Novel therapies to achieve the recommended low-density lipoprotein cholesterol concentration (LDL-C) targets for patients after coronary artery bypass grafting

Central MessageWider use of recently introduced nonstatin agents should help to reduce the residual risk of adverse cardiac events in high-risk patients post-CABG.See Commentary on page XXX. Wider use of recently introduced nonstatin agents should help to reduce the residual risk of adverse cardiac events in high-risk patients post-CABG. See Commentary on page XXX. Coronary artery bypass grafting (CABG) is a common cardiac surgical procedure, with approximately 400,000 cases performed annually in the United States alone.1Bowdish M.E. D’Agostino R.S. Thourani V.H. Schwann T.A. Krohn C. Desai N. et al.STS Adult Cardiac Surgery database: 2021 update on outcomes, quality, and research.Ann Thorac Surg. 2021; 111: 1770-1780Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar,2Bachar B.J. Manna B. Coronary artery bypass graft.in: StatPearls. StatPearls Publishing, 2023Google Scholar Over the years, the comorbidity of patients undergoing CABG has increased, with more patients having pre-existing diabetes mellitus, heart failure, chronic kidney disease, peripheral artery, or cerebrovascular disease, with greater use of emergent surgery.3Raza S. Deo S.V. Kalra A. Zia A. Altarabsheh S.E. Deo V.S. et al.Stability after initial decline in coronary revascularization rates in the United States.Ann Thorac Surg. 2019; 108: 1404-1408Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 4Dani S.S. Minhas A.M.K. Arshad A. Krupica T. Goel S.S. Virani S.S. et al.Trends in characteristics and outcomes of hospitalized young patients undergoing coronary artery bypass grafting in the United States, 2004 to 2018.J Am Heart Assoc. 2021; 10e021361Crossref Scopus (11) Google Scholar, 5Ohri S.K. Benedetto U. Luthra S. Grant S.W. Goodwin A.T. Trivedi U. et al.Coronary artery bypass surgery in the UK, trends in activity and outcomes from a 15-year complete national series.Eur J Cardiothorac Surg. 2022; 61: 449-456Crossref PubMed Scopus (14) Google Scholar, 6Gaudino M. Samadashvili Z. Hameed I. Chikwe J. Girardi L.N. Hannan E.L. Differences in long-term outcomes after coronary artery bypass grafting using single versus multiple arterial grafts and the association with sex.JAMA Cardiol. 2020; 6: 401-409Crossref PubMed Scopus (24) Google Scholar Contemporary postoperative outcomes among patients who undergo CABG are excellent, with low in-hospital mortality (1.8%),1Bowdish M.E. D’Agostino R.S. Thourani V.H. Schwann T.A. Krohn C. Desai N. et al.STS Adult Cardiac Surgery database: 2021 update on outcomes, quality, and research.Ann Thorac Surg. 2021; 111: 1770-1780Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar but avoiding recurrent major adverse cardiovascular events (MACE) largely depends on adopting appropriate secondary prevention measures.7Kulik A. Ruel M. Jneid H. Ferguson T.B. Hiratzka L.F. Ikonomidis J.S. et al.Secondary prevention after coronary artery bypass graft surgery: a scientific statement from the American Heart Association.Circulation. 2015; 131: 927-964Crossref PubMed Scopus (266) Google Scholar To increase the uptake of secondary prevention strategies after CABG, in 2015 the American Heart Association (AHA) and in 2018 the European Association of Cardiothoracic Surgery provided clear guidance on the therapies considered optimal medical therapy after surgery. Along with lifestyle modifications, as per these guidelines, optimal medical therapy consisted of antiplatelet therapy (aspirin, P2Y12 inhibitors), blood pressure control (beta-blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors), glycemic control, and effective low-density lipoprotein cholesterol (LDL-C) reduction. Among these measures, one could argue that LDL-C reduction may likely be one of the most important for patients post-CABG. We have clear evidence that lipid-lowering after CABG is associated with better graft patency and improved outcomes. In the Post-Coronary Artery Bypass Graft trial (post-CABG) trial, compared with patients with LDL-C concentrations between 132 and 136 mg/dL (3.4 mmol/L), those with LDL-C concentrations <100 mg/dL (2.6 mmol/L) had improved saphenous vein graft patency on coronary angiography.8Waters D.D. Azar R.R. Postscripts from the Post-Coronary Artery Bypass Graft trial: the sustained benefit of more aggressive cholesterol lowering and the enigma of low-dose anticoagulation.Circulation. 2000; 102: 144-146Crossref PubMed Scopus (8) Google Scholar Over a 7-year follow-up, this trial also reported a lower incidence of MACE in patients with LDL-C concentrations <100 mg/dL. A more contemporary analysis of 3 randomized trials showed a dose–response relationship between attained LDL-C and MACE outcomes in patients with type 2 diabetes undergoing CABG.9Farkouh M.E. Godoy L.C. Brooks M.M. Mancini G.B.J. Vlachos H. Bittner V.A. et al.Influence of LDL-cholesterol lowering on cardiovascular outcomes in patients with diabetes mellitus undergoing coronary revascularization.J Am Coll Cardiol. 2020; 76: 2197-2207Crossref PubMed Scopus (15) Google Scholar We already have randomized trial data on the effectiveness of statin therapy for many decades, yet most patients post-CABG are grossly undertreated. More recently, the importance of treating elevated LDL-C in secondary prevention was further supported by recent genetic studies that reported a causal relationship between LDL-C concentrations and atherogenesis.10Ference B.A. Ginsberg H.N. Graham I. Ray K.K. Packard C.J. Bruckert E. et al.Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.Eur Heart J. 2017; 38: 2459-2472Crossref PubMed Scopus (1784) Google Scholar Furthermore, initiating appropriate lipid-lowering therapies immediately after surgery may promote better long-term medication adherence and substantial life-years gained. Therefore, in this review, we aim to (1) introduce the “very-high risk” definition and updated intensity of LDL-C lowering in patients who undergo CABG. (2) Discuss recent updates on statin intolerance (statin-associated side effects; SASEs). (3) Provide an overview of the recent advances in nonstatin therapy (NST). (4) Briefly discuss the relevance of triglycerides (TG) in secondary atherosclerotic cardiovascular disease (ASCVD) prevention. (5) Present current opinions regarding possible concerns of an extremely low LDL-C concentration. The European Society of Cardiology (ESC) and the AHA/American College of Cardiology (ACC) recently introduced guidelines regarding the choice of coronary revascularization.11Lawton J.S. Tamis-Holland J.E. Bangalore S. Bates E.R. Beckie T.M. Bischoff J.M. et al.2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association Joint committee on clinical practice guidelines.Circulation. 2022; 145: e18-e114PubMed Google Scholar,12Neumann F.-J. Sousa-Uva M. Ahlsson A. Alfonso F. Banning A.P. Benedetto U. et al.2018 ESC/EACTS guidelines on myocardial revascularization.Eur Heart J. 2019; 40: 87-165Crossref PubMed Scopus (3947) Google Scholar However, they provide little guidance regarding secondary prevention strategies after CABG. Therefore, our strategies on secondary prevention are based on the 2018 AHA/ACC and the 2019 ESC Scientific committee statements for the treatment of blood cholesterol.13Grundy S.M. Stone N.J. Bailey A.L. Beam C. Birtcher K.K. Blumenthal R.S. et al.2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.Circulation. 2019; 139: e1082-e1143PubMed Google Scholar,14Mach F. Baigent C. Catapano A.L. Koskinas K.C. Casula M. Badimon L. et al.2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Eur Heart J. 2020; 41: 111-188Crossref PubMed Scopus (1) Google Scholar Both ACC/AHA and ESC identify LDL-C as the primary therapeutic target in secondary prevention and created a new group of “very high-risk” patients with ASCVD whom they consider are at greatest risk to have recurrent MACE (Table 1). From Table 1, clearly the ESC definition for a “very high-risk” patient is more liberal than that provided by the AHA/ACC. In our recent study using data from US veterans, using the 2018 AHA/ACC criteria, approximately one third (32%) of the patients undergoing CABG were classified as “very high-risk” by the ACC/AHA criteria.15Deo S. Ueda P. Sheikh A.M. Altarabsheh S. Elgudin Y. Rubelowsky J. et al.Lipid lowering in “very high risk” patients undergoing coronary artery bypass surgery and its projected reduction in risk for recurrent vascular events: a Monte Carlo stepwise simulation approach.J Cardiovasc Pharmacol. 2023; 81: 120-128Crossref PubMed Scopus (3) Google Scholar However, according to the ESC criteria, all patients would be classified as “very high-risk.” Even if we hypothesize that US veterans have a greater comorbidity burden than non-veterans and apply the stricter ACC/AHA criteria, we expect that at least 20% of all patients post-CABG treated at non-Veterans Affairs hospitals in the United States are likely “very high-risk” for recurrent MACE. Therefore, accurate risk-stratification after surgery is the first step toward initiating intensive secondary prevention measures. Another important difference between guidelines is the lower target (LDL-C <55 mg/dL; 1.42 mmol/L per ESC guideline) versus a threshold of 70 mg/dL; 1.81 mmol/L to consider nonstatin therapies as per the AHA/ACC guideline (Figure 1). In the latter sections, we discuss the available therapies to achieve such extremely low LDL-C concentrations.Table 1The AHA/ACC and ESC criteria for very high riskMethod to define ‘very high risk’ as per AHA/ACC and ESC criteriaThe 2018 AHA/ACC “very high risk” definition Multiple major ASCVD events OR one ASCVD event + multiple high-risk conditions. Major ASCVD events Recent acute coronary syndrome (within the past 12 mo) Previous history of myocardial infarction (other than the recent acute coronary syndrome) Previous history of ischemic stroke Symptomatic peripheral arterial disease/previous history of lower-limb revascularization/previous lower-limb amputation for vascular disease High-risk conditions Age ≥65 y Heterozygous familial hypercholesterolemia History of previous CABG/percutaneous revascularization Diabetes mellitus Hypertension Chronic kidney disease (eGFR <60 mL/min/1.73 m2) Current smoking LDL-C ≥ 100 mg/dL (≥2.6 mmol/L) despite maximally tolerated statin therapy Previous congestive heart failureThe 2019 ESC “very high risk” definition Clinically documented ASCVD (having at least 1 of the following)Previous acute coronary syndrome (myocardial infarction or unstable angina)Stable anginaPrevious revascularization (coronary or peripheral vascular)Previous stroke/TIAPeripheral arterial diseaseDocumented ASCVD using imaging (unequivocal)Significant plaque on a coronary angiogram or CT scan (at least 2 major epicardial vessels having >50% stenosis)Significant carotid stenosis on a carotid ultrasoundDiabetes mellitus with target organ damage (microalbuminuria, retinopathy or neuropathy)Severe chronic kidney disease (eGFR <30 mL/min/1.73 m2)A calculated SCORE predicting ≥10% risk of fatal ASCVD at 10 y.This table presents the criteria to define a “very-high risk” patient according to the professional society guidelines. AHA, American Heart Association; ACC, American College of Cardiology; ESC, European Society of Cardiology; ASCVD, atherosclerotic cardiovascular disease; CABG, coronary artery bypass grafting; eGFR, estimated glomerular filtration rate; LDL-C, low-density lipoprotein cholesterol; TIA, transient ischemic attack; CT, computed tomography; SCORE, Systematic Coronary Risk Evaluation. Open table in a new tab This table presents the criteria to define a “very-high risk” patient according to the professional society guidelines. AHA, American Heart Association; ACC, American College of Cardiology; ESC, European Society of Cardiology; ASCVD, atherosclerotic cardiovascular disease; CABG, coronary artery bypass grafting; eGFR, estimated glomerular filtration rate; LDL-C, low-density lipoprotein cholesterol; TIA, transient ischemic attack; CT, computed tomography; SCORE, Systematic Coronary Risk Evaluation. Although statins remain the first-line therapy for LDL-C reduction, poor long-term adherence, high rates of discontinuation, and statin intolerance (SI) due to perceived side effects often limit effective risk reduction.16Banach M. Stulc T. Dent R. Toth P.P. Statin non-adherence and residual cardiovascular risk: there is need for substantial improvement.Int J Cardiol. 2016; 225: 184-196Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar Depending upon the data sources, statin-associated muscle symptoms and SI may occur in 5% to 30% people receiving statin therapy, with observational studies reporting greater event rates than randomized trials.17Stroes E.S. Thompson P.D. Corsini A. Vladutiu G.D. Raal F.J. Ray K.K. et al.Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society consensus panel statement on assessment, aetiology and management.Eur Heart J. 2015; 36: 1012-1022Crossref PubMed Scopus (963) Google Scholar,18Bytyçi I. Penson P.E. Mikhailidis D.P. Wong N.D. Hernandez A.V. Sahebkar A. et al.Prevalence of statin intolerance: a meta-analysis.Eur Heart J. 2022; 43: 3213-3223Crossref PubMed Scopus (78) Google Scholar Although definitions of statin-associated muscle symptoms/SI vary (Table E1) multiple studies reported that Black or Asian race, age ≥65 years, female sex, statin intensity, intense exercise, and increased alcohol intake were associated with increased SI.18Bytyçi I. Penson P.E. Mikhailidis D.P. Wong N.D. Hernandez A.V. Sahebkar A. et al.Prevalence of statin intolerance: a meta-analysis.Eur Heart J. 2022; 43: 3213-3223Crossref PubMed Scopus (78) Google Scholar, 19Raju S.B. Varghese K. Madhu K. Management of statin intolerance.Indian J Endocrinol Metab. 2013; 17: 977-982Crossref PubMed Google Scholar, 20Virani S.S. Akeroyd J.M. Ahmed S. Krittanawong C. Martin L.A. Slagle J. et al.The use of structured data elements to identify ASCVD patients with statin-associated side effects. Insights from the Department of Veterans Affairs.J Clin Lipidol. 2019; 13: 797-803.e1Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 21Jia X. Lee M.T. Ramsey D.J. Mahtta D. Akeroyd J.M. Turchin A. et al.Association of patient, provider and facility related characteristics with statin associated side effects and statin use: insight from the Veteran’s Affairs healthcare system.J Clin Lipidol. 2021; 15: 832-839Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Furthermore, SI was associated with a 50% increase in the relative risk for myocardial infarction among 56,000 Medicare beneficiaries22Serban M.-C. Colantonio L.D. Manthripragada A.D. Monda K.L. Bittner V.A. Banach M. et al.Statin intolerance and risk of coronary heart events and all-cause mortality following myocardial infarction.J Am Coll Cardiol. 2017; 69: 1386-1395Crossref PubMed Scopus (215) Google Scholar and patients with SI were 85% less likely to meet recommended LDL-C thresholds of <100 mg/dL (patients with coronary heart disease, ischemic stroke, peripheral artery disease, or diabetes) and <70 mg/dL (patients with recent acute coronary syndrome).23Graham J.H. Sanchez R.J. Saseen J.J. Mallya U.G. Panaccio M.P. Evans M.A. Clinical and economic consequences of statin intolerance in the United States: results from an integrated health system.J Clin Lipidol. 2017; 11: 70-79.e1Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Due to the greater MACE rates, compared with patients tolerating high-intensity statins, patients with SI also incurred greater overall treatment costs.23Graham J.H. Sanchez R.J. Saseen J.J. Mallya U.G. Panaccio M.P. Evans M.A. Clinical and economic consequences of statin intolerance in the United States: results from an integrated health system.J Clin Lipidol. 2017; 11: 70-79.e1Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar However, the recently introduced NSTs (proprotein convertase subtilsin/kexin type 9 inhibitors [PCSK9i] monoclonal antibodies, small interfering ribonucleic acid [siRNA] therapies, and bempedoic acid) will help to bridge this gap. Statin agents (simvastatin, atorvastatin, lovastatin, pravastatin, pitavastatin, and rosuvastatin) have been the first-line agents for reducing LDL-C. They inhibit hydroxy-methyl coenzyme-A reductase, which is the rate-limiting step in de novo cholesterol synthesis (Figure E1). Based on their projected LDL-C reduction from the untreated baseline concentration, drugs can be classified as low-intensity (<30% LDL-C reduction), moderate intensity (30%-49%), and high-intensity (≥50% LDL-C reduction) (Table 2). A large patient-level pooled meta-analysis of 27 trials reported that every 1 mmol/L (38 mg/dL) reduction in LDL-C concentration resulted in a 21% relative risk reduction (RRR) for MACE24Cholesterol Treatment Trialists' (CTT) CollaboratorsThe effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.Lancet. 2012; 380: 581-590Abstract Full Text Full Text PDF PubMed Scopus (2071) Google Scholar Currently, ezetimibe, bempedoic acid, PCSK9i monoclonal antibodies (evolocumab, alirocumab), and inclisiran are the NST that are approved in the United States for lowering LDL-C concentration. Although ezetimibe and bempedoic acid require daily oral dosing, the PCSK9i are subcutaneous injections that can be administered either biweekly or monthly (evolocumab, alirocumab) whereas inclisiran (an siRNA molecule) needs dosing every 6 months after the initial doses at days 0 and 90. The ORION-4 (NCT 03705234) randomized trial evaluating the clinical benefit of inclisiran, an siRNA molecule, is currently ongoing, whereas all other drugs have demonstrated cardiovascular benefit (https://clinicaltrials.gov/ct2/show/NCT03705234).25Sabatine M.S. Giugliano R.P. Keech A.C. Honarpour N. Wiviott S.D. Murphy S.A. et al.Evolocumab and clinical outcomes in patients with cardiovascular disease.N Engl J Med. 2017; 376: 1713-1722Crossref PubMed Scopus (3513) Google Scholar,E1Cannon C.P. Blazing M.A. Giugliano R.P. McCagg A. White J.A. Theroux P. et al.Ezetimibe added to statin therapy after acute coronary syndromes.N Engl J Med. 2015; 372: 2387-2397Crossref PubMed Scopus (2977) Google Scholar, E2Nissen S.E. Lincoff A.M. Brennan D. Ray K.K. Mason D. Kastelein J.J.P. et al.Bempedoic acid and cardiovascular outcomes in statin-intolerant patients.N Engl J Med. 2023; 288: 1353-1364Crossref Scopus (40) Google Scholar, E3Schwartz G.G. Steg P.G. Szarek M. Bhatt D.L. Bittner V.A. Diaz R. et al.Alirocumab and cardiovascular outcomes after acute coronary syndrome.N Engl J Med. 2018; 379: 2097-2107Crossref PubMed Scopus (1803) Google Scholar Table 3 provides summary information on NST outcome trials.Table 2Statin drugs grouped according to their LDL-C reducing intensityLow-intensity statin therapy daily dose lowers LDL-C by <30% (on average)Moderate intensity statin therapy daily dose lowers LDL-C by 30%-49% (on average)High intensity statin therapy daily dose lowers LDL-C by ≥50% (on average)Simvastatin 10 mgAtorvastatin 10-20 mgAtorvastatin 40-80 mgPravastatin 10-20 mgRosuvastatin 5-10 mgRosuvastatin 20-40 mgLovastatin 20 mgSimvastatin 20-40 mgFluvastatin 20-40 mgPravastatin 40-80 mgLovastatin 40 mgFluvastatin XL 80 mgFluvastatin 40 mg BIDPitavastatin 2-4 mgThis table was created from data provided in the 2018 AHA/ACC Guidelines on the Management of Blood Cholesterol.13Grundy S.M. Stone N.J. Bailey A.L. Beam C. Birtcher K.K. Blumenthal R.S. et al.2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.Circulation. 2019; 139: e1082-e1143PubMed Google Scholar Items in bold denote those therapies that were included in randomized trials of statin therapy. LDL-C, Low-density lipoprotein cholesterol; BID, bis in die (twice a day). Open table in a new tab Table 3Summary of the trials included in this reviewDrugPivotal trialTrial overviewResultsDrug-related adverse eventsLDL-C reduction EzetimibeIMROVE-IT•18,144 patients with acute coronary syndrome and an LDL-C >50 mg/dL•Simvastatin 40 mg vs Simvastatin 40 mg + ezetimibe 10 mg•Dosing: 10 mg of ezetimibe orally daily•Median duration: 6 y•Primary end point: composite of CV death, major coronary event (nonfatal MI, unstable angina, coronary revascularization 30 d beyond randomization)•2% absolute risk reduction favoring ezetimibe therapy•HR, 0.94 (95% CI, 0.89-0.99)•No difference observed in the prespecified safety end points•Discontinuation of study medication due to adverse events similar in both armsPCSK9iEvolocumabFOURIER•27,564 patients with established ASCVD already on stable statin therapy and LDL-C >70 mg/dL•70% and 5% received high-intensity statin and ezetimibe at baseline•Dosing: evolocumab subcutaneous injection, 140 mg biweekly or 420 mg monthly per patient preference•Median duration: 26 mo•Primary end point: composite of CV death, major coronary event (nonfatal MI, unstable angina, coronary revascularization)•1.5% absolute risk reduction favoring evolocumab•HR, 0.85 (95% CI, 0.73-0.88)•No difference observed in the prespecified safety end points•Injection-site reactions more frequent with evolocumab (2.1% vs 1.6%)•Rate of new onset diabetes comparable between arms [HR 1.05 (95% CI, 0.94-1.17)] AlirocumabODYSSEY OUTCOMES•18,924 patients with remote acute coronary syndrome already on high-intensity statin therapy with LDL-C >70 mg/dL (1.8 mmol/L)•High-intensity statin therapy vs high-intensity statin therapy + alirocumab•Dosing: alirocumab subcutaneous injection, 75-150 mg biweekly to ensure LDL-C 25-50 mg/dL, but above 15 mg/dL.•Primary end point: composite of CV death, major coronary event (nonfatal MI, unstable angina, coronary revascularization)•1.6% absolute risk reduction•HR, 0.85 (95% CI, 0.78-0.93)•No difference observed in the prespecified safety end points•Local injection-site reactions greater with alirocumab (3.8% vs 2.1%)•Rate of new-onset diabetes comparable in both arms Bempedoic acidCLEAR Outcomes•13,970 patients with established, or at high risk for ASCVD and statin intolerant at randomization•Tolerated statin therapy vs tolerated statin therapy + bempedoic acid•Dosing: 180 mg of bempedoic acid orally daily•Primary end point: composite of CV death, major coronary event (nonfatal MI, unstable angina, coronary revascularization)•1.6% absolute risk reduction•HR, 0.87 (95% CI, 0.76-0.96)•The overall incidence of serious adverse events and adverse events leading to study drug discontinuation was similar between groups•Renal events (11.6% vs 8.6%), hyperuricemia (10.9% vs 5.6%), gout (3.1% vs 2.1%), and cholelithiasis (2.2% vs 1.2%) greater in patients treated with bempedoic acidTriglyceride reductionIcosapent ethyl (IPE)REDUCE-IT•8179 patients with ASCVD on statin therapy with elevated fasting triglycerides (135-499 mg/dL; 0.52-5.64 mmol/L)•Dosing: IPE 4 g twice daily vs placebo•Primary end point: composite of CV death, major coronary event (nonfatal MI, unstable angina, coronary revascularization)•5% absolute risk reduction•HR, 0.75 (95% CI, 0.68-0.83)•Pneumonia was present in 2% in either group•Atrial fibrillation greater with IPE (5% vs 2%)•Pedal edema greater with IPE (6.5% vs 5%)•Anemia, GI upset, and diarrhea lower with IPEThis table presents a summary of trials included in our review. The cardiovascular outcomes trial for inclisiran is currently ongoing (ORION-4; NCT03705234). LDL-C, Low-density lipoprotein cholesterol; IMPROVE-IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial; CV, cardiovascular; MI, myocardial infarction; HR, hazard ratio; CI, confidence interval; PCSK9i, proprotein convertase subtilsin/kexin type 9 inhibitor; FOURIER, Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; ASCVD, atherosclerotic cardiovascular disease; REDUCE-IT, Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial; GI, gastrointestinal. Open table in a new tab This table was created from data provided in the 2018 AHA/ACC Guidelines on the Management of Blood Cholesterol.13Grundy S.M. Stone N.J. Bailey A.L. Beam C. Birtcher K.K. Blumenthal R.S. et al.2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.Circulation. 2019; 139: e1082-e1143PubMed Google Scholar Items in bold denote those therapies that were included in randomized trials of statin therapy. LDL-C, Low-density lipoprotein cholesterol; BID, bis in die (twice a day). This table presents a summary of trials included in our review. The cardiovascular outcomes trial for inclisiran is currently ongoing (ORION-4; NCT03705234). LDL-C, Low-density lipoprotein cholesterol; IMPROVE-IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial; CV, cardiovascular; MI, myocardial infarction; HR, hazard ratio; CI, confidence interval; PCSK9i, proprotein convertase subtilsin/kexin type 9 inhibitor; FOURIER, Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; ASCVD, atherosclerotic cardiovascular disease; REDUCE-IT, Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial; GI, gastrointestinal. Ezetimibe is a selective cholesterol inhibitor that targets the Niemann-Pick CI-Like 1 (NPC1L1; SLC65A2) (Figure E1).E4Bardolia C. Amin N.S. Turgeon J. Emerging non-statin treatment options for lowering low-density lipoprotein cholesterol.Front Cardiovasc Med. 2021; 8: 789931Crossref PubMed Google Scholar In IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial; 2015), a combination of moderate-intensity simvastatin monotherapy versus combination therapy (moderate-intensity simvastatin + 10 mg oral daily ezetimibe) resulted in a 24% relative reduction in LDL-C compared with the baseline.E1Cannon C.P. Blazing M.A. Giugliano R.P. McCagg A. White J.A. Theroux P. et al.Ezetimibe added to statin therapy after acute coronary syndromes.N Engl J Med. 2015; 372: 2387-2397Crossref PubMed Scopus (2977) Google Scholar At 6 years' median follow-up, ezetimibe resulted in a 6% RRR for MACE. Currently, both AHA/ACC and ESC recommend ezetimibe as an inexpensive add-on therapy with statins. Importantly, in this trial, patients post-CABG seemed to derive a greater benefit from ezetimibe (absolute risk reduction [ARR] 8.8% for CABG vs 2% in the overall trial).E5Eisen A. Cannon C.P. Blazing M.A. Bohula E.A. Park J.G. Murphy S.A. et al.The benefit of adding ezetimibe to statin therapy in patients with prior coronary artery bypass graft surgery and acute coronary syndrome in the IMPROVE-IT trial.Eur Heart J. 2016; 37: 3576-3584Crossref PubMed Scopus (67) Google Scholar However, a small fraction of eligible patients post-CABG currently receive ezetimibe.E6Barrios V. Soronen J. Carter A.M. Anastassopoulou A. Lipid management across Europe in the real-world setting: a rapid evidence review.Curr Med Res Opin. 2021; 37: 2049-2059Crossref PubMed Scopus (11) Google Scholar, E7Clemens K.K. Shariff S.Z. McArthur E. Hegele R.A. Ezetimibe prescriptions in older Canadian adults after an acute myocardial infarction: a population-based cohort study.Lipids Health Dis. 2018; 17: 8Crossref PubMed Scopus (6) Google Scholar A single-center study of 484 patients post-CABG from Australia reported that despite only 50% patients at LDL-C thresholds according to 2018 AHA/ACC guidelines, less than 1% of total patients received ezetimibe as a second-line agent.E8Lan N.S.R. Ali U.S. Yeap B.B. Fegan P.G. Larbalestier R. Bell D.A. Attainment of lipid targets following coronary artery bypass graft surgery: can we do better?.J Lipid Atheroscler. 2022; 11: 187Crossref PubMed Scopus (3) Google Scholar In our analysis of 8948 “very high-risk” post-CABG US veterans, only 1.4% received ezetimibe therapy and only 30% were at the recommended threshold LDL-C concentrations before CABG.15Deo S. Ueda P. Sheikh A.M. Altarabsheh S. Elgudin Y. Rubelowsky J. et al.Lipid lowering in “very high risk” patients undergoing coronary artery bypass surgery and its projected reduction in risk for recurrent vascular events: a Monte Carlo stepwise simulation approach.J Cardiovasc Pharmacol. 2023; 81: 120-128Crossref PubMed Scopus (3) Google Scholar Thus, increasing the use of ezetimibe is a relatively inexpensive way to get more patients post-CABG at their recommended LDL-C thresholds before discharge. PCSK9, a protein, binds to hepatocyte LDL receptors and prevents the hepatic uptake of circulating LDL particle. PCSK9i are monoclonal antibodies that bind and inhibit the activity of PCSK9, which results in increased hepatocyte uptake of circulating LDL (Figure E1). Both drugs can be given biweekly or monthly. In trials that enrolled high-risk patients with ASCVD, evolocumab (FOURIER; Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) and alirocumab