Incremental Prognostic Utility of CBC-derived Inflammatory Indices After Incomplete Coronary Revascularization: Association With 12-months Cardiovascular Outcomes

. Introduction Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide. Guideline-directed medical therapy is the foundation of treatment for all patients with CAD and can stabilize or regress coronary artery atherosclerotic plaques, preventing coronary thrombosis, acute myocardial infarction (MI) and cardiac death. Revascularization with either percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery in selected patients with extensive CAD, including those with left ventricular dysfunction, left main CAD or multivessel disease (MVD), and acute coronary syndromes (ACS) can further reduce angina, improve functional capacity and quality of life, and increase infarct-free survival. Depending on whether residual CAD is present after treatment, PCI and CABG surgery can be described as having achieved complete revascularization (CR) or incomplete revascularization (ICR), the extent of which might have important prognostic implications.

The residual SYNTAX score (rSS), initially developed to quantify the extent and complexity of residual coronary stenosis, is calculated by reapplying the SYNTAX scoring system to post-PCI coronary angiograms. This score serves as an objective measure of the angiographic completeness of revascularization. Previous studies have demonstrated that a higher rSS is predictive of worse long-term outcomes after PCI.

Over the years, researchers have elucidated the multifaceted roles played by systemic and localized inflammatory processes in ACS, encompassing aspects such as endothelial dysfunction, immune response modulation, plaque stability, and thrombus formation. Inflammation can destabilize atherosclerotic plaques, inducing acute coronary events. Furthermore, inflammation is increasingly recognized as a contributor to the pathogenesis of ACS and an important determinant of prognosis and therapeutic response in affected patients. Understanding the inflammatory status in CAD can potentially lead to the development of more effective prognostic strategies.

Despite significant advances in reperfusion strategies, pharmacologic therapy, and the management of modifiable risk factors such as diabetes, dyslipidemia, and hypertension, adverse cardiovascular events continue to occur after acute myocardial infarction. The determinants of this residual risk (ie, the risk that persists despite optimal control of known modifiable factors) remain uncertain. Among these determinants, inflammation plays a complex but increasingly recognized role. Recent studies suggest that residual inflammatory risk is a stronger predictor of recurrent events and mortality.

It is known that coronary artery disease is characterized by a high inflammatory burden, and several studies demonstrated that hematological parameters are associated with the severity and prognosis of coronary artery disease . Complete blood count (CBC)-derived inflammatory indices provide inexpensive and readily available markers of systemic inflammatory status.

Four increasingly studied indices are : Neutrophil-to-lymphocyte ratio (NLR), Platelet-to-lymphocyte ratio (PLR), Systemic immune-inflammation index (SII) and Monocyte-to-lymphocyte ratio (MLR).

Gap in knowledge Despite extensive evidence that the rSS quantifies the burden of untreated coronary disease and predicts adverse outcomes after PCI, most studies have evaluated rSS alone or in combination with traditional clinical risk factors, without integrating inexpensive CBC-derived inflammatory indices into a unified prognostic framework for patients with incomplete revascularization. Recent work has shown that systemic immune-inflammatory indices such as the NLR, PLR, SII, and MLR are associated with rSS and with poorer outcomes in ACS, but these investigations have largely focused on ST elevation myocardial infarction (STEMI) or general PCI patients and have rarely focused on isolated patients with angiographically confirmed residual coronary disease. Furthermore, prior studies have typically relied on single measurements of inflammatory indices and have not systematically examined the incremental discriminative value of baseline and post-procedural inflammatory indices - nor their dynamic changes- over rSS In addition, the relationship between these CBC-derived indices, rSS, and MACE in the specific context of incomplete revascularization.

Study hypotheses Based on these considerations, The investigators hypothesize that CBC-derived inflammatory indices (NLR, PLR, SII, and MLR) measured at baseline and 24 hours after PCI, as well as their changes post PCI, are independently associated with the occurrence of MACE in patients with angiographically documented incomplete coronary revascularization, after adjustment for established clinical, laboratory, and angiographic risk factors. The investigators further hypothesize that adding these inflammatory indices to rSS significantly improves prognostic discrimination for MACE compared with rSS alone, as reflected by higher area under the ROC curve (AUC) and favorable NRI and IDI values.

1. Aim of the work Primary Aim To determine whether the addition of baseline and post-PCI CBC-derived inflammatory indices (NLR and SII) to rSS improves discrimination for MACE compared with rSS alone.

Secondary Aims

1. To determine whether the addition of baseline and post-PCI PLR and MLR to rSS improves discrimination for MACE compared with rSS alone.
2. To assess the correlation between baseline and post-PCI NLR, PLR, SII, MLR and rSS as a continuous variable.
3. To determine whether inflammatory indices are independently associated with MACE after adjustment for demographic, clinical, laboratory, angiographic, and procedural variables.
4. To assess whether changes in NLR, PLR, SII, and MLR from baseline to 24 h post-PCI provide incremental prognostic information beyond static values and rSS.

Patient and Methods The study will be conducted at the Assiut University Heart Hospital 300 STEMI patients and 140 high risk NSTEMI patients undergoing primary PCI, who have residual untreated coronary disease after the index PCI, will be consecutively enrolled and followed prospectively for clinical outcomes.

All patients will be subjected to the following:

I- History taking and examination: to assess cardiovascular risk factors blood pressure, heart rate and cardiac examination. The time of symptom onset (or last-known-well time) will be documented for all patients.

II- Clinical presentation classification:

Patients will be classified as STEMI (group A) and high risk NSTEMI (group B) according to current ESC/ACC diagnostic criteria at presentation. This classification will be recorded as a pre-specified covariate for all subsequent analyses.

III- Residual SYNTAX Score (rSS) calculation:

After completion of the index PCI, Incomplete revascularization will be defined as the presence of significant residual coronary artery disease, resulting in a rSS >0 31. Any subsequent staged PCI performed for the residual disease during the 12-month follow-up period will be recorded, together with its date; staged-PCI status will be modeled as a time-varying covariate in the survival analysis (see Statistical Analysis) rather than as a fixed baseline characteristic, in order to avoid immortal time bias. The index rSS, measured immediately after the index procedure, will remain the fixed exposure variable of interest throughout follow-up.

rSS will be calculated by a cardiologist blinded to outcomes and CBC indices results.

rSS will be calculated by summing up the individual scores for each residual lesion with diameter stenosis ≥50% in vessels with a diameter ≥ 1.5 mm in the angiography obtained after the procedure 31.

rSS will be calculated using both the original SYNTAX Score Calculator, currently found on http:// syntaxscore. org, and the web version of the updated SYNTAX Score 2020 Calculator, which is found on http:// synta xscor e2020. com.

IV- CBC-Derived Inflammatory Indices A baseline CBC will be obtained immediately after admission, before coronary angiography/PCI and before administration of treatments likely to significantly modify the inflammatory response. The interval between documented symptom onset and baseline CBC sampling (symptom-to-draw interval, in hours) will be recorded and used as a covariate in the multivariable analysis.

A second CBC will be obtained (24±2 hours) after PCI, the interval between PCI and 2nd CBC sampling will be recorded (balloon-to-draw interval, in hours).

• The following will be recorded:
• Total leukocyte count
• Absolute neutrophil count
• Absolute lymphocyte count
• Absolute monocyte count
• Platelet count
• The following indices will be calculated:

NLR = absolute Neutrophil count\ Absolute Lymphocyte count PLR = Platelet count\Absolute Lymphocyte count SII = Platelets count x neutrophils count \ lymphocytes count MLR = Monocytes count \lymphocytes count

V- Biomarkers of myocardial injury:

Peak troponin or CK-MB will be recorded after 12-24 hours of onset of symptoms and used as a surrogate measure of infarct size and included as a covariate in the multivariable analysis.

VI- Echocardiography:

Transthoracic echocardiography will be performed by cardiologists blinded to the study within the first 24hr after PCI according to current practice guidelines, using a commercially available device (GE Vivid S6 ultrasound device). The left ventricular ejection fraction (EF) will be obtained by the modified Simpson's rule.

VII- Medications:

Any medications that may affect inflammatory indices (Antiplatelets, statins, corticosteroids, ACE-I, ARBs, B-blockers or SGLT2-I) will be recorded

VIII- Follow-Up:

Patients will be followed for 12 months after the index PCI.

Follow-up will be performed through:

• Outpatient visits
• Telephone interviews
• Review of hospital records
• Review of repeat angiographic procedures
• Review of death certificates or official records where available. IX- The primary endpoint will be the occurrence of major adverse cardiovascular events (MACE) during follow-up.

MACE will be defined as a composite of:

• Cardiovascular death due to new ischemic event.
• Non-fatal myocardial infarction
• Unplanned ischemia-driven repeat coronary revascularization
• Secondary end point : Onset of new ischemic events (UA, worsening of chest pain or ischemic induced heart failure)