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Lipid Management

Secondary Prevention- Clinical ASCVD

Jennifer G. Robinson, MD, MPH 
Reviewed on July 22, 2024
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Introduction

The 2018 multi-society cholesterol guideline considers all patients with clinical atherosclerotic cardiovascular disease (ASCVD) a statin benefit group. Women and men with clinical ASCVD are at high risk of another ASCVD event and death. The definition of clinical ASCVD comes from the populations enrolled in the randomized trials, and includes acute coronary syndromes, history of myocardial infarction (MI), stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral arterial disease presumed to be of atherosclerotic origin. Individuals with clinical ASCVD and advanced heart failure or who are receiving maintenance hemodialysis do not generally appear to benefit from statin therapy (see Special Clinical Populations). Based on recommendations from the 2013 ACC/AHA risk assessment guideline, individuals with subclinical atherosclerosis identified through noninvasive testing should be evaluated for treatment…

Introduction

The 2018 multi-society cholesterol guideline considers all patients with clinical atherosclerotic cardiovascular disease (ASCVD) a statin benefit group. Women and men with clinical ASCVD are at high risk of another ASCVD event and death. The definition of clinical ASCVD comes from the populations enrolled in the randomized trials, and includes acute coronary syndromes, history of myocardial infarction (MI), stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral arterial disease presumed to be of atherosclerotic origin. Individuals with clinical ASCVD and advanced heart failure or who are receiving maintenance hemodialysis do not generally appear to benefit from statin therapy (see Special Clinical Populations). Based on recommendations from the 2013 ACC/AHA risk assessment guideline, individuals with subclinical atherosclerosis identified through noninvasive testing should be evaluated for treatment using the primary prevention recommendations.

Clinical Highlight I

  • All patients with clinical ASCVD should receive a statin unless they have a contraindication.
    • In patients with very high-risk ASCVD, use a high-intensity (or maximally-tolerated) statin, and consider adding ezetimibe and/or a PCSK9 monoclonal antibody as first-line nonstatins if LDL-C reduction is <50% and LDL-C level is ≥55 mg/dL.
    • In patients without very high-risk ASCVD, start a high-intensity statin (atorvastatin 80 mg or rosuvastatin 20 mg) up to (and including) age 75 years (unless there are safety concerns). Continue the high-intensity statin after age 75 if tolerated. Consider adding ezetimibe (first line) and/or a PCSK9 monoclonal antibody (second line) if LDL-C reduction is <50% and LDL-C level is ≥70 mg/dL.
    • Consider a moderate-intensity statin if safety concerns or age >75 years.
    • In general, use the maximally-tolerated statin intensity.
  • May consider adding another nonstatin in selected patients with clinical ASCVD
  • Encourage healthy lifestyle habits and risk factor control.

Statin Therapy in Patients with Clinical ASCVD

On the basis of an extensive, high-quality body of randomized trial evidence, statins are the first-line choice for the secondary prevention of ASCVD events in patients with clinical ASCVD. Statins reduce the risk of MI, ischemic stroke, coronary revascularization and cardiovascular (CV) death in these patients. The 2018 multi-society cholesterol guideline was based on evidence from the Cholesterol Treatment Trialists’ (CTT) meta-analysis of statin trials and several other relevant trials. The clinical approach to intermediate density lipoprotein cholesterol (LDL-C) lowering therapy is shown in Figure 8-2.

Multiple randomized trials of moderate- and high- intensity statin therapy have found that statins reduce ASCVD risk in individuals with clinical ASCVD. The reduction is ASCVD risk is proportional to the magnitude of LDL-C lowering. In the CTT meta- analysis of 26 statin trials, each 39 mg/dL reduction in LDL-C reduced major CV events by 21%. Women with clinical ASCVD experience the same relative reduction in ASCVD risk as men. Similar relative risk reductions occur across various risk factor levels and other patient characteristics, including LDL-C levels, hypertension, blood pressure levels, smoking status, body mass index (BMI), high-density lipoprotein cholesterol (HDL-C) or triglyceride levels, and glomerular filtration rate (GFRs).

Figure 10-1 shows LDL reduction with a moderate and a high-intensity statin, uptitration from a moderate- to high-intensity statin and placebo.The only patient groups with ASCVD who do not appear to benefit from statin therapy are those with NYHA class II-IV heart failure or undergoing maintenance hemodialysis (with more data suggesting a potential benefit at least in some patients within these groups; see Special Clinical Populations for further discussion).

Enlarge  Figure 8-2: 2018 ACC/AHA Cholesterol Guideline Algorithm for Secondary Prevention of ASCVD. Clinical history of ASCVD consists of acute coronary syndrome, history of myocardial infarction, stable or unstable angina, or coronary other arterial revascularization, stroke, transient ischemic attack, or peripheral artery disease including aortic aneurysm, all of atherosclerotic origin. Very high-risk includes a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions (Table 8.1). Source: Adapted from Grundy SM, et al. J Am Coll Cardiol. 2019;73(24):3168-3209
Figure 8-2: 2018 ACC/AHA Cholesterol Guideline Algorithm for Secondary Prevention of ASCVD. Clinical history of ASCVD consists of acute coronary syndrome, history of myocardial infarction, stable or unstable angina, or coronary other arterial revascularization, stroke, transient ischemic attack, or peripheral artery disease including aortic aneurysm, all of atherosclerotic origin. Very high-risk includes a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions (Table 8.1). Source: Adapted from Grundy SM, et al. J Am Coll Cardiol. 2019;73(24):3168-3209
Enlarge  Figure 10-1: Waterfall Plots of Percent LDL-C Reduction With a Moderate-Intensity Statina, a High-Intensity Statinb, Uptitration From a Moderate- to a High-Intensity Statinc, and in the Placebo Arm of a Primary Prevention RCT. Key: a. Pravastatin 40 mg. b Rosuvastatin 20 mg. c Atorvastatin 10 mg to 80 mg. Source: Boekholdt SM, et al. J Am Coll Cardiol. 2014;64:485-494.
Figure 10-1: Waterfall Plots of Percent LDL-C Reduction With a Moderate-Intensity Statina, a High-Intensity Statinb, Uptitration From a Moderate- to a High-Intensity Statinc, and in the Placebo Arm of a Primary Prevention RCT. Key: a. Pravastatin 40 mg. b Rosuvastatin 20 mg. c Atorvastatin 10 mg to 80 mg. Source: Boekholdt SM, et al. J Am Coll Cardiol. 2014;64:485-494.

Initial Evaluation

A fasting lipid panel and an ALT should be performed at baseline prior to initiating statin therapy. Evaluation for secondary causes of hyperlipidemia should be undertaken if a patient has newly identified LDL-C ≥190 mg/dL or triglycerides ≥500 mg/dL. Patients with unexplained ALT >3 times the upper limit of normal should undergo additional evaluation. A creatine kinase (CK) is only recommended for patients with a history of previous statin-associated side effects, muscle diseases, or elevated CK levels.

High-Intensity Statin Therapy

Three randomized trials (TNT, IDEAL, PROVE-IT) have shown that the high-intensity statin atorvastatin 80 mg reduced ASCVD risk by about 25% more than moderate-intensity statins. TNT and PROVE-IT enrolled patients up to (and including) age 75, and IDEAL enrolled patients up to age 80 years. In IDEAL, adverse effects and discontinuation rates were higher in participants 64-80 years of age who received atorvastatin 80 mg. These findings resulted in recommendation to initiate high-intensity statins in individuals age ≤75 years, unless safety concerns are present (Figure 10-2). This is a Class of Recommendation (COR) I (“should do”) Level of Evidence A (three trials showing ASCVD risk reduction benefit, two trials up to age 75) recommendation.

Women with clinical ASCVD experience the same relative reduction in ASCVD risk from high-intensity statins as men.

It is reasonable (COR IIa) to continue high-intensity statin therapy in individuals >75 years if there are no adverse effects. High-intensity statin therapy may (COR IIa) be initiated in patients >75 years at the discretion of the physician if the expected benefit outweighs risks, and taking patient preference into consideration.

In IDEAL, patients could be downtitrated to 40 mg if they were unable to tolerate atorvastatin 80 mg. Whether patients stable on long-term atorvastatin 40 mg should be increased to 80 mg is left to clinical discretion and patient preference. The additional 6% reduction in LDL-C is unlikely to have a large impact on ASCVD risk over a 5-year period.

In patients with high-risk ASCVD, defined by a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions (Table 8-2), high-intensity or maximally-tolerated statin therapy is indicated (COR I) regardless of age (Figure 8-2).

Enlarge  Figure 10-2: Reduction in Major Cardiovascular Events in Trials Comparing Higher Dose With Lower Dose Statins. Major cardiovascular disease (CVD) events (including coronary revascularization) were reduced only in trials evaluating a high-intensity statin (atorvastatin 80 mg [TNT, IDEAL]) compared with moderate-intensity statins (pravastatin 40 mg, atorvastatin 10 mg, or simvastatin 20 mg to 40 mg) (above the red line). Major CVD events were not reduced in trials comparing simvastatin 80 mg with lower doses of simvastatin (SEARCH and A to Z) (below the red line). Source: Modified from Cholesterol Treatment Trialists’ (CTT) Collaboration, et al. Lancet. 2010;376(9753):1670-1681.
Figure 10-2: Reduction in Major Cardiovascular Events in Trials Comparing Higher Dose With Lower Dose Statins. Major cardiovascular disease (CVD) events (including coronary revascularization) were reduced only in trials evaluating a high-intensity statin (atorvastatin 80 mg [TNT, IDEAL]) compared with moderate-intensity statins (pravastatin 40 mg, atorvastatin 10 mg, or simvastatin 20 mg to 40 mg) (above the red line). Major CVD events were not reduced in trials comparing simvastatin 80 mg with lower doses of simvastatin (SEARCH and A to Z) (below the red line). Source: Modified from Cholesterol Treatment Trialists’ (CTT) Collaboration, et al. Lancet. 2010;376(9753):1670-1681.
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Enlarge  Figure 8-2: 2018 ACC/AHA Cholesterol Guideline Algorithm for Secondary Prevention of ASCVD. Clinical history of ASCVD consists of acute coronary syndrome, history of myocardial infarction, stable or unstable angina, or coronary other arterial revascularization, stroke, transient ischemic attack, or peripheral artery disease including aortic aneurysm, all of atherosclerotic origin. Very high-risk includes a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions (Table 8.1). Source: Adapted from Grundy SM, et al. <em>J Am Coll Cardiol</em>. 2019;73(24):3168-3209
Figure 8-2: 2018 ACC/AHA Cholesterol Guideline Algorithm for Secondary Prevention of ASCVD. Clinical history of ASCVD consists of acute coronary syndrome, history of myocardial infarction, stable or unstable angina, or coronary other arterial revascularization, stroke, transient ischemic attack, or peripheral artery disease including aortic aneurysm, all of atherosclerotic origin. Very high-risk includes a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions (Table 8.1). Source: Adapted from Grundy SM, et al. J Am Coll Cardiol. 2019;73(24):3168-3209

Moderate-Intensity Statin Therapy

Moderate-intensity statins reduced ASCVD events more than placebo/control in three secondary prevention (CARE, HPS and LIPID) and in the CTT meta-analysis of statin trials. Moderate-intensity statins reduce ASCVD events, revascularizations and total mortality (Figures 10-3 and 10-4).

In the CTT meta-analysis of moderate-intensity statins vs placebo/control, individuals >75 years experienced the same relative risk reductions as those ≤75 years. This and other accumulated evidence supports the recommendation that moderate-intensity statins should be initiated in patients with clinical ASCVD ≤75 years who are not candidates for high-intensity statin therapy (COR I), and are reasonable (COR IIa) in patients who are >75 years of age. Clinical judgment should guide decisions on whether to initiate or continue moderate-intensity statin therapy in individuals aged >75 years after weighing benefits in reducing ASCVD events, harms (e.g., adverse events, drug-drug interactions, the burden of polypharmacy) and patient preferences.

In patients with clinical ASCVD ≤75 years receiving moderate-intensity statin therapy, it is reasonable to uptitrate to high-intensity statin therapy. In patients with high-risk ASCVD (Table 8-2) of any age, a maximally tolerated statin therapy (which may be moderate-intensity statin therapy) is indicated (COR I).

Enlarge  Figure 10-3: Heart Protection Study: Reduction in Ischemic ASCVD Events and Revascularizations with Simvastatin 40 mg vs Placebo. Source: Heart Protection Study Collaborative Group. Lancet. 2002;360(9326):7-22.
Figure 10-3: Heart Protection Study: Reduction in Ischemic ASCVD Events and Revascularizations with Simvastatin 40 mg vs Placebo. Source: Heart Protection Study Collaborative Group. Lancet. 2002;360(9326):7-22.
Enlarge  Figure 10-4: Heart Protection Study: Reduction in Mortality with Simvastatin 40 mg vs Placebo. Source: Heart Protection Study Collaborative Group. Lancet. 2002;360(9326):7-22.
Figure 10-4: Heart Protection Study: Reduction in Mortality with Simvastatin 40 mg vs Placebo. Source: Heart Protection Study Collaborative Group. Lancet. 2002;360(9326):7-22.
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Healthy Lifestyle Habits and Risk Factor Control

All patients, including those with clinical ASCVD, should be counseled to adhere to healthy lifestyle habits (physical activity, a heart-healthy diet) and maintain a healthy weight (see Lifestyle and Blood Pressure). Participants in randomized trials were counseled on healthy lifestyle habits and the ASCVD risk reduction benefit of statins added to this. Smokers should be strongly advised to quit and other risk factors should be controlled and antiplatelet agents administered according to current guidelines.

Monitor Response to Therapy and Adherence

After initiating statin therapy, patients should return within 4 to 12 weeks for a fasting lipid panel to assess response to therapy and adverse effects; monitoring should continue at a 3-12 month schedule thereafter, as needed (COR I).

See Therapeutic Response and Adverse Effects Management for further discussion.

Nonstatins in Secondary Prevention

Several groups of patients with clinical ASCVD may benefit from additional LDL-C reduction with nonstatin therapy (Table 10-1).

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Nonstatins Added to Statin Therapy: Cardiovascular Outcomes Trials

Because of its favorable risk-benefit and cost-benefit profile, ezetimibe is the preferred nonstatin for additional LDL-C lowering. Ezetimibe lowers LDL-C by approximately 20% when added to a statin and was shown to reduce ASCVD events in a large, long-term ASCVD outcomes trial (IMPROVE-IT).

Other nonstatins may be also be useful for LDL-C lowering and ASCVD event reduction, although not all have been shown to have a beneficial effect:

  • Anti-PCSK9 monoclonal antibodies (alirocumab or evolocumab) reduce LDL-C by up to about 65% when added to a statin with or without other lipid-lowering therapy in patients with and without heterozygous familial hypercholesterolemia (HeFH). Evolocumab and alirocumab have been shown to significantly reduce the incidence of ASCVD events in the FOURIER and ODYSSEY OUTCOMES trials, respectively. The anti-PCSK9 siRNA inclisiran lowers LDL-C by approximately 50% in combination with a statin regimen in patients with ASCVD, or ~40% in patients with HeFH; no data are yet available on its efficacy for ASCVD event reduction.
  • Bempedoic acid provides an additional 12-16% of LDL-C reduction when added to a background statin therapy, and ~40% in combination with ezetimibe and a background statin therapy. An ongoing trial is testing the efficacy of bempedoic acids in reducing ASCVD outcomes.
  • Bile acid sequestrants have not been evaluated in cardiovascular outcomes trials in secondary prevention patients, in women, or added to background statin therapy. Bile acid sequestrants have significant gastrointestinal tolerability issues and drug-drug interactions.
  • Fenofibrate did not further reduce LDL-C levels or ASCVD events added to moderate-intensity statin therapy in ACCORD. There was evidence of harm in women, although there was a trend to an ASCVD event reduction those with low HDL-C and high triglyceride levels.
  • The combination of niacin/laropiprant did not further reduce ASCVD events when added to moderate-intensity statin therapy in patients with clinical ASCVD and well-controlled LDL-C levels in the HPS2-THRIVE trial. There was some evidence of a treatment benefit in those with higher LDL-C levels.

Nonstatin Monotherapy: Cardiovascular Outcome Trials

Niacin, bile acid sequestrants and gemfibrozil monotherapy have been shown to reduce coronary heart disease events in men in the pre-statin era (CAD: CDP, VA-HIT; no CAD: LRC and HHS).

  • Niacin reduced CAD events in hypercholesterolemic men with CAD (CDP). However, niacin has numerous adverse effects.
  • Gemfibrozil reduced ASCVD events in men with CAD and low LDL-C and low HDL-C (VA-HIT).
  • Fenofibrate monotherapy did not reduce ASCVD events in secondary prevention patients with diabetes (FIELD), although this may have been due to cross-over to statin therapy in the placebo group.

Clinical ASCVD With History of Untreated LDL-C ≥190 mg/dL

Patients with untreated primary LDL-C ≥190 mg/dL often have very premature onset CAD due to exposure to very high LDL-C levels from birth. One in 12 patients with premature CAD have genetically high cholesterol levels, and many meet the criteria for FH. These patients almost always need the addition of a nonstatin to high-intensity statin therapy to begin to approach an LDL- C <100 mg/dL. An LDL-C <100 mg/dL was achieved in the high-intensity statin randomized trials, which excluded patients with severely elevated LDL-C. Individuals with FH have a high burden of atherosclerosis for their age due to lifetime exposure to high LDL-C levels. It may be reasonable to try to achieve an LDL-C <70 mg/dL for at least some period of time to stabilize and perhaps regress their atherosclerosis. To date, PCSK9 monoclonal antibodies have been the only agents that can reduce LDL-C sufficiently to achieve LDL-C <70 mg/dL in the majority of patients with HeFH.

Clinical ASCVD and Unable to Tolerate a High-Intensity Statin or With a Suboptimal LDL-C Reduction

Patients with clinical ASCVD who have a suboptimal reduction in LDL-C on maximally-tolerated statin therapy or who are intolerant of high-intensity statins may benefit from further LDL-C lowering from a nonstatin shown to reduce ASCVD events.

About half of patients receiving a high-intensity statin will achieve a ≥50% reduction in LDL-C, and few will do so while receiving a moderate-intensity statin (Figure 10-1). Note also that increasing from a moderate- to a high-intensity statin lowers LDL-C by an additional 20% on average.

The 2018 multi-society guidelines contain the following recommendations for the addition of nonstatins in patients unable to tolerate high-intensity statins:

  • Adding ezetimibe may be reasonable (COR IIb) in patients without very high-risk ASCVD who are on maximally-tolerated statin therapy and whose LDL-C levels are ≥70 mg/dL
  • Adding ezetimibe is reasonable (COR IIa) in patients with very high-risk ASCVD who are on maximally tolerated statin therapy and whose LDL-C levels are ≥70 mg/dL
  • Adding a PCSK9 inhibitor is reasonable (COR IIa) in patients with very high-risk ASCVD who are on maximally-tolerated LDL-C lowering therapy (which must include ezetimibe before PCSK9 inhibitors are considered [COR I]).

The nonstatin recommendations have been updated in the 2022 ACC Expert Consensus Decision Pathway (ECDP) on nonstatins. For patients with clinical ASCVD on maximally-tolerated statin therapy, the 2022 ACC EDCP provides separate recommendations for patients with very high-risk ASCVD and those without:

  • In patients with very high-risk ASCVD who do not achieve ≥50% LDL-C reduction and whose LDL-C level is ≥55 mg/dL, consider adding ezetimibe and/or an anti-PCSK9 monoclonal antibody (mAb) as first-line nonstatin therapy, and bempedoic acid or inclisiran as second-line nonstatin therapy
  • In patients with ASCVD without very high-risk features who do not achieve ≥50% LDL-C reduction and whose LDL-C level is ≥70 mg/dL, consider adding ezetimibe as a first-line option, an a PCSK9 mAb as a second-line option, or bempedoic acid or inclisiran as a third-line option.
Enlarge  Figure 10-1: Waterfall Plots of Percent LDL-C Reduction With a Moderate-Intensity Statina, a High-Intensity Statinb, Uptitration From a Moderate- to a High-Intensity Statinc, and in the Placebo Arm of a Primary Prevention RCT. Key: a. Pravastatin 40 mg. b Rosuvastatin 20 mg. c Atorvastatin 10 mg to 80 mg. Source: Boekholdt SM, et al. J Am Coll Cardiol. 2014;64:485-494.
Figure 10-1: Waterfall Plots of Percent LDL-C Reduction With a Moderate-Intensity Statina, a High-Intensity Statinb, Uptitration From a Moderate- to a High-Intensity Statinc, and in the Placebo Arm of a Primary Prevention RCT. Key: a. Pravastatin 40 mg. b Rosuvastatin 20 mg. c Atorvastatin 10 mg to 80 mg. Source: Boekholdt SM, et al. J Am Coll Cardiol. 2014;64:485-494.

Clinical ASCVD on Maximal Statin Therapy Who Might Benefit From Additional LDL-C Lowering

Although the 2013 ACC/AHA cholesterol guideline moved away from absolute LDL-C treatment targets and the 2018 multi-society guideline largely continued with this approach, data suggest there may be benefit to lowering LDL-C to <70 mg and perhaps well below 50 mg/dL. However, the potential for a net ASCVD risk reduction benefit depends on the absolute risk of the patient, the expected reduction in the relative risk of ASCVD events from the added nonstatin therapy, safety considerations and patient preferences.

Since risk prediction equations have not yet been developed for statin-treated patients, an interim approach using patient risk categories and LDL-C thresholds may be useful for guiding them to consider adding a nonstatin for further ASCVD risk reduction (Table 10-1). There are many considerations of efficacy, safety and tolerability, cost, adherence and patient preferences that should be discussed within the context of a clinician-patient discussion.

Depending on efficacy and safety of the nonstatin chosen, most high-risk patients with clinical ASCVD are likely to experience an ASCVD risk reduction benefit from additional LDL-C lowering when LDL-C is >130 mg/dL. Selected high-risk patients with additional high-risk characteristics are likely to experience an ASCVD risk reduction benefit when LDL-C is 100-129 mg/dL. Selected very high-risk patients (such as those with clinical ASCVD and diabetes or HeFH) may have the potential to benefit from additional LDL-C lowering when LDL-C is <100 mg/dL.

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