Commentary

Differences in dyslipidemia guidelines underscore complexity of CVD prevention

The use of lipid-lowering therapy has been a hallmark of CV risk reduction for several decades. The cornerstone of CV prevention is risk assessment because patients at higher risk for atherosclerotic events typically derive a higher absolute benefit from preventive therapies, which tend to have similar relative risk reductions across different populations.

Both the 2018 Guideline on the Management of Blood Cholesterol from the American Heart Association, the American College of Cardiology and 10 other societies and the 2019 Joint European Society of Cardiology/European Atherosclerosis Society (EAS) Dyslipidemia Guidelines stratify patients into different risk categories based on multiple risk factors. As a general principle, patients with prior atherosclerotic CV events typically fall into the highest-risk category. Certain conditions will also inherently lead to a high-risk classification, such as diabetes that is long-standing or associated with end-organ damage, or markedly elevated lipid levels (LDL 190 mg/dL).

Risk stratification

For most patients who do not have these high-risk conditions, a formal risk assessment tool is recommended to estimate 10-year ASCVD risk. The AHA/ACC guideline stratifies patients into primary or secondary prevention. As previously mentioned, secondary prevention patients are considered high risk. The AHA/ACC guideline specifically recognizes a subgroup of very high-risk individuals within the secondary prevention population. These are individuals with two or more prior ASCVD events or those with one ASCVD event with multiple other high-risk conditions. Those with diabetes or severe hypercholesterolemia, defined as LDL of at least 190 mg/dL, have separate categories tailored to their specific prevention needs. Other primary prevention populations are subdivided into low, borderline, intermediate and high risk, based on the Pooled Cohort Equations 10-year ASCVD risk estimate of fatal and nonfatal MI and stroke of less than 5%, 5% to less than 7.5%, 7.5% to less than 20% and 20% or more, respectively.

Ethan Tumarkin, MD, PhD
Ethan Tumarkin
Marc Engels, MD, PhD
Marc Engels
Seth S. Martin, MD, MHS
Seth S. Martin
Rhanderson Cardoso, MD
Rhanderson Cardoso

In contrast, the ESC/EAS guideline stratifies patients into four categories: low, moderate, high and very high risk. The latter includes known ASCVD, clinical or unequivocal on imaging, diabetes with target organ damage or at least three major risk factors, or early onset of type 1 diabetes of long duration of more than 20 years, severe chronic kidney disease (estimated glomerular filtration rate < 30 mL/min/1.73 m2), familial hypercholesterolemia with prior ASCVD or another major risk factor or a 10-year risk estimate for CV mortality of at least 10% by the Systematic Coronary Risk Evaluation (SCORE) system. In this regard, the ESC/EAS guidelines have a broader very high-risk category, which includes a subset of primary prevention patients at increased risk. ACC/AHA guidelines, however, reserve the highest-risk category only for patients with recurrent ASCVD events or known ASCVD plus multiple risk factors.

LDL targets

Both guidelines state that patients in high-risk or very high-risk categories should receive statin therapy as the mainstay of lipid-lowering therapy, in addition to intensive lifestyle modifications for global CV health. Both guidelines, driven by findings from IMPROVE-IT, FOURIER and ODYSSEY Outcomes, share a philosophy of aggressive lipid lowering using nonstatin therapy in addition to statins for individuals at elevated ASCVD risk, although with notable differences in the therapeutic recommendations and lipid targets.

The 2018 AHA/ACC guideline maintains that among patients with ASCVD, high-intensity statin therapy should be used to reduce LDL by at least 50%. If LDL remains at or above a threshold of 70 mg/dL, ezetimibe should be considered. PCSK9 inhibitors should also be considered in the very high-risk group if LDL remains at least 70 mg/dL despite maximally tolerated statin therapy and ezetimibe. Initiating these nonstatin therapies should be done on the basis of shared decision-making.

On the other hand, the ESC/EAS guideline targets specific LDL levels according to each risk strata: less than 116 mg/dL, less than 100 mg/dL, less than 70 mg/dL and less than 55 mg/dL for low risk, moderate risk, high risk and very high risk, respectively. Ezetimibe is recommended as adjunct therapy in all groups if the goal LDL is not achieved despite maximally tolerated statin therapy, whereas PCSK9 inhibitors are recommended only in the very high-risk category if the LDL goal of less than 55 mg/dL is not achieved despite maximally tolerated statin and ezetimibe therapy.

Implications of risk definitions

Although the recommendations for ezetimibe and PCSK9 inhibitors may appear similar between society guidelines at first glance, the broader definition of the very high-risk and high-risk categories in the ESC/EAS guidelines has important implications for treatment. More specifically, it increases the group of patients eligible for ezetimibe and PCSK9 inhibitors substantially to include certain subgroups at increased risk but still within the primary prevention domain, particularly in the setting of such strict LDL goals. This broad approach is debatable in the context of the results from prior randomized trials.

In a recent follow-up to the IMPROVE-IT trial, Arman Qamar, MD, MPH, and colleagues demonstrated increasing benefit in aggressive lipid lowering for patients at high risk for stable ischemic heart disease. Classification of risk in this population was based on the presence of elevated levels of specific biomarkers: high-sensitivity troponin, N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein and growth-differentiation factor 15. Low, intermediate and high risk were classified as 0, 1 or 2, and 3 or 4 elevated biomarkers, respectively. In the high- and intermediate-risk groups, adding ezetimibe yielded an absolute risk reduction of 7.3% and 4.4%, respectively, for risk for CV death, MI or stroke. Low-risk patients did not appear to benefit from adding ezetimibe to statin therapy.

The AHA/ACC and ESC/EAS guideline recommendations for PCSK9 inhibitor use also differ for familial hypercholesterolemia (FH). In the AHA/ACC guideline, PCSK9 inhibitors are recommended in heterozygous FH if the LDL remains at least 100 mg/dL despite maximally tolerated statin and ezetimibe therapy (class IIb). For patients with FH and an ASCVD event and one other high-risk condition such as diabetes, or with other risk factors, PCSK9 inhibitors are recommended for LDL of at least 70 mg/dL. More liberal use of PCSK9 inhibitors is recommended by the ESC/EAS guidelines to attain LDL less than 55 mg/dL in their broad very high-risk patient category, which includes patients with FH and a previous ASCVD event or other risk factors.

The guidelines are more similar in the recommendations for older people. Compared with younger individuals, the elderly are at higher risk for incident ASCVD and have a higher mortality rate from acute ischemic events. Nearly 50% of patients who die of CAD are older than 85 years. A recent meta-analysis from the Cholesterol Treatment Trialists’ Collaboration demonstrated that individuals older than 75 years with prior ASCVD achieve the same relative risk reduction per unit of LDL reduction from statin therapy as younger people. Fewer data are available in the primary prevention population. Therefore, both guidelines give a class I recommendation for statin therapy in patients older than 75 years with prior ASCVD and a class IIb recommendation for primary prevention statin initiation older than 75 years.

Key differences in dyslipiddemia guidelines

Complexity of prevention

The differences between the AHA/ACC and ESC/EAS guidelines highlight the complexity of the current state of preventive CV medicine. They raise questions about how broadly we should extrapolate evidence for the benefits of intensive treatment and how cost-effective therapy will be when extrapolated to lower-risk patients. Other CV fields have faced similar questions recently, particularly with the advent of new medication regimens and the decision points of when to initiate them.

Perhaps analogous to the addition of a PCSK9 inhibitor, consider an individual with ischemic cardiomyopathy and a left ventricular ejection fraction of 40% to 45%. Current guidelines suggest medical optimization of the patient with an ACE inhibitor/angiotensin receptor blocker, a beta-blocker and a mineralocorticoid receptor antagonist. Individuals with NYHA class II HF who are still symptomatic can consider more aggressive therapy with the use of an angiotensin receptor-neprilysin inhibitor as shown in the PARADIGM-HF study of sacubitril/valsartan (Entresto, Novartis), albeit this leads to increased risk for hypotension and medication intolerance with a much higher drug cost. Should patients with NYHA class I HF be considered for angiotensin receptor-neprilysin inhibitor therapy to maximize medical benefit and optimization? We feel that the evidence does not support the cost-effectiveness of this management strategy. Conversely, PCSK9 inhibitors and ezetimibe are associated with a favorable safety profile, but the high cost of PCSK9 inhibitors warrants ongoing cost-effectiveness studies.

In another analogous scenario, consider an individual with stable atherosclerotic vascular disease. The COMPASS trial recently demonstrated superiority of aspirin and low-dose rivaroxaban (Xarelto, Janssen/Bayer) 2.5 mg twice daily compared with aspirin alone or moderate-dose rivaroxaban alone at reducing CV events — CV death, stroke or MI — albeit with an increase in major bleeding events (3% vs. 1.9%). Should low-dose rivaroxaban be utilized more liberally for stable patients needing secondary prevention? Similarly, we do not think that this strategy is cost-effective for all patients with atherosclerotic vascular disease.

A similar line of questioning stands for the use of both ezetimibe and PCSK9 inhibitors, although the main trade-off is cost rather than cost and adverse effects. The ESC/EAS guideline recommends a more aggressive use of these medications to achieve LDL goals less than 55 mg/dL in very high-risk patients or less than 40 mg/dL in selective patients with recurrent vascular events, whereas the AHA/ACC guideline maintains a higher threshold for initiation of these medications, focusing on achieving percent reduction of LDL and the use of LDL thresholds to consider use of ezetimibe and/or a PCSK9 inhibitor as part of a thoughtful clinician-patient risk discussion.

Future work in the field will be needed to explore the incremental benefits and cost-effectiveness of the very aggressive lipid lowering in stable patients with moderate clinical or subclinical atherosclerotic vascular disease.

Disclosures: The authors report no relevant financial disclosures.

The use of lipid-lowering therapy has been a hallmark of CV risk reduction for several decades. The cornerstone of CV prevention is risk assessment because patients at higher risk for atherosclerotic events typically derive a higher absolute benefit from preventive therapies, which tend to have similar relative risk reductions across different populations.

Both the 2018 Guideline on the Management of Blood Cholesterol from the American Heart Association, the American College of Cardiology and 10 other societies and the 2019 Joint European Society of Cardiology/European Atherosclerosis Society (EAS) Dyslipidemia Guidelines stratify patients into different risk categories based on multiple risk factors. As a general principle, patients with prior atherosclerotic CV events typically fall into the highest-risk category. Certain conditions will also inherently lead to a high-risk classification, such as diabetes that is long-standing or associated with end-organ damage, or markedly elevated lipid levels (LDL 190 mg/dL).

Risk stratification

For most patients who do not have these high-risk conditions, a formal risk assessment tool is recommended to estimate 10-year ASCVD risk. The AHA/ACC guideline stratifies patients into primary or secondary prevention. As previously mentioned, secondary prevention patients are considered high risk. The AHA/ACC guideline specifically recognizes a subgroup of very high-risk individuals within the secondary prevention population. These are individuals with two or more prior ASCVD events or those with one ASCVD event with multiple other high-risk conditions. Those with diabetes or severe hypercholesterolemia, defined as LDL of at least 190 mg/dL, have separate categories tailored to their specific prevention needs. Other primary prevention populations are subdivided into low, borderline, intermediate and high risk, based on the Pooled Cohort Equations 10-year ASCVD risk estimate of fatal and nonfatal MI and stroke of less than 5%, 5% to less than 7.5%, 7.5% to less than 20% and 20% or more, respectively.

Ethan Tumarkin, MD, PhD
Ethan Tumarkin
Marc Engels, MD, PhD
Marc Engels
Seth S. Martin, MD, MHS
Seth S. Martin
Rhanderson Cardoso, MD
Rhanderson Cardoso

In contrast, the ESC/EAS guideline stratifies patients into four categories: low, moderate, high and very high risk. The latter includes known ASCVD, clinical or unequivocal on imaging, diabetes with target organ damage or at least three major risk factors, or early onset of type 1 diabetes of long duration of more than 20 years, severe chronic kidney disease (estimated glomerular filtration rate < 30 mL/min/1.73 m2), familial hypercholesterolemia with prior ASCVD or another major risk factor or a 10-year risk estimate for CV mortality of at least 10% by the Systematic Coronary Risk Evaluation (SCORE) system. In this regard, the ESC/EAS guidelines have a broader very high-risk category, which includes a subset of primary prevention patients at increased risk. ACC/AHA guidelines, however, reserve the highest-risk category only for patients with recurrent ASCVD events or known ASCVD plus multiple risk factors.

LDL targets

Both guidelines state that patients in high-risk or very high-risk categories should receive statin therapy as the mainstay of lipid-lowering therapy, in addition to intensive lifestyle modifications for global CV health. Both guidelines, driven by findings from IMPROVE-IT, FOURIER and ODYSSEY Outcomes, share a philosophy of aggressive lipid lowering using nonstatin therapy in addition to statins for individuals at elevated ASCVD risk, although with notable differences in the therapeutic recommendations and lipid targets.

The 2018 AHA/ACC guideline maintains that among patients with ASCVD, high-intensity statin therapy should be used to reduce LDL by at least 50%. If LDL remains at or above a threshold of 70 mg/dL, ezetimibe should be considered. PCSK9 inhibitors should also be considered in the very high-risk group if LDL remains at least 70 mg/dL despite maximally tolerated statin therapy and ezetimibe. Initiating these nonstatin therapies should be done on the basis of shared decision-making.

On the other hand, the ESC/EAS guideline targets specific LDL levels according to each risk strata: less than 116 mg/dL, less than 100 mg/dL, less than 70 mg/dL and less than 55 mg/dL for low risk, moderate risk, high risk and very high risk, respectively. Ezetimibe is recommended as adjunct therapy in all groups if the goal LDL is not achieved despite maximally tolerated statin therapy, whereas PCSK9 inhibitors are recommended only in the very high-risk category if the LDL goal of less than 55 mg/dL is not achieved despite maximally tolerated statin and ezetimibe therapy.

Implications of risk definitions

Although the recommendations for ezetimibe and PCSK9 inhibitors may appear similar between society guidelines at first glance, the broader definition of the very high-risk and high-risk categories in the ESC/EAS guidelines has important implications for treatment. More specifically, it increases the group of patients eligible for ezetimibe and PCSK9 inhibitors substantially to include certain subgroups at increased risk but still within the primary prevention domain, particularly in the setting of such strict LDL goals. This broad approach is debatable in the context of the results from prior randomized trials.

PAGE BREAK

In a recent follow-up to the IMPROVE-IT trial, Arman Qamar, MD, MPH, and colleagues demonstrated increasing benefit in aggressive lipid lowering for patients at high risk for stable ischemic heart disease. Classification of risk in this population was based on the presence of elevated levels of specific biomarkers: high-sensitivity troponin, N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein and growth-differentiation factor 15. Low, intermediate and high risk were classified as 0, 1 or 2, and 3 or 4 elevated biomarkers, respectively. In the high- and intermediate-risk groups, adding ezetimibe yielded an absolute risk reduction of 7.3% and 4.4%, respectively, for risk for CV death, MI or stroke. Low-risk patients did not appear to benefit from adding ezetimibe to statin therapy.

The AHA/ACC and ESC/EAS guideline recommendations for PCSK9 inhibitor use also differ for familial hypercholesterolemia (FH). In the AHA/ACC guideline, PCSK9 inhibitors are recommended in heterozygous FH if the LDL remains at least 100 mg/dL despite maximally tolerated statin and ezetimibe therapy (class IIb). For patients with FH and an ASCVD event and one other high-risk condition such as diabetes, or with other risk factors, PCSK9 inhibitors are recommended for LDL of at least 70 mg/dL. More liberal use of PCSK9 inhibitors is recommended by the ESC/EAS guidelines to attain LDL less than 55 mg/dL in their broad very high-risk patient category, which includes patients with FH and a previous ASCVD event or other risk factors.

The guidelines are more similar in the recommendations for older people. Compared with younger individuals, the elderly are at higher risk for incident ASCVD and have a higher mortality rate from acute ischemic events. Nearly 50% of patients who die of CAD are older than 85 years. A recent meta-analysis from the Cholesterol Treatment Trialists’ Collaboration demonstrated that individuals older than 75 years with prior ASCVD achieve the same relative risk reduction per unit of LDL reduction from statin therapy as younger people. Fewer data are available in the primary prevention population. Therefore, both guidelines give a class I recommendation for statin therapy in patients older than 75 years with prior ASCVD and a class IIb recommendation for primary prevention statin initiation older than 75 years.

Key differences in dyslipiddemia guidelines

Complexity of prevention

The differences between the AHA/ACC and ESC/EAS guidelines highlight the complexity of the current state of preventive CV medicine. They raise questions about how broadly we should extrapolate evidence for the benefits of intensive treatment and how cost-effective therapy will be when extrapolated to lower-risk patients. Other CV fields have faced similar questions recently, particularly with the advent of new medication regimens and the decision points of when to initiate them.

Perhaps analogous to the addition of a PCSK9 inhibitor, consider an individual with ischemic cardiomyopathy and a left ventricular ejection fraction of 40% to 45%. Current guidelines suggest medical optimization of the patient with an ACE inhibitor/angiotensin receptor blocker, a beta-blocker and a mineralocorticoid receptor antagonist. Individuals with NYHA class II HF who are still symptomatic can consider more aggressive therapy with the use of an angiotensin receptor-neprilysin inhibitor as shown in the PARADIGM-HF study of sacubitril/valsartan (Entresto, Novartis), albeit this leads to increased risk for hypotension and medication intolerance with a much higher drug cost. Should patients with NYHA class I HF be considered for angiotensin receptor-neprilysin inhibitor therapy to maximize medical benefit and optimization? We feel that the evidence does not support the cost-effectiveness of this management strategy. Conversely, PCSK9 inhibitors and ezetimibe are associated with a favorable safety profile, but the high cost of PCSK9 inhibitors warrants ongoing cost-effectiveness studies.

PAGE BREAK

In another analogous scenario, consider an individual with stable atherosclerotic vascular disease. The COMPASS trial recently demonstrated superiority of aspirin and low-dose rivaroxaban (Xarelto, Janssen/Bayer) 2.5 mg twice daily compared with aspirin alone or moderate-dose rivaroxaban alone at reducing CV events — CV death, stroke or MI — albeit with an increase in major bleeding events (3% vs. 1.9%). Should low-dose rivaroxaban be utilized more liberally for stable patients needing secondary prevention? Similarly, we do not think that this strategy is cost-effective for all patients with atherosclerotic vascular disease.

A similar line of questioning stands for the use of both ezetimibe and PCSK9 inhibitors, although the main trade-off is cost rather than cost and adverse effects. The ESC/EAS guideline recommends a more aggressive use of these medications to achieve LDL goals less than 55 mg/dL in very high-risk patients or less than 40 mg/dL in selective patients with recurrent vascular events, whereas the AHA/ACC guideline maintains a higher threshold for initiation of these medications, focusing on achieving percent reduction of LDL and the use of LDL thresholds to consider use of ezetimibe and/or a PCSK9 inhibitor as part of a thoughtful clinician-patient risk discussion.

Future work in the field will be needed to explore the incremental benefits and cost-effectiveness of the very aggressive lipid lowering in stable patients with moderate clinical or subclinical atherosclerotic vascular disease.

Disclosures: The authors report no relevant financial disclosures.