The Role of Non-statin Therapy for Secondary Prevention of ASCVD

Clinical Case

Xiaoming Jia, MD; Salim S. Virani, MD, PhD, FACC; Reviewer: Jay H. Shubrook, DO


November 15, 2019

Editorial Collaboration

Medscape &


Per the 2018 American Heart Association/American College of Cardiology Multisociety Guideline for the Management of Blood Cholesterol (2018 AHA/ACC Guideline),[1] the cardiologist should discuss the benefits of adjunctive nonstatin therapy with the cholesterol absorption inhibitor ezetimibe with this patient.

Patients at the highest absolute baseline risk for ASCVD will benefit most from aggressive therapy to lower their LDL-C levels, so the AHA/ACC identified a "very high-risk" group among patients who need secondary prevention. As set forth in the 2018 AHA/ACC Guideline,[1] if maximally tolerated statin therapy and lifestyle modifications fail to lower the LDL-C level < 70 mg/dL in patients at very high risk, clinicians may consider adjunctive nonstatin therapy.

Patients are classified as very high risk if they have a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions. Major ASCVD events include:

  • Recent acute coronary syndrome (ACS) within the past 12 months

  • A history of MI other than the recent ACS event

  • A history of ischemic stroke

  • Symptomatic peripheral artery disease (defined as history of claudication with ankle-brachial index < 0.85, or previous revascularization or amputation)

High-risk conditions include the following:

  • Patient aged at least 65 years

  • Heterozygous familial hypercholesterolemia

  • History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the major ASCVD event(s)

  • DM

  • Hypertension

  • Chronic kidney disease (estimated glomerular filtration rate, 15-59 mL/min/1.73 m2)

  • Current smoking/tobacco use

  • Persistently elevated LDL-C (LDL-C ≥ 100 mg/dL) despite maximally tolerated statin therapy and ezetimibe adjunct therapy

  • History of congestive heart failure

Based on the 2018 AHA/ACC Guideline, this patient needing secondary prevention meets the criteria for very high risk for future ASCVD because she has had multiple major ASCVD events and has three risk-enhancing factors—DM, hypertension, and CKD. Previous studies have shown that patients with these risk-enhancing factors are at increased risk for future ASCVD events when compared with patients needing secondary prevention who do not meet the criteria for very high risk.[2]

Ezetimibe is the recommended first-line adjunct therapy to maximally tolerated statin therapy due to its easy accessibility, affordability, availability in generic form, efficacy, and longer-term safety data.[3] However, in cases where a patient's LDL-C level remains ≥ 70 mg/dL, clinicians may consider treatment with a PCSK9 inhibitor (alirocumab or evolocumab).[4,5]

A fibrate such as fenofibrate 145 mg once daily would not be recommended as an adjunctive therapy for this patient. Although fibrates are effective in lowering TG levels, and the patient in this case does have a mildly elevated TG level, randomized controlled trials (RCTs) on fibrates have not consistently demonstrated efficacy in risk reduction of ASCVD events.[6,7] Although fibrates have been associated with a reduction in ASCVD events in some patients with elevated TG and HDL-C levels, these study data were mainly from subgroup and post-hoc analyses.[7] Moreover, the patient in this case only has a mildly elevated TG level and normal-range HDL-C level, and therefore, treatment with a fibrate is not indicated.

Regarding nicotinic acid, there is currently a lack of evidence supporting the addition of this supplement to further reduce ASCVD risk. Nicotinic acid is used to lower TG levels in patients with significant hypertriglyceridemia and also to increase HDL-C levels. However, RCTs on the addition of nicotinic acid to statin therapy demonstrated no efficacy in reducing the risk for ASCVD events.[8,9] In addition to the lack of efficacy data, nicotinic acid is associated with notable side effects, including flushing and increased mean plasma glucose level.

Regarding alirocumab 150 mg SC every 2 weeks, PCSK9 inhibitors are not considered first-line adjunct therapy, as previously noted, and would therefore not be the appropriate recommendation for this patient at this time.

The currently available PCSK9 inhibitors, alirocumab and evolocumab, are human monoclonal antibodies and potent cholesterol-lowering agents. When given along with statin therapy, PCSK9 inhibitors can further reduce LDL-C levels an additional 43%-64%.[1] These drugs have been shown in RCTs to reduce risk for ASCVD events, demonstrating an even more pronounced risk reduction in patients at very high risk for future events.[4,5] However, the long-term safety and efficacy of these agents are currently unknown. Also, compared with ezetimibe, the cost of these subcutaneously administered drugs remains expensive despite recent price reductions.

Regarding the role of PCSK9 inhibitors as second-line adjunctive therapy, some patients who receive ezetimibe as an adjunct therapy to maximally tolerated statin therapy may not need further addition of a PCSK9 inhibitor; the addition of ezetimibe on top of statin therapy could lead to a further 18%-25% reduction in LDL-C levels. However, if this patient's LDL-C levels remain ≥ 70 mg/dL or if her non-HDL-C levels remain ≥ 100 mg/dL despite the addition of adjunctive ezetimibe to statin therapy, it would be reasonable for the clinician to consider the addition of a PCSK9 inhibitor.


The patient in this case is considered to be at very high risk for future ASCVD events. Based on current evidence, she will likely further benefit from the addition of nonstatin therapy to her current regimen to reduce ASCVD risk. Moreover, as this patient has taken and continues to take an active role in her healthcare (medication adherence and lifestyle modifications) and is interested in further reducing her risk of ASCVD events, a clinician-patient discussion about adjunctive nonstatin therapies to reduce future risk of ASCVD events is warranted.