New guidance for clinicians offers advice on use of nonstatin therapies
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LDL reduction is the major focus in the primary and secondary prevention of atherosclerotic CVD.
In August, the American College of Cardiology published an expert consensus decision pathway on the role of nonstatin therapies, which provides very helpful new perspectives on appropriate degrees of LDL lowering in a variety of patients. This document builds upon the 2018 American Heart Association/ACC/Multisociety Guideline on the Management of Blood Cholesterol, which provided recommendations for the use of statin, ezetimibe and PCSK9 inhibitor therapy in patients with established ASCVD or at increased risk for ASCVD. Statin therapy remains the first-line approach; however, advances in technology and understanding of lipid metabolism facilitated the development of several novel therapeutic targets and medications within the last decade.
Since the advent of the 2018 guideline, three new agents — bempedoic acid (Nexletol, Esperion Therapeutics), evinacumab-dgnb (Evkeeza, Regeneron) and inclisiran (Leqvio, Novartis) — have been approved for the management of hypercholesterolemia. (A summary of those agents appears in Table 1.) In this context, the ACC expert consensus decision pathway was developed to address current gaps in care for LDL reduction and to provide practical guidance for clinicians and patients not previously addressed in the 2018 guidelines. Additionally, guidance is offered regarding the specific patient populations, clinical scenarios and sequence in which these newer nonstatin therapies should be considered.
Expert consensus decision pathways
The ACC expert consensus decision pathway identifies four main patient management groups previously endorsed by the 2018 Cholesterol Guideline: secondary prevention in adults aged 20 years or older with clinical ASCVD; primary prevention in adults aged 20 years or older with primary severe hypercholesterolemia (LDL > 190 mg/dL); primary prevention in adults aged 40 to 75 years without ASCVD but with diabetes and LDL less than 190 mg/dL; and primary prevention in adults aged 40 to 75 years without ASCVD or diabetes with LDL 70 mg/dL to 189 mg/dL and an estimated 10-year risk for ASCVD of at least 7.5% on statin therapy. The potential for net ASCVD risk-reduction benefit for the use or addition of nonstatin therapies is considered in each of the groups and higher-risk subgroups, which are approached individually. In all groups, evidence-based statin therapy of appropriate intensity is recommended as first-line therapy.
Secondary prevention
In the cohort of very high-risk patients (criteria defined in Table 2) on statin therapy for secondary prevention in adults aged 20 years or older with clinical ASCVD, the desired reduction of LDL is at least 50% from baseline and less than 55 mg/dL. (This more aggressive target is the same that the 2019 European Society of Cardiology/European Atherosclerosis Society Guideline for the Management of Dyslipidemias recommended.) If there is a less-than-desired response (< 50% or LDL 55 mg/dL) with maximally tolerated statin therapy, the addition of nonstatin therapy should be considered after excluding secondary causes. Based on available CV outcomes trials, either ezetimibe or a PCSK9 inhibitor is preferred. The 2018 AHA/ACC/Multisociety cholesterol guideline had recommended ezetimibe routinely before consideration of PCSK9 inhibitor use.
The 2022 ACC expert consensus decision pathway stated that ezetimibe may be preferred if less than 25% additional lowering is required, or due to other factors such as cost and ease of use. Although some patients will experience more than 25% LDL reduction with ezetimibe, a PCSK9 inhibitor may be favored if more than 25% additional LDL lowering is necessary. Simultaneous upfront addition of maximally tolerated statin and either of these agents may also be considered if greater LDL reduction than any single agent can expect to achieve is necessary.
If additional LDL lowering is desired despite addition of ezetimibe and/or a PCSK9 inhibitor, bempedoic acid may be considered. Inclisiran is an option as an alternative to a PCSK9 inhibitor in patients with adverse effects from both PCSK9 inhibitors on the U.S. market, compliance issues or difficulties with self-injections. Patients who do not meet LDL targets after these steps should be referred to a lipid disorder specialist.
In patients with ASCVD on statin therapy for secondary prevention but not at very high risk (criteria defined in Table 2), a desirable response to therapy is at least 50% reduction in LDL from baseline and LDL less than 70 mg/dL. In these patients, ezetimibe is the preferred first nonstatin agent. If targets are not achieved with a statin/ezetimibe combination, a PCSK9 inhibitor should be considered. Bempedoic acid should be discussed at this point if LDL targets (< 50% reduction in LDL from baseline or LDL < 70 mg/dL) have not been achieved after the addition of ezetimibe and/or a PCSK9 monoclonal antibody, but patients should be informed that there are no clinical trial data with this mode of therapy.
Similarly, for patients with ASCVD on statin therapy for secondary prevention and LDL more than 190 mg/dL, ezetimibe should be considered as the initial nonstatin therapy of choice; however, if these patients require more than 25% additional lowering of LDL or have additional high-risk factors, a PCSK9 monoclonal antibody may be preferred as the initial agent. Bempedoic acid can be considered at this point if LDL targets (< 50% reduction in LDL from baseline or LDL < 70 mg/dL) have not been achieved after the addition of ezetimibe and/or a PCSK9 inhibitor. Specialized therapies, such as LDL apheresis, evinacumab-dgnb or lomitapide (Juxtapid, Aegerion Pharmaceuticals), may be required to control LDL in patients with homozygous familial hypercholesterolemia who have an inadequate response to statins with or without ezetimibe and PCSK9 inhibitors.
Primary prevention for adults with LDL 190 mg/dL
Patients with baseline elevation of LDL of at least 190 mg/dL not due to secondary modifiable causes are at markedly elevated risk of first and recurrent ASCVD events and require high-intensity statin therapy. A target of at least 50% reduction in LDL and LDL less than 130 mg/dL is a reasonable goal for patients without additional high-risk features or comorbidities. However, if additional high-risk features are present, an at least 50% reduction in LDL from baseline and LDL-C less than 100 mg/dL should be targeted. Nonstatin therapy is then considered if the patient has not achieved these targets despite maximally tolerated statin therapy.
The 2022 ACC expert consensus decision pathway advises that ezetimibe or a PCSK9 inhibitor is reasonable as a first choice of nonstatin therapy. Bempedoic acid or switching from PCSK9 inhibitor to inclisiran can be considered at this point if LDL targets (< 50% reduction in LDL from baseline or LDL < 100 mg/dL) have not been achieved after the addition of ezetimibe and/or a PCSK9 inhibitor. Failure to meet targets after an adequate trial of these medications should prompt referral to a lipid specialist for consideration of specialized therapies (evinacumab-dgnb, lomitapide, apheresis).
Primary prevention for adults with diabetes
For patients aged 40 to 75 years with diabetes in the primary prevention setting, nonstatin therapy should generally only be considered if 10-year predicted ASCVD risk is more than 20% and there is failure to achieve at least 50% reduction in LDL from baseline and LDL less than 100mg/dL; aside from ezetimibe, no additional nonstatin agents are routinely recommended based on available clinical trial evidence.
Primary prevention for adults without diabetes or clinical ASCVD
Patients aged 40 to 75 years without clinical ASCVD or diabetes who have LDL 70 mg/dL to 189 mg/dL and an estimated 10-year ASCVD risk of 5% to less than 7.5% (borderline risk) may experience benefit from moderate-intensity statin therapy. In patients at borderline or intermediate risk (5% to < 20% estimated 10-year ASCVD risk), coronary artery calcium scoring can be considered to help inform the decision on whether to start statin therapy.
For those with a 10-year predicted risk of 5% to less than 20% and CAC scores of 0 Agatston units (AU), in the absence of diabetes, LDL of at least 190 mg/dL, a family history of premature CHD, or active cigarette smoking, statin therapy may be deferred with a plan for CAC reassessment in 3 to 5 years. Conversely, those with CAC scores of at least 1,000 AU have high annual clinical ASCVD event rates compared with the patients in the FOURIER clinical trial of the PCSK9 inhibitor evolocumab (Repatha, Amgen). Based on the elevated ASCVD risk in such individuals, if maximally tolerated statin and ezetimibe therapy does not achieve more than 50% LDL reduction or LDL less than 70 mg/dL, the addition of a PCSK9 inhibitor may be considered.
For primary prevention patients aged 40 to 75 years at high (> 20%) 10-year estimated ASCVD risk, consideration of high-intensity statin therapy to achieve at least 50% reduction in LDL and LDL less than 70 mg/dL (or non-HDL < 100 mg/dL) is recommended. Ezetimibe is the primary recommended nonstatin therapy in this population, and should be considered if at least 50% LDL reduction or LDL less than 70 mg/dL (non-HDL < 100 mg/dL) is not achieved with high-intensity statin therapy.
Statin intolerance
In patients with clinical ASCVD and partial or complete statin intolerance as described by the National Lipid Association definition published in June, a trial of ezetimibe or a PCSK9 inhibitor may be considered as first-line nonstatin therapy. Second-line options that may be considered are bempedoic acid and inclisiran.
Summary and conclusions
The 2022 ACC expert consensus decision pathway builds on the 2018 AHA/ACC/Multisociety cholesterol guideline and provides helpful guidance in several key areas on the use of newer nonstatin therapies for primary and secondary prevention. From a secondary prevention perspective, the categorization of patients with clinical ASCVD into two groups — “not at very high risk” or “at very high risk”— is an important distinction from the 2018 cholesterol guideline. Practically, this identifies a subgroup of patients with ASCVD who are at very high risk for future ASCVD events and for whom a more aggressive LDL target of 55 mg/dL or less (rather than just < 70 mg/dL) should be strongly considered. In this very high-risk subgroup, a PCSK9 inhibitor may be preferred over ezetimibe as the initial nonstatin therapy if more than 25% additional lowering of LDL is needed to achieve target thresholds.
For patients with clinical ASCVD who are not at very high risk, the 2022 ACC expert consensus decision pathway writing committee considered an LDL of less than 70 mg/dL as a desirable target and specified ezetimibe as the initial nonstatin agent for patients not at goal regardless of estimated additional lipid lowering required. From a primary prevention perspective, CAC scoring assumes a more prominent role in the risk assessment and treatment of adults without diabetes or severe hypercholesterolemia. In borderline to intermediate patients with a CAC score of 0, statin therapy may be deferred, and a repeat CAC measurement could be obtained in 3 to 5 years.
Moreover, individuals with CAC of at least 1,000 AU have high annual clinical ASCVD event rates (comparable to patients from FOURIER), and a PCSK9 inhibitor may be considered if combination statin/ezetimibe does not reduce LDL less than 70 mg/dL.
While the process for the creation of these interim recommendations did not involve formal systematic reviews or grading of evidence, this very useful document provides practical guidance on the use of nonstatin therapies for ASCVD risk reduction, and is an important addition to the ACC solution set for the management of cholesterol in patients with or at risk for ASCVD.
References:
- Cheeley MK, et al. J Clin Lipidol. 2022;doi:10.1016/j.jacl.2022.05.068.
- Grundy SM, et al. Circulation. 2018;doi:10.1161/CIR.0000000000000625.
- Lloyd-Jones DM, et al. J Am Coll Cardiol. 2022;doi:10.1016/j.jacc.2022.07.006.
- Peng AW, et al. Circulation. 2021;doi:10.1161/CIRCULATIONAHA.120.050545.
For more information:
Sean P. Gaine, MB BCh, BAO, is a medical resident at Johns Hopkins Medicine.
Matthew Belanger, MD, is a cardiovascular disease fellow at Johns Hopkins Medicine.
Roger S. Blumenthal, MD, is director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease and professor of medicine at Johns Hopkins University School of Medicine. He is also the editor of the Prevention section of the Cardiology Today Editorial Board. Twitter: @rblument1.
Jaideep Patel, MD, is a cardiologist at Johns Hopkins Heart and Vascular Institute and director of preventive cardiology at GBMC Health Care. Twitter: @jaideeppatelmd.
The authors can be reached at Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Halsted 560, Baltimore, MD 21827.
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