In spite of the availability of many evidence-based therapies, patients presenting with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) remain at increased risk of recurrent ischemic cardiovascular events, especially in the acute phase following the index event [1, 2, 3]. The excessive risk is more pronounced in patients with multivessel disease (MVD). Multiple large-scale clinical trials have demonstrated that patients with MVD are at significantly elevated risk of myocardial infarction (MI), major adverse cardiovascular events and all-cause mortality [4, 5, 6, 7].

Low-density lipoprotein cholesterol (LDL-C) is an accepted and independent risk factor for cardiovascular disease. The 2019 European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guideline identified patients with recent ACS as extremely high risk and recommended an LDL-C target of 1.4 mmol/L, in whom a high-intensity statin is recommended to be initiated in the acute phase following the index event [8]. In clinical practice, many ACS patients fail to achieve the guideline-recommended LDL-C target regardless of potent and stable statin treatment [9, 10]. In addition, the therapeutic benefits of statins are limited by the delayed onset of action, statin intolerance [11], the residual high risk of recurrent cardiovascular events [12], as well as inertia with regard to dose maximization [13]. This cumulative data emphasize the potential necessity for developing alternative intensive lipid-lowering treatments to further reduce the risk of recurrence of cardiovascular events.

Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, as new lipid-lowering drugs, can rapidly and substantially reduce LDL-C levels. Evolocumab has been demonstrated to significantly lower major cardiovascular events in subjects with stable atherosclerotic cardiovascular disease (ASCVD) in the secondary prevention setting [14, 15, 16]. Nevertheless, the safety, efficacy and feasibility for the early addition of the PCSK9 inhibitor evolocumab to statin treatment in ACS patients with MVD undergoing PCI are presently unclear. In the current study, we tested the hypothesis that evolocumab combined with statins would result in a more favorable reduction in recurrent cardiovascular events as compared to statins alone among patients presenting with ACS within days and with MVD undergoing PCI.

In the present clinical trial evaluating in-hospital use of evolocumab in ACS patients with MVD undergoing PCI, the addition of evolocumab at 140 mg every 2 weeks to statin treatment, compared with statins alone, resulted in sustained reductions in LDL-C levels throughout the follow-up period. At 18 months, the primary efficacy endpoint and principal secondary efficacy endpoint were substantially reduced by evolocumab plus statins compared with statin therapy alone. Regarding safety outcomes, there were no statistically significant differences between groups in the 18-month rates of adverse events.

Genetic and epidemiological data have identified a causal role for LDL-C in ASCVD [19, 20]. A meta-analysis involving 26 randomized trials demonstrated that an additional reduction of 1 mmol/L in LDL-C levels was associated with a 22% reduction in the incidence of major vascular events, a 10% reduction in all-cause mortality, and a 20% reduction in CHD mortality [21]. Accordingly, current guidelines emphasize the importance of intensifying lipid-lowering treatment and achieving very low LDL-C levels in patients at high risk of cardiovascular events, including those with recent ACS or MVD or those undergoing coronary revascularization [8, 22]. For lipid management in patients with a recent ACS, most guidelines favor a step-by-step regimen that includes early administration of statins at a high-intensity dose, followed by combination with ezetimibe. PCSK9 inhibitors will be taken into account if the recommended treatment targets have not been achieved [8, 22]. With this scheme, PCSK9 inhibitor therapy was not considered for ACS patients with substantially elevated LDL-C levels until several months after the index event. Considering statin intolerance [11], the delayed effect of statins, as well as inertia with regard to dose maximization [13], ACS patients frequently fail to attain guideline-recommended LDL-C levels despite intensive statin treatment [9, 10]. Nevertheless, the risk of recurrent cardiovascular events is greatest in the early post-ACS period [23]. This highlights the potential necessity for a fast-acting and more potent drug, in addition to statins, to rapidly and significantly lower LDL-C levels and further improve cardiovascular outcomes.

The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial [15] demonstrated that the evolocumab combined with intensive statin treatment, as compared with statins alone, significantly decreased the risk of major ischemic cardiovascular events among patients with stable ASCVD. Similarly, a meta-analysis of 39 randomized controlled trials including 66,478 patients indicated that PCSK9 inhibitors lowered the risk of MI by 20% (95% CI, 14–26%; p 0.0001), ischemic stroke by 22% (95% CI, 11–33%; p = 0.0005) and coronary revascularization by 17% (95% CI, 11–22%; p 0.0001) [24]. In these studies, however, evolocumab treatment was only considered in subjects with off-target LDL-C levels after receiving maximally tolerated statin therapy. Given the high risk of early recurrent ischemic events after ACS, we put forward a novel scheme of the early addition of PCSK9 antibody treatment to statins in patients who were not expected to achieve guideline-recommended LDL-C targets with high-intensity statins alone. The results indicated that evolocumab plus statin therapy lowered LDL-C levels to a mean of 0.75 mmol/L and reduced the risk of recurrent cardiovascular events.

EPIC-STEMI (Effects of Acute, Rapid Lowering of Low Density Lipoprotein Cholesterol with Alirocumab in Patients with ST Segment Elevation Myocardial Infarction Undergoing Primary PCI) [25] is a recently conducted randomized, double-blind, and sham-controlled clinical trial with the aim of investigating the impact of PCSK9 inhibitors added to high-intensity statin therapy on LDL-C levels in STEMI patients who underwent PCI. At a median of 45 days, the PCSK9 inhibitor alirocumab reduced LDL-C levels by 72.9% compared to 48.1% in the sham control group. More patients achieved the European dyslipidemia guideline target of LDL-C $\le$1.4 mmol/L in the alirocumab group (92.1%) than the sham control group (56.7%) [25]. In our study, the one-month follow-up showed a decrease in LDL-C levels of 77.02% in the evolocumab group, which is consistent with the findings of the EPIC-STEMI study. However, the standard-of-care group only showed a decrease of 26.20%, which is lower than that observed in the EPIC-STEMI study. We speculate that the differences in inclusion criteria between these two studies may have caused this discrepancy. The EPIC-STEMI study enrolled patients who received PCSK9 inhibitors regardless of their baseline LDL-C levels. In contrast, our study focused on early administration of PCSK9 inhibitors in patients who remained suboptimal after receiving statins for at least one week or presented with very high LDL-C levels upon admission. It is plausible to assume that the LDL-C lowering effect in our standard-of-care group was moderate, with lower rates of achieving LDL-C goals. However, regardless of the inclusion criteria, both studies demonstrated a substantial reduction in LDL-C levels with the use of PCSK9 inhibitors. Our research has shown that long-term treatment with PCSK9 inhibitors can significantly improve the prognosis of patients with ACS and with MVD undergoing PCI.

Multiple clinical trials have shown that patients with MVD experience a significantly increased risk of recurrent cardiovascular events. A register-based study conducted in patients with MI demonstrated that CHD severity was a critical risk factor for the composite endpoint of MI, stroke, or cardiovascular mortality within 1 year (3-vessel disease: odds ratio and 95% CI, 4.18, 3.66–4.77; 2-vessel disease, 3.23, 2.81–3.72) [4]. In a cohort study involving 37,674 patients undergoing coronary angiography for CHD, patients with multivessel obstructive CHD had a substantially higher 1-year risk of MI than those without apparent CHD (3-vessel obstructive CHD: HR and 95% CI, 19.5, 9.9–38.2; 2-vessel obstructive CHD, 16.5, 8.1–33.7) [5]. In the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) trial [6], 20.4% of patients with ACS who underwent PCI and current evidence-based treatments had recurrent major adverse cardiovascular events within 3 years, which were equally divided between those associated with culprit lesions and those associated with non-culprit lesions. Accordingly, ACS patients with MVD undergoing PCI represent a very high-risk group. A secondary analysis from the FOURIER trial showed that patients with stable ASCVD and with MVD are at substantially higher risk for major cardiovascular events despite maximally tolerated statin therapy, and derive significant risk reduction with LDL-C-lowering treatment with evolocumab [7]. In the present study, relative to statins alone, the addition of evolocumab to statin treatment substantially lowered the risk of primary and principal secondary efficacy end points, mainly due to a reduction in the rate of MI. The incidence of MI in both target and non-target vessels tended to be reduced in the evolocumab group compared with the control group, suggesting potential benefits of evolocumab in plaque stabilization and inhibition of neo-atherosclerosis in both culprit and non-culprit lesions. These results corresponded well with the findings in the HUYGENS (High-Resolution Assessment of Coronary Plaques in a Global Evolocumab Randomized Study) trial [26], which showed that evolocumab along with statin treatment resulted in favorable effects on stabilization and regression of coronary atherosclerosis compared with statins alone, as evidenced by a significant increase in minimum fibrous cap thickness and reduction in maximum lipid arc and macrophage index. Based on these findings, it would be reasonable to preferentially target evolocumab treatment for ACS patients with MAD undergoing PCI.

Our subgroup analysis showed that the effect of evolocumab on the primary outcome was greater in individuals with low hs-CRP levels than those with high hs-CRP levels, which is consistent with a previous study that demonstrated the impact of inflammation on the vascular benefits of PCSK9 inhibitors [27]. This prospective observational study aimed to investigate the influence of neutrophil-to-lymphocyte ratio (NLR) on the cardiovascular benefit of PCSK9 inhibitors in familial hypercholesterolemia (FH) subjects with ASCVD. The study found that only FH subjects with low NLR experienced a significant reduction in pulse wave velocity (PWV) after six months of PCSK9 inhibitors therapy, while no significant changes were observed in the high-NLR group [27]. A previous study has demonstrated a positive association between NLR and hs-CRP levels in individuals with high risk of cardiovascular disease [28]. The authors noted in their discussion that despite intensive lipid-lowering therapy, the interplay between neutrophils and lymphocytes promoted a significant systemic inflammatory state [27, 29]; furthermore, a recent study has found that NLR can serve as a valuable prognostic biomarker independently predicting all-cause death and major adverse cardiovascular events [27, 28]. The findings of these studies could elucidate why only subjects with lower inflammatory states were able to benefit from PCSK9 inhibitors therapy, while those with higher inflammatory states did not show significant improvements in prognosis. Further randomized controlled trials will be necessary to substantiate our preliminary discoveries.

It is worth noting that recent studies have revealed that the protective effects of evolocumab may not be solely attributed to the reduction of LDL-C levels, but also potentially arise from pleiotropic effects. Nicola Ferri et al. [30] have identified five supporting evidences supporting the investigation of PCSK9 inhibitors as a rapid and aggressive treatment option for patients with ACS. Firstly, during ACS, levels of circulating PCSK9 increase. Secondly, higher levels of circulating PCSK9 have been directly correlated with platelet reactivity, a crucial factor in the recurrence of ischemic cardiovascular events [31]. Thirdly, PCSK9 is correlated with activation of macrophage, inflammation, and endothelial dysfunction within plaques [32]. Fourth, PCSK9 concentration is related to inflammation during the acute phase of ACS [32, 33]. Finally, statin therapy can rapidly and sometimes markedly increase PCSK9 levels [34]. Therefore, it can be speculated that the cardiovascular protective effects of evolocumab may not only arise from reducing LDL-C levels, but also from its capacity to inhibit platelet activation, alleviate plaque inflammation and macrophage activation, improve endothelial function, and attenuate the increased PCSK9 levels induced by statin therapy. Additional clinical and fundamental research investigations must be formulated to validate our hypotheses.

The current randomized controlled trials (RCTs) evaluating evolocumab in the field of cardiovascular disease have mainly focused on patients with high ischemic risk, such as those with a history of MI, MVD, ACS, or non-ST-segment elevation myocardial infarction [15, 18, 26]. These studies indicated that evolocumab has significant potential to lower LDL-C levels, stabilize and reverse plaque vulnerability, and ultimately decrease the incidence of cardiovascular events in these high-risk populations [15, 18, 26]. However, our trial experienced a permanent discontinuation rate of 8.0% (25 patients) due to the high cost of evolocumab treatment. Fortunately, the price of evolocumab in China has significantly dropped to $\$$43 per 140 mg, thus easing the financial burden for patients with ASCVD. Considering the reasonable price and superior therapeutic efficacy of evolocumab, physicians are increasingly considering the administration of evolocumab in low- or moderate-risk patients, including those with single-vessel disease, stable CHD, intermediate coronary stenosis, and type A lesions. In view of the benefits of evolocumab in reducing the risk of recurrent cardiovascular events, this shift in LDL-C-lowering has the potential to bring enormous clinical benefits to Chinese patients with ASCVD. It will also provide a wealth of real-world evidence for the efficacy, safety and feasibility of evolocumab in ASCVD patients with low, moderate or high-risk status.

Some limitations should be acknowledged. Due to the retrospective nature of this study, the use of evolocumab was at the discretion of the attending physician, which may introduce a potential selection bias. Although the multivariable Cox regression model minimized the potential confounders related to the study endpoints, residual unmeasured confounders cannot be eliminated. Consequently, future multicenter, prospective, randomized trials are required to determine the optimal intensive lipid-lowering strategy, especially in patients at very high ischemic risk.

Among ACS patients with MVD taken for PCI, evolocumab initiated in-hospital along with statin treatment lowered LDL-C levels to a mean of 0.75 mmol/L and reduced the risk of recurrent cardiovascular events, with favorable safety and tolerability.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

JD and YaZ were responsible for designing the trial. AZ and KC conducted the research. YangZ and YW performed graphical editing and data analysis. YaZ, YangZ, WH, and PC were responsible for collecting the data. All authors contributed to the manuscript’s editorial revisions. All authors have reviewed and approved the final manuscript. All authors have participated sufficiently in this study and agreed to be responsible for all aspects of the research.

All procedures performed in this study were in accordance with the standards of the ethics committees of Zhongda Hospital Southeast University (2020ZDSYLL051-P01) and the First Affiliated Hospital of Zhengzhou University (2020-KY-0218-001), and the ethics committees waived the need for written informed consent.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.