Clinical Effect of Evolocumab treatment in coronary artery bypass surgery

Clinical Effect of Evolocumab treatment in coronary artery bypass surgery | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Clinical Effect of Evolocumab treatment in coronary artery bypass surgery Giuseppe Nasso, Giuseppe Santarpino, Walter Vignaroli, Vincenzo Calabrese, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6744088/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Aims – Evolocumab, a PCSK9 inhibitor, has been shown to significantly reduce cholesterol levels when added to statin + ezetimibe therapy after coronary artery bypass grafting (CABG), though short-term follow-up did not reveal reductions in major clinical events. Beyond lipid-lowering, PCSK9 inhibitors may offer anti-inflammatory and plaque-stabilizing effects, especially relevant in the perioperative phase of CABG. Evolocumab enhances LDL clearance by upregulating LDL receptor recycling and may also reduce lipoprotein(a) and inflammatory markers. Importantly, residual inflammatory risk remains a contributor to post-CABG events, even in patients with well-controlled lipid levels. Due to its unique pharmacologic profile, Evolocumab warrants dedicated evaluation in surgical populations. Methods and Results – This retrospective study included 254 dyslipidemic patients undergoing CABG. Of these, 111 received statin + ezetimibe plus Evolocumab, while 143 received only statin + ezetimibe. Over 18 months of follow-up, the two groups were compared for lipid levels and cardiovascular outcomes. Cox regression analysis identified significant predictors of events, including treatment group, hypertension, EUROSCORE_II, and prior stroke. Evolocumab treatment showed a protective effect on major cardiovascular events—such as recurrent angina, myocardial infarction, cerebrovascular events, revascularization procedures, and cardiac death—with a hazard ratio (HR) of 0.38 (95% CI 0.15–0.99, p = 0.047). Cholesterol levels decreased more rapidly in the Evolocumab group, with a mean total cholesterol reduction of 27 mg/dL (p < 0.01), LDL by 30 mg/dL (p < 0.001), triglycerides by 18.77 mg/dL (p < 0.001), and an HDL increase of 2.7 mg/dL (p < 0.001), compared to the control group. Conclusion – In patients undergoing CABG, the addition of Evolocumab to standard lipid-lowering therapy significantly reduced cholesterol levels and, importantly, lowered the incidence of major cardiac events at 18-month follow-up. These findings, the first of their kind in the surgical setting, support the use of Evolocumab perioperatively, particularly in patients resistant to statin therapy. Health sciences/Cardiology Health sciences/Cardiology/Cardiovascular biology dyslipidemia cardiac surgery PCSK9 Figures Figure 1 Introduction Monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) are entering by right as a new class of drugs to lower LDL cholesterol levels ( 1 ), especially following an acute coronary syndrome ( 2 ). The basis of this effect is genetics: the carriage of PCSK9 loss-of-function alleles is linked to lower LDL cholesterol levels, reducing the risk of myocardial infarction ( 3 , 4 ). In particular, the acute coronary syndromes (ACS) patients are at increased risk of recurrent ischemic events ( 5 ) and Evolocumab demonstrated to reduce major cardiovascular events in secondary prevention ( 6 – 9 ). Indeed, an early and strong strategy to lipid-lowering using PCSK9i in patients with ACS is safe and effective in clinical practice ( 10 ). However, the LDL-C-lowering efficacy of PCSK9 antibody treatment during the ACS in patients who underwent coronary artery bypass surgery (CABG) is unknown. Only in our previous study we analyzed and showed the short-term effect of Evolocumab in this cohort of patients ( 11 ). The CABG population is complicated to analyze and understand: ischemic and reperfusion myocardial injury is often reported in patients who underwent coronary artery bypass grafting (CABG) ( 12 , 13 ) despite substantial advancements in cardiopulmonary support devices and surgical techniques ( 14 – 16 ). We recorded a significant reduction of the cholesterol and LDL in the patients who underwent Evolocumab without a recorded immediate clinical effect ( 11 ). Also in elective CABG patients with hypercholesterolemia not statin responsive, we tried and demonstrated an immediate efficacy of Evolocumab to ameliorate the laboratory ( 17 ). However, given the potential cardioprotective effects, we hypothesize that Evolocumab would give a beneficial clinical effect for patients undergoing cardiovascular surgery. Up to now, we are not able with the previous studies to demonstrate that. We are waiting for an ongoing study on the effect of PCSK9 inhibitors following bypass surgery ( 18 ), but in the present study we added the ACS patients who underwent CABG and the elective CABG patients for a longer follow-up focused on the clinical efficacy of the immediate treatment with Evolocumab. To date, no study to our knowledge has demonstrated an improvement in cardiovascular clinical effects in patients treated with Evolocumab and submitted to CABG. Methods From January 2017 to June 2022, all CABG patients due to chronic coronary artery disease or acute coronary syndrome were retrospectively analyzed. Of these, all patients affected by dyslipidemia (defined as LDL-C concentration ≥ 70 mg/dL), or patients already in pre-operative treatment with statin ± ezetimibe alone or with statin ± ezetimibe plus Evolocumab met the criteria to be enrolled in the retrospective analysis. The Evolocumab group included all dyslipidemic patients submitted to CABG and treated with subcutaneous PCS-K9 inhibitor plus statin ± ezetimibe. The standard group provides patients submitted to CABG in treatment only with statin ± ezetimibe. Until December 2019 on optimized lipid-lowering therapy foresaw a high- or moderate-intensity statin with or without ezetimibe in order to obtain an LDL-C concentration ≥ 70 mg/dL. Since January 2020, once Evolocumab treatment was usable according to Italian legislation in patients with high LDL-C values (≥ 70 mg/dL), all the patients with these values and with the same characteristics as the previous ones added to statin therapy with or without ezetimibe also the treatment with subcutaneous PCS-K9 inhibitor, either 140 mg every 2 weeks. Evolocumab was administered at baseline “as early as possible”, usually before the coronary angiography or at the end of the procedure when CABG treatment was proposed to the patient or immediately after surgery. All patients were followed up on clinical endpoints and laboratory levels (every three months) and the results were compared between the two groups. The follow-up period for this study was set at a minimum of thirty months to enable a comparative analysis between the two groups. The primary clinical endpoint was the composite incidence of recurrent angina, myocardial infarction, cerebrovascular events, need for coronary re-angiography or re-intervention (PCI/CABG), and cardiovascular death. Laboratory endpoints included serial measurements of total cholesterol, LDL-C, HDL-C, triglycerides, and alanine aminotransferase (ALT) at baseline, 3 months, and final follow-up. Ethics, Data and Material Availability - The data used and analyzed in this study are available upon reasonable request from the corresponding author. All methodological details, including patient selection criteria, treatment procedures, and statistical analyses, are described in the manuscript. Any additional data or supplementary materials can be provided upon request, in compliance with ethical regulations and patient privacy policies. The present study conforms to the Declaration of Helsinki. It was approved by our institutional review board (Anthea Hospital and Santa Maria Hospital GVM Care&Research) for human research for retrospective studies with two different protocols for elective (Prot. N. 001.06.96. Study number 7815) and “acute coronary syndrome” patients (Prot. N. 22.01.24. Study number 7809). Patients gave informed consent to use their clinical data for research purposes. Statistical Analysis - Data were described as mean ± standard deviation, median and interquartile range, or proportion, as appropriate. The distribution of variables was investigated by the Kolmogorov-Smirnov test, followed by graphic evaluation. No missing data was retrieved in the database. The sample was divided into two groups based on Evolocumab therapy. 111 patients took Evolocumab (EVOLOCUMAB GROUP) and 143 were allocated in the control group (STANDARD GROUP). The comparisons between the two groups were computed using the student T-test, the Mann-Whitney test and the Pearson Chi-square test, as appropriate. A machine learning Cox regression method with ridge regularization was applied to detect confounding variables. Variables with impact above the median were included in the multivariate Cox analysis. Furthermore, generalized linear models for repeated measures were used to detect the differences in total cholesterol, LDL, HDL, triglycerides and ALT slopes in time between the two groups. Results 254 dyslipidemic patients submitted to CABG were enrolled in the analysis. 111 patients (EVOLOCUMAB GROUP) were treated with statin ± ezetimibe plus Evolocumab (31 with acute coronary syndrome and 80 with chronic coronary artery disease) before surgery or immediately after. 143 patients (STANDARD GROUP) were treated only with statin ± ezetimibe (43 with acute coronary disease and 100 with chronic coronary artery disease) with the same time treatment. Patients were aged 68 years (63–73), males were 190 (75%), with a BMI of 27 (24–29) kg/m². 126 (50%) had arterial hypertension, 70 (28%) had diabetes and 73 (29%) had smoking habits. The mean follow-up was 70 ± 20 months and 48 ± 18, respectively, and 39 patients manifested CV events (15%), 7 (6%) in the Evolocumab group and 32 (22%) in the control group (p < 0.001). On the basis of this difference in the event incidence, a sample of 68 patients for each group was enough to reach the statistical power of 80% (Fig. 1). The following clinical events were observed: Evolocumab group: Two patients experienced recurrent angina, three patients required re-intervention (PCI), and one patient succumbed to cardiovascular death. Control group: Five patients presented with recurrent angina, four patients experienced myocardial infarction, one patient had a cerebrovascular event, and fifteen patients required re-intervention (fourteen PCI and one CABG). Seven patients experienced cardiovascular death. Table 1 shows the preoperative characteristics of the two groups (Standard and Evolocumab treated). The two groups differed at the baseline for age, BMI, arterial hypertension, HDL, triglycerides and ALT. In detail, the Evolocumab group was older, with a lower BMI, lower LDL and higher ALT. Using machine learning methods, we identified which variables are most associated with the event and we took those with an impact higher than the median (Table 2). Variables with an impact coefficient on the event above the median (0.00532), detected by Ridge Cox regression, were BMI, diabetes, smoking habits, previous IMA, previous coronary artery bypass surgery, previous stroke, vascular diseases, malignancies, EUROSCORE II, arterial hypertension, number of bypasses, sex and Evolocumab use (Table 2). These variables have been included in the multivariate Cox regression model, which showed a significant impact for Evolocumab use, arterial hypertension, EUROSCORE II, and history of stroke. In detail, Evolocumab treatment reduced the risk of adverse cardiac events, with an HR of 0.39 (95% CI 0.15–0.99, p = 0.047). Harrel’s C index of this model was 0.7338 (Table 3). Furthermore, cholesterol levels decreased more quickly over time in the Evolocumab-treated group than in the conventional group, with an average difference of 27 mg/dL (p < 0.01). Similarly, LDL decreased by approximately 30 mg/dL (p < 0.001), triglycerides by approximately 18.77 mg/dL (p < 0.001), while HDL increased by an average of 2.7 mg/dL more than in the conventional therapy (p < 0.001). Regarding safety, no serious adverse events related to Evolocumab administration were reported during the study period. Liver enzyme levels (ALT) remained within normal ranges across both groups, with no treatment discontinuation due to drug intolerance. These findings confirm the favorable tolerability profile of Evolocumab previously demonstrated in broader cardiovascular populations. Discussion We previously demonstrated that Evolocumab treatment is able to reduce total cholesterol and LDL levels after cardiac surgery in elective patients ( 17 ) and in patients who underwent acute coronary syndrome ( 11 ). However, given its potential cardioprotective effects, it can be speculated that Evolocumab would be beneficial for patients undergoing cardiovascular surgery. In the present paper, with a longer follow-up, the patients submitted to CABG who underwent Evolocumab treatment suffered fewer cardiac events (combined risks of recurrent angina, myocardial infarction, cerebrovascular events, need for coronary re-angiography, coronary artery re-angioplasty/re-bypass and cardiac death) compared with the control group (statin plus ezetimibe alone). The clinical efficacy of PCSK9 inhibitors in patients undergoing cardiovascular surgery has not been demonstrated. We present our preliminary results to investigate the efficacy of a PCSK9 inhibitor (Evolocumab) in preventing ischemic and reperfusion myocardial injury in multivessel coronary disease patients undergoing elective or urgent/emergent CABG surgery. Due to these clinical consequences, the results of our study confirm the Fourier Trial ( 6 ) in the cardiac surgery field: they found that the addition of Evolocumab to statin therapy significantly reduced the risk of cardiovascular events, with a 15% reduction in the risk of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. In the same way, we recorded 32 events in the conventional therapy patients (22%) and 7 events in the Evolocumab-treated patients (6.3%); a reduction of 15.7%. These positive long-term effects of the addition of Evolocumab are, however, probably still only partially known, given that the long-term results of the therapy in patients at cardiovascular risk have also been published, demonstrating that the long-term LDL-C lowering with Evolocumab was associated with persistently low rates of adverse events that did not exceed those observed in the original placebo arm ( 16 ). Therefore, also in support of our study, it appears important to underline the early intake of the drug itself as proposed by us in our approach immediately, i.e., one month after the surgical revascularization procedure. On the other hand, an early start is a hypothesis on which our study is based and has had clear bibliographical support for several years. In fact, a delay between the onset of LDL cholesterol lowering and the emergence of the full clinical benefit of the intervention in terms of clinical risk reduction has been well documented in many trials ( 6 , 19 – 22 ). The benefit of decreasing LDL cholesterol levels therefore remains indisputable, given that even studies prior to the use of Evolocumab showed significant reductions in major cardiovascular events using statins alone in the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction (PROVE IT–TIMI) and Treating to New Targets (TNT) trials ( 23 , 24 ). We have to highlight that our study is the first clinical and laboratory analysis of the Evolocumab initiated in-hospital in patients presenting with STE- and NSTE-ACS who underwent urgent surgical revascularization or elective CABG, and we recorded a difference in the cardioprotective effect associated with a substantially greater reduction in LDL-C levels. Our results build upon previous studies that investigated Evolocumab in ACS ( 25 ), patients with statin intolerance ( 26 ) or familial hypercholesterolemia ( 27 ), and patients with stable manifestations of ischemic cardiomyopathy ( 6 , 28 ). In our study we were not able to demonstrate an immediate clinical effect ( 17 ); but our actually longer follow-up is able to obtain the goal and demonstrate a protective effect on clinical cardiovascular effect. Also following a longer follow-up, the incidence of adverse events was overall similar between groups. So, we confirm that the results are consistent with safety and tolerability data from previous studies with Evolocumab in more stable clinical settings. Limitations of the study Several limitations of this study must be acknowledged. First, its retrospective and single-center design may introduce inherent selection biases. Although multivariate and machine-learning-based adjustments were applied, residual confounding cannot be excluded. Second, the study period spans both the pre- and post-commercial availability of Evolocumab in Italy (January 2020), which may have introduced temporal variability in prescribing practices and patient selection. Third, while lipid parameters were rigorously collected, we lacked systematic measurement of inflammatory markers (e.g., hs-CRP) or atherosclerotic imaging (e.g., coronary CT angiography, IVUS), which would have allowed for mechanistic insights into plaque stabilization. Finally, the relatively small number of clinical events limits the statistical power of subgroup analyses and precludes definitive conclusions regarding mortality reduction. Perspectives These findings support the need for prospective, multicenter randomized controlled trials evaluating PCSK9 inhibitors in surgical revascularization settings. Future studies should aim to include biomarker-based risk stratification, explore the timing of therapy initiation, and assess long-term atheroma burden through imaging modalities. Additionally, combinations of Evolocumab with novel anti-inflammatory or cardiometabolic agents—such as GLP-1 receptor agonists in diabetic CABG patients—may offer synergistic benefits in reducing residual cardiovascular risk. Conclusion This study provides compelling evidence that Evolocumab, when integrated into the lipid-lowering regimen of CABG patients, significantly enhances lipid control and reduces cardiovascular events during intermediate follow-up. These findings support the incorporation of PCSK9 inhibitors into clinical practice for patients at high cardiovascular risk undergoing surgical revascularization. Future randomized controlled trials are essential to confirm these observations and to inform evidence-based guidelines. Declarations Author Contribution : G.N. and G.Sa conceived the study, performed surgeries, and wrote the manuscript. W.V. revised the manuscript, V.C., G.T., C.L, I.R., F.B., V.M., P.M, F.F., G.S., M.S.B., G.C. F.A. and E.G. contributed to data analysis and interpretation. G.Sp. supervised the project. All authors reviewed and approved the final manuscript. Acknowledgements: We would like to thank all the authors for their valuable contributions and participation in the study, and we thank Valeria Cosco, Jlenia D’Agnano and Veronica D’Anna for manuscript review and editorial assistance. Funding None. Disclosures None declared. 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Lancet 2015; 385: 331-340. Sabatine MS, De Ferrari GM, Giugliano RP, Huber K, Lewis BS, Ferreira J et al. Clinical benefit of evolocumab by severity and extent of coronary artery disease. Circulation 2018; 138: 756-766. Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files table1.pdf table2.pdf table3.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Care\u0026Research","correspondingAuthor":false,"prefix":"","firstName":"Gaetano","middleName":"","lastName":"Contegiacomo","suffix":""},{"id":489527186,"identity":"2d67ef8b-dc0d-407a-bdc3-a4c0b2ed8d28","order_by":14,"name":"Felice Agrò","email":"","orcid":"","institution":"Campus Bio-Medico University","correspondingAuthor":false,"prefix":"","firstName":"Felice","middleName":"","lastName":"Agrò","suffix":""},{"id":489527187,"identity":"80ee5589-548f-43e8-a751-3ce326202f9b","order_by":15,"name":"Ernesto Greco","email":"","orcid":"","institution":"European University of Rome","correspondingAuthor":false,"prefix":"","firstName":"Ernesto","middleName":"","lastName":"Greco","suffix":""},{"id":489527188,"identity":"e5c0c45c-9792-4751-ab66-f6d6682020d7","order_by":16,"name":"Giuseppe Speziale","email":"","orcid":"","institution":"Anthea Hospital and Santa Maria Hospital GVM Care\u0026Research","correspondingAuthor":false,"prefix":"","firstName":"Giuseppe","middleName":"","lastName":"Speziale","suffix":""}],"badges":[],"createdAt":"2025-05-25 13:53:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6744088/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6744088/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87706115,"identity":"8d23c300-7656-46bc-aa3c-a22bb4e67388","added_by":"auto","created_at":"2025-07-28 08:02:11","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":92413,"visible":true,"origin":"","legend":"\u003cp\u003eDifference of proportion power calculation for binomial distribution (arcsine transformation). The plot shows the relationship between the sample size and the statistical power (1 - β) for a two-sided hypothesis test with a significance level (α) of 0.05 and an effect size (h) of 0.481. The vertical dotted line indicates the optimal sample size of n = 68 for achieving a desired power, assuming equal sample sizes in both groups.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6744088/v1/b8487564146c6d581f346403.png"},{"id":94074126,"identity":"66db7f7c-08b3-4106-bc2a-8d730822723c","added_by":"auto","created_at":"2025-10-22 08:25:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":595330,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6744088/v1/f5b0cb07-b3bd-48ac-9a4f-e8b831d792c8.pdf"},{"id":87706119,"identity":"53e02e0d-17ee-436d-b40d-e5335509c6d6","added_by":"auto","created_at":"2025-07-28 08:02:11","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":150792,"visible":true,"origin":"","legend":"","description":"","filename":"table1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6744088/v1/2d67565d95d3fed115c7727e.pdf"},{"id":87706117,"identity":"45c01937-9945-49ca-a983-eebf8afe50d6","added_by":"auto","created_at":"2025-07-28 08:02:11","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":135020,"visible":true,"origin":"","legend":"","description":"","filename":"table2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6744088/v1/d32d425e3d0405c1d186e2d7.pdf"},{"id":87707766,"identity":"6ebcc605-cccc-4f95-8061-d0555883753f","added_by":"auto","created_at":"2025-07-28 08:10:11","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":132263,"visible":true,"origin":"","legend":"","description":"","filename":"table3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6744088/v1/f8ec2dbca2cbe6370a297b39.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical Effect of Evolocumab treatment in coronary artery bypass surgery","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMonoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) are entering by right as a new class of drugs to lower LDL cholesterol levels (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), especially following an acute coronary syndrome (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The basis of this effect is genetics: the carriage of PCSK9 loss-of-function alleles is linked to lower LDL cholesterol levels, reducing the risk of myocardial infarction (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn particular, the acute coronary syndromes (ACS) patients are at increased risk of recurrent ischemic events (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) and Evolocumab demonstrated to reduce major cardiovascular events in secondary prevention (\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Indeed, an early and strong strategy to lipid-lowering using PCSK9i in patients with ACS is safe and effective in clinical practice (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). However, the LDL-C-lowering efficacy of PCSK9 antibody treatment during the ACS in patients who underwent coronary artery bypass surgery (CABG) is unknown. Only in our previous study we analyzed and showed the short-term effect of Evolocumab in this cohort of patients (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). The CABG population is complicated to analyze and understand: ischemic and reperfusion myocardial injury is often reported in patients who underwent coronary artery bypass grafting (CABG) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) despite substantial advancements in cardiopulmonary support devices and surgical techniques (\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eWe recorded a significant reduction of the cholesterol and LDL in the patients who underwent Evolocumab without a recorded immediate clinical effect (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAlso in elective CABG patients with hypercholesterolemia not statin responsive, we tried and demonstrated an immediate efficacy of Evolocumab to ameliorate the laboratory (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eHowever, given the potential cardioprotective effects, we hypothesize that Evolocumab would give a beneficial clinical effect for patients undergoing cardiovascular surgery. Up to now, we are not able with the previous studies to demonstrate that. We are waiting for an ongoing study on the effect of PCSK9 inhibitors following bypass surgery (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), but in the present study we added the ACS patients who underwent CABG and the elective CABG patients for a longer follow-up focused on the clinical efficacy of the immediate treatment with Evolocumab. To date, no study to our knowledge has demonstrated an improvement in cardiovascular clinical effects in patients treated with Evolocumab and submitted to CABG.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eFrom January 2017 to June 2022, all CABG patients due to chronic coronary artery disease or acute coronary syndrome were retrospectively analyzed.\u003c/p\u003e\u003cp\u003eOf these, all patients affected by dyslipidemia (defined as LDL-C concentration\u0026thinsp;\u0026ge;\u0026thinsp;70 mg/dL), or patients already in pre-operative treatment with statin\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;ezetimibe alone or with statin\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;ezetimibe plus Evolocumab met the criteria to be enrolled in the retrospective analysis.\u003c/p\u003e\u003cp\u003eThe Evolocumab group included all dyslipidemic patients submitted to CABG and treated with subcutaneous PCS-K9 inhibitor plus statin\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;ezetimibe.\u003c/p\u003e\u003cp\u003eThe standard group provides patients submitted to CABG in treatment only with statin\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;ezetimibe.\u003c/p\u003e\u003cp\u003eUntil December 2019 on optimized lipid-lowering therapy foresaw a high- or moderate-intensity statin with or without ezetimibe in order to obtain an LDL-C concentration\u0026thinsp;\u0026ge;\u0026thinsp;70 mg/dL. Since January 2020, once Evolocumab treatment was usable according to Italian legislation in patients with high LDL-C values (\u0026ge;\u0026thinsp;70 mg/dL), all the patients with these values and with the same characteristics as the previous ones added to statin therapy with or without ezetimibe also the treatment with subcutaneous PCS-K9 inhibitor, either 140 mg every 2 weeks.\u003c/p\u003e\u003cp\u003eEvolocumab was administered at baseline \u0026ldquo;as early as possible\u0026rdquo;, usually before the coronary angiography or at the end of the procedure when CABG treatment was proposed to the patient or immediately after surgery.\u003c/p\u003e\u003cp\u003eAll patients were followed up on clinical endpoints and laboratory levels (every three months) and the results were compared between the two groups. The follow-up period for this study was set at a minimum of thirty months to enable a comparative analysis between the two groups.\u003c/p\u003e\u003cp\u003eThe primary clinical endpoint was the composite incidence of recurrent angina, myocardial infarction, cerebrovascular events, need for coronary re-angiography or re-intervention (PCI/CABG), and cardiovascular death. Laboratory endpoints included serial measurements of total cholesterol, LDL-C, HDL-C, triglycerides, and alanine aminotransferase (ALT) at baseline, 3 months, and final follow-up.\u003c/p\u003e\u003cp\u003e\u003cb\u003eEthics, Data and Material Availability -\u003c/b\u003e The data used and analyzed in this study are available upon reasonable request from the corresponding author. All methodological details, including patient selection criteria, treatment procedures, and statistical analyses, are described in the manuscript. Any additional data or supplementary materials can be provided upon request, in compliance with ethical regulations and patient privacy policies. The present study conforms to the Declaration of Helsinki. It was approved by our institutional review board (Anthea Hospital and Santa Maria Hospital GVM Care\u0026amp;Research) for human research for retrospective studies with two different protocols for elective (Prot. N. 001.06.96. Study number 7815) and \u0026ldquo;acute coronary syndrome\u0026rdquo; patients (Prot. N. 22.01.24. Study number 7809). Patients gave informed consent to use their clinical data for research purposes.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStatistical Analysis\u003c/b\u003e \u003cem\u003e-\u003c/em\u003e Data were described as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, median and interquartile range, or proportion, as appropriate. The distribution of variables was investigated by the Kolmogorov-Smirnov test, followed by graphic evaluation. No missing data was retrieved in the database. The sample was divided into two groups based on Evolocumab therapy. 111 patients took Evolocumab (EVOLOCUMAB GROUP) and 143 were allocated in the control group (STANDARD GROUP). The comparisons between the two groups were computed using the student T-test, the Mann-Whitney test and the Pearson Chi-square test, as appropriate. A machine learning Cox regression method with ridge regularization was applied to detect confounding variables. Variables with impact above the median were included in the multivariate Cox analysis. Furthermore, generalized linear models for repeated measures were used to detect the differences in total cholesterol, LDL, HDL, triglycerides and ALT slopes in time between the two groups.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e254 dyslipidemic patients submitted to CABG were enrolled in the analysis. 111 patients (EVOLOCUMAB GROUP) were treated with statin\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;ezetimibe plus Evolocumab (31 with acute coronary syndrome and 80 with chronic coronary artery disease) before surgery or immediately after.\u003c/p\u003e\u003cp\u003e143 patients (STANDARD GROUP) were treated only with statin\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;ezetimibe (43 with acute coronary disease and 100 with chronic coronary artery disease) with the same time treatment.\u003c/p\u003e\u003cp\u003ePatients were aged 68 years (63\u0026ndash;73), males were 190 (75%), with a BMI of 27 (24\u0026ndash;29) kg/m\u0026sup2;. 126 (50%) had arterial hypertension, 70 (28%) had diabetes and 73 (29%) had smoking habits. The mean follow-up was 70\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;20 months and 48\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;18, respectively, and 39 patients manifested CV events (15%), 7 (6%) in the Evolocumab group and 32 (22%) in the control group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). On the basis of this difference in the event incidence, a sample of 68 patients for each group was enough to reach the statistical power of 80% (Fig.\u0026nbsp;1).\u003c/p\u003e\u003cp\u003eThe following clinical events were observed:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eEvolocumab group: Two patients experienced recurrent angina, three patients required re-intervention (PCI), and one patient succumbed to cardiovascular death.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eControl group: Five patients presented with recurrent angina, four patients experienced myocardial infarction, one patient had a cerebrovascular event, and fifteen patients required re-intervention (fourteen PCI and one CABG). Seven patients experienced cardiovascular death.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;1 shows the preoperative characteristics of the two groups (Standard and Evolocumab treated). The two groups differed at the baseline for age, BMI, arterial hypertension, HDL, triglycerides and ALT. In detail, the Evolocumab group was older, with a lower BMI, lower LDL and higher ALT. Using machine learning methods, we identified which variables are most associated with the event and we took those with an impact higher than the median (Table\u0026nbsp;2). Variables with an impact coefficient on the event above the median (0.00532), detected by Ridge Cox regression, were BMI, diabetes, smoking habits, previous IMA, previous coronary artery bypass surgery, previous stroke, vascular diseases, malignancies, EUROSCORE II, arterial hypertension, number of bypasses, sex and Evolocumab use (Table\u0026nbsp;2). These variables have been included in the multivariate Cox regression model, which showed a significant impact for Evolocumab use, arterial hypertension, EUROSCORE II, and history of stroke. In detail, Evolocumab treatment reduced the risk of adverse cardiac events, with an HR of 0.39 (95% CI 0.15\u0026ndash;0.99, p\u0026thinsp;=\u0026thinsp;0.047). Harrel\u0026rsquo;s C index of this model was 0.7338 (Table\u0026nbsp;3). Furthermore, cholesterol levels decreased more quickly over time in the Evolocumab-treated group than in the conventional group, with an average difference of 27 mg/dL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Similarly, LDL decreased by approximately 30 mg/dL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), triglycerides by approximately 18.77 mg/dL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), while HDL increased by an average of 2.7 mg/dL more than in the conventional therapy (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003cp\u003eRegarding safety, no serious adverse events related to Evolocumab administration were reported during the study period. Liver enzyme levels (ALT) remained within normal ranges across both groups, with no treatment discontinuation due to drug intolerance. These findings confirm the favorable tolerability profile of Evolocumab previously demonstrated in broader cardiovascular populations.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe previously demonstrated that Evolocumab treatment is able to reduce total cholesterol and LDL levels after cardiac surgery in elective patients (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) and in patients who underwent acute coronary syndrome (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). However, given its potential cardioprotective effects, it can be speculated that Evolocumab would be beneficial for patients undergoing cardiovascular surgery. In the present paper, with a longer follow-up, the patients submitted to CABG who underwent Evolocumab treatment suffered fewer cardiac events (combined risks of recurrent angina, myocardial infarction, cerebrovascular events, need for coronary re-angiography, coronary artery re-angioplasty/re-bypass and cardiac death) compared with the control group (statin plus ezetimibe alone).\u003c/p\u003e\u003cp\u003eThe clinical efficacy of PCSK9 inhibitors in patients undergoing cardiovascular surgery has not been demonstrated. We present our preliminary results to investigate the efficacy of a PCSK9 inhibitor (Evolocumab) in preventing ischemic and reperfusion myocardial injury in multivessel coronary disease patients undergoing elective or urgent/emergent CABG surgery.\u003c/p\u003e\u003cp\u003eDue to these clinical consequences, the results of our study confirm the Fourier Trial (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) in the cardiac surgery field: they found that the addition of Evolocumab to statin therapy significantly reduced the risk of cardiovascular events, with a 15% reduction in the risk of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. In the same way, we recorded 32 events in the conventional therapy patients (22%) and 7 events in the Evolocumab-treated patients (6.3%); a reduction of 15.7%.\u003c/p\u003e\u003cp\u003eThese positive long-term effects of the addition of Evolocumab are, however, probably still only partially known, given that the long-term results of the therapy in patients at cardiovascular risk have also been published, demonstrating that the long-term LDL-C lowering with Evolocumab was associated with persistently low rates of adverse events that did not exceed those observed in the original placebo arm (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Therefore, also in support of our study, it appears important to underline the early intake of the drug itself as proposed by us in our approach immediately, i.e., one month after the surgical revascularization procedure. On the other hand, an early start is a hypothesis on which our study is based and has had clear bibliographical support for several years. In fact, a delay between the onset of LDL cholesterol lowering and the emergence of the full clinical benefit of the intervention in terms of clinical risk reduction has been well documented in many trials (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). The benefit of decreasing LDL cholesterol levels therefore remains indisputable, given that even studies prior to the use of Evolocumab showed significant reductions in major cardiovascular events using statins alone in the Pravastatin or Atorvastatin Evaluation and Infection Therapy\u0026ndash;Thrombolysis in Myocardial Infarction (PROVE IT\u0026ndash;TIMI) and Treating to New Targets (TNT) trials (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eWe have to highlight that our study is the first clinical and laboratory analysis of the Evolocumab initiated in-hospital in patients presenting with STE- and NSTE-ACS who underwent urgent surgical revascularization or elective CABG, and we recorded a difference in the cardioprotective effect associated with a substantially greater reduction in LDL-C levels. Our results build upon previous studies that investigated Evolocumab in ACS (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), patients with statin intolerance (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) or familial hypercholesterolemia (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), and patients with stable manifestations of ischemic cardiomyopathy (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). In our study we were not able to demonstrate an immediate clinical effect (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e); but our actually longer follow-up is able to obtain the goal and demonstrate a protective effect on clinical cardiovascular effect. Also following a longer follow-up, the incidence of adverse events was overall similar between groups. So, we confirm that the results are consistent with safety and tolerability data from previous studies with Evolocumab in more stable clinical settings.\u003c/p\u003e\n\u003ch3\u003eLimitations of the study\u003c/h3\u003e\n\u003cp\u003eSeveral limitations of this study must be acknowledged. First, its retrospective and single-center design may introduce inherent selection biases. Although multivariate and machine-learning-based adjustments were applied, residual confounding cannot be excluded. Second, the study period spans both the pre- and post-commercial availability of Evolocumab in Italy (January 2020), which may have introduced temporal variability in prescribing practices and patient selection. Third, while lipid parameters were rigorously collected, we lacked systematic measurement of inflammatory markers (e.g., hs-CRP) or atherosclerotic imaging (e.g., coronary CT angiography, IVUS), which would have allowed for mechanistic insights into plaque stabilization. Finally, the relatively small number of clinical events limits the statistical power of subgroup analyses and precludes definitive conclusions regarding mortality reduction.\u003c/p\u003e\n\u003ch3\u003ePerspectives\u003c/h3\u003e\n\u003cp\u003eThese findings support the need for prospective, multicenter randomized controlled trials evaluating PCSK9 inhibitors in surgical revascularization settings. Future studies should aim to include biomarker-based risk stratification, explore the timing of therapy initiation, and assess long-term atheroma burden through imaging modalities. Additionally, combinations of Evolocumab with novel anti-inflammatory or cardiometabolic agents\u0026mdash;such as GLP-1 receptor agonists in diabetic CABG patients\u0026mdash;may offer synergistic benefits in reducing residual cardiovascular risk.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study provides compelling evidence that Evolocumab, when integrated into the lipid-lowering regimen of CABG patients, significantly enhances lipid control and reduces cardiovascular events during intermediate follow-up. These findings support the incorporation of PCSK9 inhibitors into clinical practice for patients at high cardiovascular risk undergoing surgical revascularization. Future randomized controlled trials are essential to confirm these observations and to inform evidence-based guidelines.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e: G.N. and G.Sa conceived the study, performed surgeries, and wrote the manuscript. W.V. revised the manuscript, V.C., G.T., C.L, I.R., F.B., V.M., P.M, F.F., G.S., M.S.B., G.C. F.A. and E.G. contributed to data analysis and interpretation. G.Sp. supervised the project. All authors reviewed and approved the final manuscript.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eWe would like to thank all the authors for their valuable contributions and participation in the study, and we thank Valeria Cosco, Jlenia D\u0026rsquo;Agnano and Veronica D\u0026rsquo;Anna for manuscript review and editorial assistance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone declared.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data underlying this article will be shared on reasonable request to the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col start=\"1\" type=\"1\"\u003e\n\u003cli\u003eGiugliano RP, Sabatine MS. 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Strike early-strike strong lipid-lowering strategy with PCSK9 inhibitors in acute coronary syndrome patients: real-world evidence from the AT-TARGET-IT registry. \u003cem\u003eEur J Prev Cardiol\u003c/em\u003e 2024; 31: 1806-1816. \u003c/li\u003e\n\u003cli\u003eNasso G, Larosa C, Bartolomucci F, Brigiani MS, Contegiacomo G, Demola MA et al. Safety and efficacy of PCSK9 inhibitors in patients with acute coronary syndrome who underwent coronary artery bypass grafts: a comparative retrospective analysis. \u003cem\u003eJ Clin Med\u003c/em\u003e 2024; 13: 907. \u003c/li\u003e\n\u003cli\u003eKim LK, Looser P, Swaminathan RV, Minutello RM, Wong SC, Girardi L\u003csup\u003e \u003c/sup\u003e et al. 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Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. \u003cem\u003eN Engl J Med\u003c/em\u003e 2009; 360: 961-972. \u003c/li\u003e\n\u003cli\u003eO\u0026apos;Donoghue ML, Giugliano RP, Wiviott SD, Atar\u003csup\u003e \u003c/sup\u003eD, Keech\u003csup\u003e \u003c/sup\u003eA, Kuder\u003csup\u003e \u003c/sup\u003eJF et al. Long-term evolocumab in patients with established atherosclerotic cardiovascular disease. \u003cem\u003eCirculation \u003c/em\u003e2022; 146: 1109-1119. \u003c/li\u003e\n\u003cli\u003eNasso G, Vignaroli W, Amodeo V, Bartolomucci F, Larosa C, Contegiacomo G et al. Evolocumab treatment in dyslipidemic patients undergoing coronary artery bypass grafting: one-year safety and efficacy results. \u003cem\u003eJ Clin Med\u003c/em\u003e 2004; 13: 2987.\u003c/li\u003e\n\u003cli\u003eNa HR, Kwon OS, Kang JK, Kim YH, Lim JY. Evolocumab administration prior to coronary artery bypass grafting in patients with multivessel coronary artery disease (EVOCABG): study protocol for a randomized controlled clinical trial. \u003cem\u003eTrials \u003c/em\u003e2022; 23: 430. \u003c/li\u003e\n\u003cli\u003eCollins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L\u003csup\u003e \u003c/sup\u003eet al. Interpretation of the evidence for the efficacy and safety of statin therapy. \u003cem\u003eLancet\u003c/em\u003e 2016; 388: 2532-2561. \u003c/li\u003e\n\u003cli\u003eThe Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. \u003cem\u003eJAMA\u003c/em\u003e 1984; 251: 351-364. \u003c/li\u003e\n\u003cli\u003eFrick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. \u003cem\u003eN Engl J Med\u003c/em\u003e 1987; 317: 1237-1245. \u003c/li\u003e\n\u003cli\u003eBuchwald H, Varco RL, Matts JP, Long JM, Fitch LL, Campbell GS et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. \u003cem\u003eN Engl J Med\u003c/em\u003e 1990; 323: 946-955. \u003c/li\u003e\n\u003cli\u003eCannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. \u003cem\u003eN Engl J Med\u003c/em\u003e 2004; 350: 1495-1504. \u003c/li\u003e\n\u003cli\u003eLaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. \u003cem\u003eN Engl J Med\u003c/em\u003e 2005; 352: 1425-1435. \u003c/li\u003e\n\u003cli\u003eSabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. \u003cem\u003eN Engl J Med \u003c/em\u003e2015; 372: 1500-1509. \u003c/li\u003e\n\u003cli\u003eKaushik A, Kapoor A, Agarwal SK, Pande S, Tewari P, Majumdar G et al. Statin reload before off-pump coronary artery bypass graft: effect on biomarker release kinetics. \u003cem\u003eAnn Card Anaesth\u003c/em\u003e 2020; 23: 27-33.\u003c/li\u003e\n\u003cli\u003eRaal FJ, Stein EA, Dufour R, Turner\u003csup\u003e \u003c/sup\u003eT, Civeira\u003csup\u003e \u003c/sup\u003eF, Burgess L et al. PCSK9 inhibition with evolocumab in heterozygous familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. \u003cem\u003eLancet\u003c/em\u003e 2015; 385: 331-340. \u003c/li\u003e\n\u003cli\u003eSabatine MS, De Ferrari GM, Giugliano RP, Huber\u003csup\u003e \u003c/sup\u003eK, Lewis\u003csup\u003e \u003c/sup\u003eBS, Ferreira J\u003csup\u003e \u003c/sup\u003e et al. Clinical benefit of evolocumab by severity and extent of coronary artery disease. \u003cem\u003eCirculation\u003c/em\u003e 2018; 138: 756-766.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"dyslipidemia, cardiac surgery, PCSK9","lastPublishedDoi":"10.21203/rs.3.rs-6744088/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6744088/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eAims\u003c/b\u003e \u0026ndash; Evolocumab, a PCSK9 inhibitor, has been shown to significantly reduce cholesterol levels when added to statin\u0026thinsp;+\u0026thinsp;ezetimibe therapy after coronary artery bypass grafting (CABG), though short-term follow-up did not reveal reductions in major clinical events. Beyond lipid-lowering, PCSK9 inhibitors may offer anti-inflammatory and plaque-stabilizing effects, especially relevant in the perioperative phase of CABG. Evolocumab enhances LDL clearance by upregulating LDL receptor recycling and may also reduce lipoprotein(a) and inflammatory markers. Importantly, residual inflammatory risk remains a contributor to post-CABG events, even in patients with well-controlled lipid levels. Due to its unique pharmacologic profile, Evolocumab warrants dedicated evaluation in surgical populations.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods and Results\u003c/b\u003e \u0026ndash; This retrospective study included 254 dyslipidemic patients undergoing CABG. Of these, 111 received statin\u0026thinsp;+\u0026thinsp;ezetimibe plus Evolocumab, while 143 received only statin\u0026thinsp;+\u0026thinsp;ezetimibe. Over 18 months of follow-up, the two groups were compared for lipid levels and cardiovascular outcomes. Cox regression analysis identified significant predictors of events, including treatment group, hypertension, EUROSCORE_II, and prior stroke. Evolocumab treatment showed a protective effect on major cardiovascular events\u0026mdash;such as recurrent angina, myocardial infarction, cerebrovascular events, revascularization procedures, and cardiac death\u0026mdash;with a hazard ratio (HR) of 0.38 (95% CI 0.15\u0026ndash;0.99, p\u0026thinsp;=\u0026thinsp;0.047).\u003c/p\u003e\u003cp\u003eCholesterol levels decreased more rapidly in the Evolocumab group, with a mean total cholesterol reduction of 27 mg/dL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), LDL by 30 mg/dL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), triglycerides by 18.77 mg/dL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and an HDL increase of 2.7 mg/dL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), compared to the control group.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion \u0026ndash;\u003c/b\u003e In patients undergoing CABG, the addition of Evolocumab to standard lipid-lowering therapy significantly reduced cholesterol levels and, importantly, lowered the incidence of major cardiac events at 18-month follow-up. These findings, the first of their kind in the surgical setting, support the use of Evolocumab perioperatively, particularly in patients resistant to statin therapy.\u003c/p\u003e","manuscriptTitle":"Clinical Effect of Evolocumab treatment in coronary artery bypass surgery","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-28 08:02:06","doi":"10.21203/rs.3.rs-6744088/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"dc74b728-3139-4ec8-baf6-5b96ba8687e9","owner":[],"postedDate":"July 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":51969248,"name":"Health sciences/Cardiology"},{"id":51969249,"name":"Health sciences/Cardiology/Cardiovascular biology"}],"tags":[],"updatedAt":"2025-10-22T08:20:09+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-28 08:02:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6744088","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6744088","identity":"rs-6744088","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}