Management of LDL‐cholesterol after an acute coronary syndrome: Key comparisons of the American and European clinical guidelines to the attention of the healthcare providers

Abstract Guidelines for the management of blood cholesterol were updated in the past year in the United States and Europe, reflecting a more intensive approach to lowering low‐density lipoprotein cholesterol (LDL‐C). The American College of Cardiology/American Heart Association task force on practice guideline released the 2018 guideline on the management of blood cholesterol on behalf of several American societies. Approximately 9 months later, the European Society of Cardiology/European Atherosclerosis Society published their 2019 guideline for the management of dyslipidemias. Both guidelines have similarities for the management of patients with acute coronary syndromes. Both emphasize risk assessment of patients as a main approach to guide therapy; those at higher risk of cardiovascular disease have a greater clinical benefit of LDL‐C reduction by at least 50%. Both guidelines reinforce the indication to lower LDL‐C as an important modifiable risk factor and consider the addition of nonstatin agents, such as ezetimibe and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, in addition to lifestyle counseling and high‐intensity statin for further reduction of LDL‐C levels. However, the guidelines have differences in the concepts of treatment thresholds (≥70 mg/dL in the United States) vs treatment goals (< 55 mg/dL in Europe), in the definition of very high‐risk category and in the classes for recommendation for the use of PCSK9 inhibitors.


| INTRODUCTION
Guidelines for the management of blood cholesterol were updated in the past year in the United States and Europe, reflecting a more aggressive approach to lowering low-density lipoprotein cholesterol (LDL-C). 1 1 The US guidelines was based on an independent systematic evidence review. The main document for the European guideline was slightly shorter (59 pages) with more references (608) and a similar number of recommendations (69), including 36 of class I (52.2%), 18 of class IIa (26.1%), 10 of class IIb (14.5%), and 5 of class III (7.2%). 2 The ability to reach low LDL-C with novel therapies and studies in patients with genetic variants resulting in very low LDL-C levels has dramatically changed lipid management. Guideline recommendations regarding the treatment goals for LDL-C in high or very high-risk patients have plummeted from 130 mg/dL (3.4 mmol/L) in 1988 to 55 mg/dL (1.4 mmol/L) in 2019. 1,3,4 The scientific evidence of lowering LDL-C levels in patients after acute coronary syndromes (ACS) is principally based on five adequately powered randomized controlled trials: the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering study (atorvastatin 80 mg/day vs placebo), 5  The guidelines have many similarities. Both emphasize cardiovascular (CVD) risk assessment of patients as a main approach to guide therapy (Figures 1,2). Both guidelines reinforce the indication to lower LDL-C as an important modifiable risk factor and consider the addition of nonstatin agents, such as ezetimibe and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, in addition to lifestyle counseling and high-intensity statin for further reduction of LDL-C levels. 1,2 Both guidelines have the potential to change the current practice, as the use of moderate dose of statin is still frequent in a large number of patients after ACS and unlikely to be sufficient to reduce efficiently the cardiovascular risk. 11,12 However, the guidelines have important differences, including the concepts of treatment thresholds (American) vs treatment goals (European) and the specific classes for recommendation most notably in secondary prevention (Table 1). In this manuscript, we summarize the key message of both guidelines focusing on the management of cholesterol in patients after ACS.
F I G U R E 1 Risk stratification and LDL-C targets as recommended by the European guideline for the management of dyslipidaemias. 2

| General comments
In the European guideline, all patients with an ACS are classified as very high risk, whereas in American guideline, a patient with ACS must also have multiple high-risk features or more than one previous atherosclerotic cardiovascular disease (ASCVD) event ( Figure 3).

| American perspectives
The 2018 ACC/AHA guideline defines patient management groups of risk with specific algorithms for treatment ( Figure 2). Secondary prevention for ASCVD is indicated in patients with a history of ACS (unstable angina or MI), stable angina or coronary revascularization, stroke, transient ischemic attack (TIA), or peripheral artery disease including aortic aneurysm. Among the patients with established ASCVD, very high-risk patients were defined by the presence of multiple major ASCVD events (recent ACS plus another event) or one major (recent ACS) and multiple high-risk conditions ( Figure 3).

| General comments
For patients with ACS, the European guideline recommends a LDL-C goal of <55 mg/dL and a LDL-C reduction by 50% (class I) to guide therapy, whereas the American guideline recommends a high-intensity statin to achieve a 50% reduction in LDL-C and a threshold of ≥70 mg/dL for treatment intensification (Table 1). 1 The approach with goals aims to reduce risks by lowering LDL-C to levels achieved in large clinical trials, whereas the approach with threshold aims to reduce risks by lowering further LDL-C when the LDL-C values are above criteria used in nonstatin trials. 1,2 Threshold has been evaluated in many randomized clinical trials, with the baseline LDL-C level predefined by the protocol inclusion criterion. Treatment goals have rarely been studied in randomized trials; therefore, the evidence is weaker and mostly based on postrandomization data (inference based on achieved LDL-C levels by assigned treatment). The hazards of drawing medical decision from postrandomization data are still a matter of debate, although the data show consistent benefits of reducing LDL-C below guideline recommendations. 13,14

| American perspectives
In secondary prevention of patients at very high-risk for ASCVD, the initiation or continuation of high-intensity statin is recommended to achieve an LDL-C reduction of ≥50%. 1 If LDL-C levels remain above the threshold of ≥70 mg/dL despite maximally tolerated therapy, the guideline recommends adding a nonstatin agent. If the LDL-C is already <70 mg/dL, the continuation of the maximally tolerated therapy is recommended Comparison of the treatment strategies in patients with ACS as recommended by the American and European cholesterol guidelines American guideline 1 European guideline 2

| European perspectives
In secondary prevention of very high-risk patients, an LDL-C reduction of ≥50% from baseline and an LDL-C goal <55 mg/dL are both recommended (class I, level A). A reduction in LDL-C by 50% from baseline with high-intensity statin is a first common step in both guidelines.

| American perspectives
In secondary prevention of patients at very high-risk, the use of ezetimibe is recommended if the LDL levels remain ≥70 mg/dL on maximally tolerated statin (class IIa). 8 However, the addition of ezetimibe is recommended to maximally tolerated statin therapy as the first step in lowering LDL-C (class I) if a combination with PCSK9 inhibitor as a third agent is being considered. The strategy of ezetimibe before PCSK9 inhibitor is recommended because generic ezetimibe is available, simple to administer (oral, once daily), and has proven safety and tolerability with long-term data. 8

| European perspectives
In patients after ACS, the guideline recommends starting high-intensity statin or the maximum tolerated dose as early as possible, and  with nonstatin agents (eg, icosapent ethyl and bempadoic acid), 18,19 and with the longer-acting PCSK9 inhibitor inclisiran recently published will need to be considered in future guidelines. 20 6 | PERSPECTIVES

| CONCLUSION
The benefit of intensive LDL-C lowering to reduce cardiovascular risk is recognized in both guidelines in patients after an ACS. The risk reduction management of patients with ACS is based on adapting lipid-lowering therapies according to the recommended treatment effect on LDL-C levels and patients' characteristics.