Secondary Prevention for Atherosclerotic Cardiovascular Disease: Comparing Recent US and European Guidelines on Dyslipidemia.

Abstract

HomeCirculationVol. 141, No. 14Secondary Prevention for Atherosclerotic Cardiovascular Disease Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBSecondary Prevention for Atherosclerotic Cardiovascular DiseaseComparing Recent US and European Guidelines on Dyslipidemia Salim S. Virani, MD, PhD, Sidney C. Smith Jr, MD, Neil J. Stone, MD and Scott M. Grundy, MD, PhD Salim S. ViraniSalim S. Virani Salim S. Virani, MD, PhD, Health Services Research and Development (152), Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Boulevard, Houston, TX 77030. Email E-mail Address: [email protected] https://orcid.org/0000-0001-9541-6954 Health Policy, Quality and Informatics Program, Michael E. DeBakey Veterans Affairs Medical Center Health Services Research and Development Center for Innovations, Houston, TX (S.S.V.). Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX (S.S.V.). Search for more papers by this author , Sidney C. Smith JrSidney C. Smith Jr Division of Cardiology, McAllister Heart Institute, University of North Carolina at Chapel Hill (S.C.S.). Search for more papers by this author , Neil J. StoneNeil J. Stone Northwestern University Feinberg School of Medicine, Chicago, IL (M.J.S.). Search for more papers by this author and Scott M. GrundyScott M. Grundy University of Texas Southwestern Medical Center and VA Medical Center, Dallas (S.M.G.). Search for more papers by this author Originally published6 Apr 2020https://doi.org/10.1161/CIRCULATIONAHA.119.044282Circulation. 2020;141:1121–1123The 2018 American Heart Association (AHA)/American College of Cardiology (ACC) Multisociety Guideline on the Management of Blood Cholesterol1 divides patients with clinical atherosclerotic cardiovascular disease (ASCVD) into high-risk and very high-risk categories. The high-risk group includes those with stable ASCVD who are treated with high-intensity statins. Very high-risk patients are those with ASCVD plus other high-risk conditions; these patients are potential candidates for maximal statin therapy plus 2 nonstatins (ezetimibe and/or proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors). This article compares and contrasts the AHA/ACC guideline with the dyslipidemia guidelines recently published by the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS)2; the latter offers a different definition of very high risk for the identification of patients deemed eligible for adding nonstatins to statin therapy (Table).Table 1. Comparison of Major Treatment Recommendations of the 2018 AHA/ACC Multisociety Cholesterol Guideline and the 2019 ESC/EAS Guidelines for Secondary ASCVD PreventionTheme2018 AHA/ACC Multisociety Cholesterol Guideline2019 ESC/EAS Guidelines for the Management of DyslipidemiaLDL-C as the primary treatment targetLDL-C is the dominant form of atherogenic cholesterolThere is a log-linear relationship between the absolute changes in plasma LDL-C and ASCVD riskImportance of a heart-healthy lifestyleHeart-healthy lifestyle is recommended for all patients with ASCVDRecommended for all patients with ASCVDVery high-risk categoryHistory of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions*Documented ASCVD and other very high-risk conditions†High-intensity statin therapy as first-line treatment for ASCVDIn patients ≤75 y of age with clinical ASCVD, high-intensity statin therapy should be initiated or continued to achieve ≥50% reduction in LDL-CFor patients with ASCVD or other very high- risk conditions, a high-intensity statin is prescribed to achieve a 50% reduction in LDL-C and, if possible, an LDL-C <55 mg/dL (1.4 mmol/L)Addition of nonstatin therapy to maximally tolerated statin in highest-risk patientsFor patients at very high risk (AHA/ACC criteria*), if LDL-C remains ≥70 mg/dL on maximally tolerated statin, first consider adding ezetimibe; if LDL-C remains ≥70 mg/dL (or non–HDL-C ≥100 mg/dL), consider adding PCSK9 inhibitorFor patients at very high risk (ESC/EAS criteria†), if LDL-C remains ≥1.4 mmol/L (≥55 mg/dL) on maximally tolerated statin, first add ezetimibe; if LDL-C remains ≥1.4 mmol/L (≥55 mg/dL), a combination with a PCSK9 inhibitor is recommendedIntensive treatment of older adults with ASCVDIn patients >75 y of age with ASCVD, it is reasonable to initiate moderate- or high-intensity statin therapy after evaluation of the potential for ASCVD risk reduction, adverse effects, drug–drug interactions, patient frailty, and patient preferencesIn patients >65 y of age with ASCVD, treatment with statins is recommended in the same way as for younger patientsMeasurement of baseline and follow-up lipid panelsEfficacy and adherence to therapy should be determined by periodic LDL-C measurementEfficacy and adherence to therapy should be determined by periodic LDL-C measurement; ApoB secondary goal is <65 mg/dL for very high-risk patientsACC indicates American College of Cardiology; AHA, American Heart Association; ApoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; EAS, European Atherosclerosis Society; ESC, European Society of Cardiology; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; and PCSK9, proprotein convertase subtilisin kexin 9.*By AHA/ACC, very high risk includes a history of multiple major ASCVD events or 1 major ASCVD event plus multiple high-risk conditions. Major ASCVD events include recent acute coronary syndrome within the past 12 months, a history of myocardial infarction other than the recent acute coronary syndrome event, a history of ischemic stroke, and symptomatic peripheral arterial disease (defined as history of claudication with ankle-brachial index <0.85 or previous revascularization or amputation). High-risk conditions include age of ≥65 years, heterozygous familial hypercholesterolemia, prior percutaneous coronary intervention/coronary bypass surgery, diabetes mellitus, hypertension, chronic kidney disease, current, smoking, history of heart failure, and LDL-C level of 100 mg/dL (to convert to millimoles per liter, multiple by 0.0259) or higher while receiving maximal statin plus ezetimibe.†By ESC/EAS, very high risk incudes documented ASCVD, either clinical or unequivocal on imaging. Also included are diabetes mellitus with complications, severe chronic kidney disease, 10-year risk for fatal CVD ≥10%, and familial hypercholesterolemia plus ASCVD or another major risk factor. Documented ASCVD includes previous acute coronary syndrome (myocardial infarction or unstable angina), stable angina, coronary revascularization procedures, stroke and transient ischemic attack, and peripheral arterial disease. Unequivocally documented ASCVD on imaging includes those findings that are known to be predictive of clinical events such as significant plaque on coronary angiography or computed tomography scan (multivessel coronary disease with 2 major epicardial arteries having >50% stenosis) or on carotid ultrasound.Both guidelines highlight the causal role of low-density lipoprotein (LDL) in atherogenesis, and they identify LDL-cholesterol (LDL-C) as the primary target of therapy. Both guidelines recognize a heart-healthy lifestyle as the foundation for treatment. Both further recommend high-intensity statin therapy in patients with ASCVD on the basis of meta-analysis of secondary prevention randomized controlled trials of statin therapy.1,2 High-intensity statins typically reduce LDL-C by ≥50%, which supports the primary goal of therapy being a ≥50% reduction in LDL-C. Periodic monitoring of the response to therapy is generally recommended. An important addition to both guidelines is the identification of very high-risk patients who may benefit with greater absolute risk reduction from the addition of nonstatins (ezetimibe±PCSK9 inhibitor) to maximal statin therapy.Although the 2 guidelines share many similarities, notable differences must be recognized and considered. For the definition of documented ASCVD, both guidelines include acute coronary syndrome, stable angina, coronary revascularization, stroke, transient ischemic attack, and peripheral arterial disease. The most important distinction is the definition of very high risk. The AHA/ACC guideline defines very high risk as a history of multiple major ASCVD events or 1 major ASCVD event plus multiple high-risk conditions (see footnote to the Table for details). According to the ESC/EAS, very high risk consists of documented ASCVD or various other higher-risk conditions in the absence of ASCVD (see footnote to the Table for details). These include subclinical atherosclerosis as detected by imaging and several other conditions, for example, diabetes mellitus with complications, severe chronic kidney disease, or 10-year risk of fatal CVD ≥10%. This may expand the number of patients who are candidates for nonstatin add-on therapy, especially patients without ASCVD who are classified as very high risk in the ESC/EAS guidelines. It is important to note that sufficient magnitude of benefit has not been demonstrated with randomized controlled trials, especially with nonstatin therapy in patients noted as very high risk without ASCVD.The AHA/ACC guideline relegates subclinical atherosclerosis to primary prevention and moderate-intensity statin therapy; high-intensity statins are reserved for those also having multiple risk factors (10-year risk for ASCVD ≥20%). However, the AHA/ACC guideline does not consider subclinical atherosclerosis as an indication for nonstatin therapies. The same can be said for high-risk conditions (except familial hypercholesterolemia) without concomitant ASCVD, for example, diabetes mellitus, chronic kidney disease, or multiple risk factors. As per the AHA/ACC guideline, these conditions alone usually trigger statin therapy but do not warrant the addition of PCSK9 inhibitors.Besides the LDL-C goal of 50% reduction in patients with ASCVD, both guidelines use numeric thresholds for enhancement of LDL-lowering therapy with nonstatins. In the AHA/ACC guideline, for very high-risk patients, when LDL-C exceeds 70 mg/dL (1.8 mmol/L) on maximal statin therapy, ezetimibe is recommended. If LDL-C remains ≥70 mg/dL or non–high-density lipoprotein cholesterol remains ≥100 mg/dL, consideration can be given to adding a PCSK9 inhibitor. ESC/EAS guidelines offer a similar recommendation for very high-risk patients except that the threshold for adding nonstatins is an LDL-C level ≥55 mg/dL (1.4 mmol/L).Marginal gains in ASCVD risk reduction diminish as LDL-C levels fall to very low levels. The reason is the curvilinear (log-linear) relation between LDL-C and ASCVD risk. Moreover, a high percentage of patients with ASCVD will have LDL-C ≥55 mg/dL even on maximal statin plus ezetimibe; thus, efficacy and cost considerations may make greatly expanded use of PCSK9 inhibitors problematic. Even in clinical trials of high-intensity statin therapy, ≈75% of patients with acute coronary syndrome continue to have LDL-C levels ≥50 mg/dL, with ≈55% of the patients with LDL-C ≥60 mg/dL.3 Whether such a large number of patients should be prescribed ezetimibe or PCSK9 inhibitors to lower LDL-C levels to <55 mg/dL, at which point gains exist but in terms of net benefit are marginal, remains worthy of further study.In summary, the AHA/ACC guideline focuses on strictly defined criteria in the clinical trials of statin and nonstatin therapy. That guideline uses the concept of LDL-C and non–high-density lipoprotein cholesterol thresholds. By defining a very high-risk patient with ASCVD subset using clinical criteria, this guideline attempts to identify patients with ASCVD who will derive a much larger absolute reduction in recurrent ASCVD risk compared with an average patient with ASCVD.4 The ESC/EAS guidelines recommend an alternative goal-based approach in all patients with either clinical or imaging-based ASCVD (moderate subclinical atherosclerosis). This approach can probably be justified on theoretical grounds and the general concept that lower is better for LDL-C. However, it lacks rigorous testing of efficacy by randomized controlled trials and cost-effectiveness analysis. We hope that further dialog and evidence will guide future iterations of both guidelines in this ever-growing field. Meanwhile, it is crucial to improve implementation of both guidelines to ensure that the maximum ASCVD events are prevented among patients with clinical ASCVD.Sources of FundingDr Virani is supported by a Department of Veterans Affairs Health Services Research and Development Service Investigator Initiated Grant (IIR 16-072), an American Heart Association Beginning Grant-in-Aid (14BGIA20460366), and a Houston Veterans Affairs Health Services Research and Development Center for Innovations grant (CIN13-413). The opinions expressed reflect those of the authors and not necessarily those of the Department of Veterans Affairs or the US government.DisclosuresDr Virani reports receiving honorarium from the American College of Cardiology (associate editor innovations, ACC.org). The other authors report no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circSalim S. Virani, MD, PhD, Health Services Research and Development (152), Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Boulevard, Houston, TX 77030. Email [email protected]edu