirin prior to the operation. Postoperatively, they were maintained on 75 mg of clopidogrel and 100 mg of aspirin daily for 12 months. The use of statins, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers followed established guidelines.⁸

Blood Sample and Platelet Reactivity Assay

To ensure pharmacological efficacy and stability of platelet function, all patients underwent a VerifyNow P2Y12 test 30 days after PCI, a time window considered adequate to the achievement of a steady state of pharmacologic activity and clinical state.¹⁰ The VerifyNow P2Y12 assay is a common tool for assessing platelet reactivity used to evaluate the responsiveness of clopidogrel and other thienopyridines.¹¹ This assay measures P2Y12 reactivity, including the P2Y12 reaction unit (PRU) post-drug treatment, baseline values (BASE), and the degree of platelet aggregation and inhibition (%INH). The formula to calculate the platelet inhibition rate is: [(BASE−PRU)/BASE]× 100 [(BASE−PRU)/BASE]×100, representing the change in values before and after treatment.¹²

Patients were considered to have poor responsiveness to clopidogrel if the PRU was ≥230³ or the inhibition rate (%INH) was <40%.¹¹ The COP-INH score was calculated based on the data obtained 30 days post-PCI: patients who exhibited both increased PRU and decreased %INH received a score of 2, those with either an increase or decrease in one category received a score of 1, and those without changes in both categories received a score of 0.

Definitions and Endpoints of the Study

The occurrence of MACE was recorded from the start of the VerifyNow test. MACE in this study was defined as death from combined cardiovascular causes, non-fatal myocardial infarctions (MIs), and target vessel revascularizations (either PCI or coronary artery bypass grafting [CABG]). All deaths, unless clearly of non-cardiac origin, were classified as cardiac deaths. The analysis of study endpoints was conducted for all patients at 12 months post-operation.

Power Calculation

We postulated that the average difference in MACE rate between the two groups would be 15%.¹³ Therefore, for 90% power and an alpha riskof 5%, we estimated that 160 patients should be included in each group. We estimated that 5% of patients would be lost to follow-up, so the target number of included patients was 337.

Statistical Analysis

Statistical analyses were performed using SPSS version 20.0. For continuous variables, means were compared using a t-test and presented as arithmetic mean ± standard deviation. Categorical variables were analyzed using chi-square tests or Fisher’s exact test when appropriate. Odds ratios and 95% confidence intervals were calculated using either univariate or multivariate regression models. The cumulative incidence of MACE was compared using Kaplan–Meier survival analysis and the Log rank test. Statistical significance was indicated by a p-value <0.05.

Results

A total of 337 patients completed the 12-month follow-up, with an average follow-up period of 12.6 ± 0.9 months. Statistical analysis revealed that the distribution of VerifyNow results, measured in PRU and percentage of inhibition (%INH), followed a normal distribution. Specifically, 64 patients (18.99%) had a COP-INH score of 2, whereas 273 (81.01%) had either a COP-INH score of 1 or 0.

Clinical Examination Findings

Except for a history of diabetes (48.44% vs 22.34%, p = 0.013) and previous CABG (15.63% vs 5.86%, p = 0.016), no significant differences were observed in other clinical indicators between the two groups (Table 1). Additionally, both groups predominantly used similar medications, including proton pump inhibitors (PPIs) and calcium-channel blockers (CCBs). No significant differences were observed in laboratory indicators between the two groups (Table 2). No significant differences were observed in the characteristics of vascular lesions, culprit vessels, or postoperative thrombosis in myocardial infraction flow velocities (Table 3).

Table 1 Patient Characteristics

Table 2 Laboratory Test Data

Table 3 Correlation Between COP-INH Score and CHD Characteristics

Association of COP-INH Score with Clinical Outcomes

Among the 337 patients (94.40%) who completed 1 year of clinical follow-up, the rate of MACE in the COP-INH score = 2 group was significantly higher, compared with the COP-INH score = 1 or 0 group (23.08% vs 5.88%, p = 0.007). No significant differences were observed in individual cardiovascular events between the two groups (Table 4).

Table 4 Follow-Up Results After 1 Year

Logistic Regression Analysis for Predictors of MACE

During the follow-up period, 32 patients (9.50%) experienced MACE, and 66 patients (19.58%) had a PRU ≥ 230. Among these, 91 patients (27.00%) had a %INH < 40%. A total of 56 patients (16.62%) met both criteria (PRU ≥ 230 and %INH < 40%). Univariate logistic regression analysis revealed that smoking (p = 0.014), diabetes (p = 0.017), history of MI (p = 0.006), history of stroke (p = 0.011), a PRU ≥ 230 (p = 0.016), and a COP-INH score = 2 (p = 0.007) predicted MACE after 1 year (Table 5). However, after adjusting for confounding factors such as age and gender, multivariate statistical analysis indicated that only diabetes, a history of MI and a COP-INH score = 2 were significant predictors of MACE after 1 year of follow-up (p < 0.05) (Table 6), whereas a PRU ≥ 230, a history of stroke, and smoking were not.

Table 5 Univariate Logistic Regression Analysis for Predictors of MACE

Table 6 Multivariate Logistic Regression Analysis for Predictors of MACE

Further analysis of patients without MACE using Kaplan–Meier survival analysis revealed significantly higher survival rates for patients with a COP-INH score = 1 or 0 compared with those with COP-INH score = 2 (p < 0.001), as illustrated in Figure 2.

Figure 2 Kaplan–Meier analysis of major adverse cardiac events (MACE)-free survival in-patients with COP-INH score of 1 or 0 and those with a COP-INH score of 2.

Discussion

Despite the widespread adoption of DAPT as a critical component of post-procedural care following PCI, challenges such as in-stent restenosis persist.¹² Current insights link these adverse events, particularly HRPR, to clopidogrel treatment.^4,10 This study introduces a composite score—the COP-INH score—which integrates P2Y12 reactivity and percentage of platelet inhibition, to assess long-term clinical outcomes in patients with ACS undergoing PCI. Key findings indicate that patients with a COP-INH score of 2 have a significantly higher incidence of MACE, compared with those with scores of 1 or 0.

Furthermore, the percentage of patients with a COP-INH score of 2 was notably higher among patients who experienced MACE than among those without MACE.

Multivariate regression analysis confirmed a COP-INH score of 2 as a significant risk factor for MACE post-PCI in patients with ACS. In contrast, there appears to be no clear correlation between PRU ≥ 230 or INH < 40% and the occurrence of MACE.

This study emphasizes the necessity for individualized therapeutic strategies based on molecular biomarkers, suggesting that patients with a COP-INH score of 2 may benefit from customized antithrombotic approaches. Further research is needed to elucidate the mechanisms linking specific biomarkers to MACE and to develop personalized treatment plans for patients with ACS undergoing PCI.

Additionally, the results reinforce that HRPR post-clopidogrel therapy serves as a predictive marker for adverse cardiovascular events following PCI.³ Previous studies have examined indicators such as PRU, BASE (baseline values of the degree of platelet aggregation), and %INH (inhibition ratio before and after treatment).¹⁴ PRU measures platelet reactivity after antiplatelet therapy; higher values indicate stronger reactivity, whereas lower values suggest weaker reactivity. BASE assesses the degree of platelet aggregation under clopidogrel therapy; a higher BASE value denotes greater aggregation. %INH quantifies the change in the inhibitor ratio and post-treatment vs pre-treatment. Notably, administering a maintenance dose of clopidogrel for 4 weeks post-PCI significantly reduces PRU in patients with ACS, establishing ≥230 as a critical threshold for PRU.³

Considering the correlation between PRU and drug response, previous studies have suggested that %INH might be a more sensitive indicator of the efficacy of antiplatelet drugs, where elevated PRU and decreased %INH indicate a poor drug response. Consequently, the incidence of MACE was notably higher in patients with COP-INH score = 2 (high PRU and low %INH) than in those with COP-INH score = 1 or 0, aligning with our findings. No significant differences were observed in the occurrence rates of individual cardiovascular events within MACE, which may be due to their lower frequency. Our univariate analysis revealed that PRU ≥ 230 and COP-INH score = 2, along with factors such as smoking, diabetes, history of myocardial infarction, and stroke, were effective predictors of MACE in patients undergoing PCI surgery, for 1 year following ACS, consistent with prior research.^3,15 After adjusting for confounding factors, a COP-INH score of 2 remained a predictive factor for MACE after 1 year in patients with ACS undergoing PCI surgery, whereas PRU ≥ 230 did not.

Our study also found that the critical values of PRU ≥ 230 at 30 days post-PCI and %INH < 40% were not predictive of MACE, consistent with previous studies.^16,17 This discrepancy might be due to the fact that most cardiovascular events occur during the acute phase, whereas HRPR is more prevalent perioperatively.¹⁸ Kaplan–Meier analysis revealed that the rate of occurrence of MACE in patients with a COP-INH score of 2 was significantly higher than that in patients with COP-INH scores of 1 or 0 (p < 0.001). Moreover, patients with elevated PRU and lower %INH had poor long-term prognosis. Our findings indicate that a higher PRU suggests greater platelet reactivity, whereas a lower %INH implies reduced efficacy of antiplatelet drugs. This suggests that the COP-INH score not only reflects changes in platelet reactivity before and after treatment but also predicts these changes over time. Hence, we believe that achieving substantial reductions in PRU may effectively reduce the risk of MACE postoperatively, which might explain why enhancing antiplatelet therapy based on PRU has not consistently improved patient outcomes in current clinical practice.

In summary, our study investigated the relationship between P2Y12 reactivity, platelet inhibition rates, and MACE in patients undergoing PCI following ACS. The findings demonstrated that the COP-INH score may help identify patients at risk for adverse cardiovascular events after PCI. In terms of predicting long-term outcomes, the COP-INH score proved to be more effective than PRU or %INH alone. These results offer valuable insights and potential guidance for optimizing antithrombotic therapy post-PCI in patients with ACS, and reducing the risk of adverse clinical events, contributing significantly to clinical practice.

Limitations of the Study

There were several limitations in the present study. First, the small sample size may have been insufficient to uncover any single component of MACE. Second, this study was a single-center design and lack of external validation. The findings of this trial warrant further investigation in a larger, multi-center cohorts.

Conclusion

The COP-INH score may facilitate earlier identification of major adverse cardiovascular event risks during antiplatelet therapy post-PCI and is expected to improve long-term prognosis in patients.