Gregory Palko, MD

The purpose of this guideline is to provide direction for the management of patients with high blood cholesterol to decrease the incidence of atherosclerotic vascular disease. The update was undertaken because new evidence has emerged since the publication of the 2013 ACC/AHA cholesterol guideline about additional cholesterol-lowering agents including ezetimibe and PCSK9 inhibitors.

Measurement and therapeutic modalities

In adults aged 20 years and older who are not on lipid-lowering therapy, measurement of a lipid profile is recommended and is an effective way to estimate atherosclerotic cardiovascular disease (ASCVD) risk and documenting baseline LDL-C.

Statin therapy is divided into three categories: High-intensity statin therapy aims for lowering LDL-C levels by more than 50%, moderate-intensity therapy by 30%-49%, and low-intensity therapy by less than 30%.
 

Cholesterol management groups

In all individuals at all ages, emphasizing a heart-healthy lifestyle, meaning appropriate diet and exercise, to decrease the risk of developing ASCVD should be advised.

Individuals fall into groups with distinct risk of ASCVD or recurrence of ASCVD and the recommendations are organized according to these risk groups.

Secondary ASCVD prevention: Patients who already have ASCVD by virtue of having had an event or established diagnosis (MI, angina, cerebrovascular accident, or peripheral vascular disease) fall into the secondary prevention category:

• Patients aged 75 years and younger with clinical ASCVD: High-intensity statin therapy should be initiated with aim to reduce LDL-C levels by 50%. In patients who experience statin-related side effects, a moderate-intensity statin should be initiated with the aim to reduce LDL-C by 30%-49%.
• In very high-risk patients with an LDL-C above 70 mg/dL on maximally tolerated statin therapy, it is reasonable to consider the use of a non–statin cholesterol-lowering agent with an LDL-C goal under 70 mg/dL. Ezetimibe (Zetia) can be used initially and if LDL-C remains above 70 mg/dL, then consideration can be given to the addition of a PCSK9-inhibitor therapy (strength of recommendation: ezetimibe – moderate; PCSK9 – strong). The guideline discusses that, even though the evidence supports the efficacy of PCSK9s in reducing the incidence of ASCVD events, the expense of PCSK9 inhibitors give them a high cost, compared with value.
• For patients more than age 75 years with established ASCVD, it is reasonable to continue high-intensity statin therapy if patient is tolerating treatment.

Severe hypercholesterolemia:

• Patients with LDL-C above 190 mg/dL do not need a 10-year risk score calculated. These individuals should receive maximally tolerated statin therapy.
• If patient is unable to achieve 50% reduction in LDL-C and/or have an LDL-C level of 100 mg/dL, the addition of ezetimibe therapy is reasonable.
• If LDL-C is still greater than 100mg/dL on a statin plus ezetimibe, the addition of a PCSK9 inhibitor may be considered. It should be recognized that the addition of a PCSK9 in this circumstance is classified as a weak recommendation.

Diabetes mellitus in adults:

• In patients aged 40-75 years with diabetes, regardless of 10-year ASCVD risk, should be prescribed a moderate-intensity statin (strong recommendation).
• In adults with diabetes mellitus and multiple ASCVD risk factors, it is reasonable to prescribe high-intensity statin therapy with goal to reduce LDL-C by more than 50%.
• In adults with diabetes mellitus and 10-year ASCVD risk of 20% or higher, it may be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce LDL-C levels by 50% or more.
• In patients aged 20-39 years with diabetes that is either of long duration (at least 10 years, type 2 diabetes mellitus; at least 20 years, type 1 diabetes mellitus), or with end-organ damage including albuminuria, chronic renal insufficiency, retinopathy, neuropathy, or ankle-brachial index below 0.9, it may be reasonable to initiate statin therapy (weak recommendation).

Primary prevention in adults: Adults with LDL 70-189 mg/dL and a 10-year risk of a first ASCVD event (fatal and nonfatal MI or stroke) should be estimated by using the pooled cohort equation. Adults should be categorized according to calculated risk of developing ASCVD: low risk (less than 5%), borderline risk (5% to less than 7.5%), intermediate risk (7.5% and higher to less than 20%), and high risk (20% and higher) (strong recommendation:

• Individualized risk and treatment discussion should be done with clinician and patient.
• Adults in the intermediate-risk group (7.5% and higher to less than 20%), should be placed on moderate-intensity statin with LDL-C goal reduction of more than 30%; for optimal risk reduction, especially in high-risk patients, an LDL-C reduction of more than 50% (strong recommendation).
• Risk-enhancing factors can favor initiation of intensification of statin therapy.
• If a decision about statin therapy is uncertain, consider measuring coronary artery calcium (CAC) levels. If CAC is zero, statin therapy may be withheld or delayed, except those with diabetes as above, smokers, and strong familial hypercholesterolemia with premature ASCVD. If CAC score is 1-99, it is reasonable to initiate statin therapy for patients older than age 55 years; If CAC score is 100 or higher or in the 75th percentile or higher, it is reasonable to initiate a statin.

Statin safety: Prior to initiation of a statin, a clinician-patient discussion is recommended detailing ASCVD risk reduction and the potential for side effects/drug interactions. In patients with statin-associated muscle symptoms (SAMS), a detailed account for secondary causes is recommended. In patients with true SAMS, it is recommended to check a creatine kinase level and hepatic function panel; however, routine measurements are not useful. In patients with statin-associated side effects that are not severe, reassess and rechallenge patient to achieve maximal lowering of LDL-C with a modified dosing regimen.
 

The bottom line

Lifestyle modification is important at all ages, with specific population-guided strategies for lowering cholesterol in subgroups as discussed above. Major changes to the AHA/ACC Cholesterol Clinical Practice Guidelines now mention new agents for lowering cholesterol and using CAC levels as predictability scoring.

Reference

Grundy SM et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: Executive Summary: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2018 Nov 10.

Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Palko is a second-year resident in the family medicine residency program at Abington Jefferson Hospital.

The purpose of this guideline is to provide direction for the management of patients with high blood cholesterol to decrease the incidence of atherosclerotic vascular disease. The update was undertaken because new evidence has emerged since the publication of the 2013 ACC/AHA cholesterol guideline about additional cholesterol-lowering agents including ezetimibe and PCSK9 inhibitors.

Measurement and therapeutic modalities

In adults aged 20 years and older who are not on lipid-lowering therapy, measurement of a lipid profile is recommended and is an effective way to estimate atherosclerotic cardiovascular disease (ASCVD) risk and documenting baseline LDL-C.

Statin therapy is divided into three categories: High-intensity statin therapy aims for lowering LDL-C levels by more than 50%, moderate-intensity therapy by 30%-49%, and low-intensity therapy by less than 30%.
 

Cholesterol management groups

In all individuals at all ages, emphasizing a heart-healthy lifestyle, meaning appropriate diet and exercise, to decrease the risk of developing ASCVD should be advised.

Individuals fall into groups with distinct risk of ASCVD or recurrence of ASCVD and the recommendations are organized according to these risk groups.

Secondary ASCVD prevention: Patients who already have ASCVD by virtue of having had an event or established diagnosis (MI, angina, cerebrovascular accident, or peripheral vascular disease) fall into the secondary prevention category:

• Patients aged 75 years and younger with clinical ASCVD: High-intensity statin therapy should be initiated with aim to reduce LDL-C levels by 50%. In patients who experience statin-related side effects, a moderate-intensity statin should be initiated with the aim to reduce LDL-C by 30%-49%.
• In very high-risk patients with an LDL-C above 70 mg/dL on maximally tolerated statin therapy, it is reasonable to consider the use of a non–statin cholesterol-lowering agent with an LDL-C goal under 70 mg/dL. Ezetimibe (Zetia) can be used initially and if LDL-C remains above 70 mg/dL, then consideration can be given to the addition of a PCSK9-inhibitor therapy (strength of recommendation: ezetimibe – moderate; PCSK9 – strong). The guideline discusses that, even though the evidence supports the efficacy of PCSK9s in reducing the incidence of ASCVD events, the expense of PCSK9 inhibitors give them a high cost, compared with value.
• For patients more than age 75 years with established ASCVD, it is reasonable to continue high-intensity statin therapy if patient is tolerating treatment.

Severe hypercholesterolemia:

• Patients with LDL-C above 190 mg/dL do not need a 10-year risk score calculated. These individuals should receive maximally tolerated statin therapy.
• If patient is unable to achieve 50% reduction in LDL-C and/or have an LDL-C level of 100 mg/dL, the addition of ezetimibe therapy is reasonable.
• If LDL-C is still greater than 100mg/dL on a statin plus ezetimibe, the addition of a PCSK9 inhibitor may be considered. It should be recognized that the addition of a PCSK9 in this circumstance is classified as a weak recommendation.

Diabetes mellitus in adults:

• In patients aged 40-75 years with diabetes, regardless of 10-year ASCVD risk, should be prescribed a moderate-intensity statin (strong recommendation).
• In adults with diabetes mellitus and multiple ASCVD risk factors, it is reasonable to prescribe high-intensity statin therapy with goal to reduce LDL-C by more than 50%.
• In adults with diabetes mellitus and 10-year ASCVD risk of 20% or higher, it may be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce LDL-C levels by 50% or more.
• In patients aged 20-39 years with diabetes that is either of long duration (at least 10 years, type 2 diabetes mellitus; at least 20 years, type 1 diabetes mellitus), or with end-organ damage including albuminuria, chronic renal insufficiency, retinopathy, neuropathy, or ankle-brachial index below 0.9, it may be reasonable to initiate statin therapy (weak recommendation).

Primary prevention in adults: Adults with LDL 70-189 mg/dL and a 10-year risk of a first ASCVD event (fatal and nonfatal MI or stroke) should be estimated by using the pooled cohort equation. Adults should be categorized according to calculated risk of developing ASCVD: low risk (less than 5%), borderline risk (5% to less than 7.5%), intermediate risk (7.5% and higher to less than 20%), and high risk (20% and higher) (strong recommendation:

• Individualized risk and treatment discussion should be done with clinician and patient.
• Adults in the intermediate-risk group (7.5% and higher to less than 20%), should be placed on moderate-intensity statin with LDL-C goal reduction of more than 30%; for optimal risk reduction, especially in high-risk patients, an LDL-C reduction of more than 50% (strong recommendation).
• Risk-enhancing factors can favor initiation of intensification of statin therapy.
• If a decision about statin therapy is uncertain, consider measuring coronary artery calcium (CAC) levels. If CAC is zero, statin therapy may be withheld or delayed, except those with diabetes as above, smokers, and strong familial hypercholesterolemia with premature ASCVD. If CAC score is 1-99, it is reasonable to initiate statin therapy for patients older than age 55 years; If CAC score is 100 or higher or in the 75th percentile or higher, it is reasonable to initiate a statin.

Statin safety: Prior to initiation of a statin, a clinician-patient discussion is recommended detailing ASCVD risk reduction and the potential for side effects/drug interactions. In patients with statin-associated muscle symptoms (SAMS), a detailed account for secondary causes is recommended. In patients with true SAMS, it is recommended to check a creatine kinase level and hepatic function panel; however, routine measurements are not useful. In patients with statin-associated side effects that are not severe, reassess and rechallenge patient to achieve maximal lowering of LDL-C with a modified dosing regimen.
 

The bottom line

Lifestyle modification is important at all ages, with specific population-guided strategies for lowering cholesterol in subgroups as discussed above. Major changes to the AHA/ACC Cholesterol Clinical Practice Guidelines now mention new agents for lowering cholesterol and using CAC levels as predictability scoring.

Reference

Grundy SM et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: Executive Summary: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2018 Nov 10.

Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Palko is a second-year resident in the family medicine residency program at Abington Jefferson Hospital.

The purpose of this guideline is to provide direction for the management of patients with high blood cholesterol to decrease the incidence of atherosclerotic vascular disease. The update was undertaken because new evidence has emerged since the publication of the 2013 ACC/AHA cholesterol guideline about additional cholesterol-lowering agents including ezetimibe and PCSK9 inhibitors.

Measurement and therapeutic modalities

In adults aged 20 years and older who are not on lipid-lowering therapy, measurement of a lipid profile is recommended and is an effective way to estimate atherosclerotic cardiovascular disease (ASCVD) risk and documenting baseline LDL-C.

Statin therapy is divided into three categories: High-intensity statin therapy aims for lowering LDL-C levels by more than 50%, moderate-intensity therapy by 30%-49%, and low-intensity therapy by less than 30%.
 

Cholesterol management groups

In all individuals at all ages, emphasizing a heart-healthy lifestyle, meaning appropriate diet and exercise, to decrease the risk of developing ASCVD should be advised.

Individuals fall into groups with distinct risk of ASCVD or recurrence of ASCVD and the recommendations are organized according to these risk groups.

Secondary ASCVD prevention: Patients who already have ASCVD by virtue of having had an event or established diagnosis (MI, angina, cerebrovascular accident, or peripheral vascular disease) fall into the secondary prevention category:

• Patients aged 75 years and younger with clinical ASCVD: High-intensity statin therapy should be initiated with aim to reduce LDL-C levels by 50%. In patients who experience statin-related side effects, a moderate-intensity statin should be initiated with the aim to reduce LDL-C by 30%-49%.
• In very high-risk patients with an LDL-C above 70 mg/dL on maximally tolerated statin therapy, it is reasonable to consider the use of a non–statin cholesterol-lowering agent with an LDL-C goal under 70 mg/dL. Ezetimibe (Zetia) can be used initially and if LDL-C remains above 70 mg/dL, then consideration can be given to the addition of a PCSK9-inhibitor therapy (strength of recommendation: ezetimibe – moderate; PCSK9 – strong). The guideline discusses that, even though the evidence supports the efficacy of PCSK9s in reducing the incidence of ASCVD events, the expense of PCSK9 inhibitors give them a high cost, compared with value.
• For patients more than age 75 years with established ASCVD, it is reasonable to continue high-intensity statin therapy if patient is tolerating treatment.

Severe hypercholesterolemia:

• Patients with LDL-C above 190 mg/dL do not need a 10-year risk score calculated. These individuals should receive maximally tolerated statin therapy.
• If patient is unable to achieve 50% reduction in LDL-C and/or have an LDL-C level of 100 mg/dL, the addition of ezetimibe therapy is reasonable.
• If LDL-C is still greater than 100mg/dL on a statin plus ezetimibe, the addition of a PCSK9 inhibitor may be considered. It should be recognized that the addition of a PCSK9 in this circumstance is classified as a weak recommendation.

Diabetes mellitus in adults:

• In patients aged 40-75 years with diabetes, regardless of 10-year ASCVD risk, should be prescribed a moderate-intensity statin (strong recommendation).
• In adults with diabetes mellitus and multiple ASCVD risk factors, it is reasonable to prescribe high-intensity statin therapy with goal to reduce LDL-C by more than 50%.
• In adults with diabetes mellitus and 10-year ASCVD risk of 20% or higher, it may be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce LDL-C levels by 50% or more.
• In patients aged 20-39 years with diabetes that is either of long duration (at least 10 years, type 2 diabetes mellitus; at least 20 years, type 1 diabetes mellitus), or with end-organ damage including albuminuria, chronic renal insufficiency, retinopathy, neuropathy, or ankle-brachial index below 0.9, it may be reasonable to initiate statin therapy (weak recommendation).

Primary prevention in adults: Adults with LDL 70-189 mg/dL and a 10-year risk of a first ASCVD event (fatal and nonfatal MI or stroke) should be estimated by using the pooled cohort equation. Adults should be categorized according to calculated risk of developing ASCVD: low risk (less than 5%), borderline risk (5% to less than 7.5%), intermediate risk (7.5% and higher to less than 20%), and high risk (20% and higher) (strong recommendation:

• Individualized risk and treatment discussion should be done with clinician and patient.
• Adults in the intermediate-risk group (7.5% and higher to less than 20%), should be placed on moderate-intensity statin with LDL-C goal reduction of more than 30%; for optimal risk reduction, especially in high-risk patients, an LDL-C reduction of more than 50% (strong recommendation).
• Risk-enhancing factors can favor initiation of intensification of statin therapy.
• If a decision about statin therapy is uncertain, consider measuring coronary artery calcium (CAC) levels. If CAC is zero, statin therapy may be withheld or delayed, except those with diabetes as above, smokers, and strong familial hypercholesterolemia with premature ASCVD. If CAC score is 1-99, it is reasonable to initiate statin therapy for patients older than age 55 years; If CAC score is 100 or higher or in the 75th percentile or higher, it is reasonable to initiate a statin.

Statin safety: Prior to initiation of a statin, a clinician-patient discussion is recommended detailing ASCVD risk reduction and the potential for side effects/drug interactions. In patients with statin-associated muscle symptoms (SAMS), a detailed account for secondary causes is recommended. In patients with true SAMS, it is recommended to check a creatine kinase level and hepatic function panel; however, routine measurements are not useful. In patients with statin-associated side effects that are not severe, reassess and rechallenge patient to achieve maximal lowering of LDL-C with a modified dosing regimen.
 

The bottom line

Lifestyle modification is important at all ages, with specific population-guided strategies for lowering cholesterol in subgroups as discussed above. Major changes to the AHA/ACC Cholesterol Clinical Practice Guidelines now mention new agents for lowering cholesterol and using CAC levels as predictability scoring.

Reference

Grundy SM et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: Executive Summary: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2018 Nov 10.

Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Palko is a second-year resident in the family medicine residency program at Abington Jefferson Hospital.

Importance

While statins remain the foundation for treating high cholesterol in order to reduce cardiovascular risk, new evidence has lead to important revisions in the American Heart Association’s recommendations for treatment of hypercholesterolemia in patients at very high cardiovascular risk (secondary prevention) with the addition of specific nonstatin agents. We will briefly review the AHA 2013 guideline recommendations, the relevant new information, and the updated AHA recommendations.

American Heart Association 2013 guidelines

The 2013 American College of Cardiology/AHA cholesterol guidelines recommend either high- or moderate-intensity statin therapy for patients in the four statin benefit groups:

1. Adult patients older than 21 years of age with clinical atherosclerotic cardiovascular disease (ASCVD).

2. Adults older than 21 years of age with low-density lipoprotein cholesterol (LDL-C) above 190 mg/dL.

3. Adults aged 40-75 years without ASCVD but with diabetes and with LDL-C 70-189 mg/dL.

4. Adults aged 40-75 years without either ASCVD or diabetes, with LDL-C 70-189 mg/dL and an estimated 10-year risk for ASCVD of over 7.5% as determined by the Pooled Cohort Equations.

At the time of the 2013 guidelines, there was little evidence to recommend the use of medications other than statins.

Recent evidence

The IMPROVE-IT trial¹ was a double-blind, randomized trial involving 18,144 men and women who were older than 50 years and hospitalized for an acute coronary syndrome within the preceding 10 days. They were randomized to either simvastatin plus ezetimibe or simvastatin plus placebo. The primary endpoints were a composite of death from cardiovascular disease, a major coronary event (nonfatal MI, unstable angina requiring admission, or coronary revascularization), or nonfatal stroke. At 1 year, the mean LDL was 69.9 mg/dL in the simvastatin-monotherapy group and 53.2 mg/dL in the simvastatin-ezetimibe group (P under .001), representing a 24% decrease in LDL between the two groups. The rate of the primary endpoints was significantly lower in the simvastatin plus ezetimibe group with a hazard ratio of 0.936 (P = .016). The risk of MI was significantly decreased with an HR of 0.87 (P = .002), and the risk of ischemic stroke significantly decreased with an HR of 0.79 (P = .008). Prespecified safety endpoints showed no significant difference between the two groups.

The FOURIER trial² examined the PCSK-9 inhibitor, evolocumab. FOURIER was a randomized, double-blind, placebo-controlled study involving 27,564 patients with atherosclerotic cardiovascular disease and LDL levels of 70 mg/dL or higher who were receiving statin therapy (at least atorvastatin 20 mg or equivalent with/without ezetimibe). Patients were between 45 and 80 years old with a history of history of MI, nonhemorrhagic stroke, or symptomatic peripheral artery disease. Patients were randomized to receive subcutaneous injections of evolocumab or matching placebo. The primary endpoints were similar to that of IMPROVE-IT: a composite of cardiovascular death, myocardial infarction, stroke, unstable angina hospitalization, and coronary revascularization. The median LDL on entry was 92 mg/dL for both groups. At 48 weeks, the evolocumab group showed a 59% decrease in LDL, compared with placebo, with a decrease in median LDL from 92 mg/dL to 30 mg/dL. The primary endpoint occurred in 9.8% of the evolocumab group and 11.3% in the placebo group for a hazard ratio of 0.85 (P less than .001) representing a total risk reduction of 13.2%. The risk of MI or stroke and need for revascularization were significantly lower values in the evolocumab group, compared with placebo. Cardiovascular death did not show significant changes. There was no significant difference in rate of serious events.

The ODYSSEY trial³ reported on another PCSK-9 inhibitor, alirocumab, in a randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an ACS in the prior 12 months. At the median follow-up (2.8 years), the LDL of the alirocumab group was 53.3 mg/dL, compared with 101.4 mg/dL in the placebo group. The primary endpoints for cardiovascular risks were similar to those in the FOURIER trial: a risk of 9.5% in the alirocumab group and 11.1% in the placebo group for a total risk reduction of 14.4%. This suggests the class of PCSK-9 inhibitors have a strong correlation with reducing LDL levels 54%-59% and reducing major cardiac adverse events by 13%-15%.
 

Recommendations

The American College of Cardiology released a focused update that integrated the new evidence regarding the use of nonstatin therapy. The current focused update recommends an overall 50% or greater reduction in LDL for patients with clinical ASCVD. If this reduction is not achieved, ACC suggests that one consider the addition of nonstatin therapy with either ezetimibe or a PCSK-9 inhibitor.4 If a patient requires less than 25% additional LDL reduction, consider ezetimibe; if a patient requires more than 25% additional LDL reduction, consider a PCSK-9 inhibitor. Specifically, the guideline states: “If the patient still has less than 50% reduction in LDL-C (and may consider LDL-C above 70 mg/dL or non–HDL-C above 100 mg/dL), the patient and clinician should enter into a discussion focused on shared decision making regarding the addition of a nonstatin medication to the current regimen.”

The other group that is mentioned in the recommendations, with an acknowledgment that the evidence for benefit in primary prevention is not available, is individuals who have an LDL above 190 mg/dL even while compliant with a maximally effective statin regimen. The guidelines make further but less strong recommendations about a number of risk groups, but the largest and strongest change, based on strong evidence, is the recommendation to consider nonstatin therapy in individuals with established ASCVD, as described above.
 

Bottom line

Recent trials show significant reductions in LDL, leading to significant reductions in cardiovascular endpoints with ezetimibe and PCSK-9 inhibitors. This has led to an additional ACC recommendation to consider the use of nonstatin therapy in addition to maximal statin therapy in selected patients with established cardiovascular disease.

References

1. Cannon C et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-97.

2. Sabatine M et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-22.

3. ODYSSEY Outcomes: Results suggest use of PCSK9 inhibitor reduces CV events, LDL-C in ACS patients. Article from American College of Cardiology. ACC News Story. 2018 Mar 10.

4. Lloyd-Jones DM et al. 2017 Focused update of the 2016 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology task force on expert consensus decision pathways. J Am Coll Cardiol. 2017 Oct 3;70(14):1785-1822. Epub 2017 Sep 5.

Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Plako is a second-year resident in the family medicine residency program at Abington Jefferson Hospital.

Importance

While statins remain the foundation for treating high cholesterol in order to reduce cardiovascular risk, new evidence has lead to important revisions in the American Heart Association’s recommendations for treatment of hypercholesterolemia in patients at very high cardiovascular risk (secondary prevention) with the addition of specific nonstatin agents. We will briefly review the AHA 2013 guideline recommendations, the relevant new information, and the updated AHA recommendations.

American Heart Association 2013 guidelines

The 2013 American College of Cardiology/AHA cholesterol guidelines recommend either high- or moderate-intensity statin therapy for patients in the four statin benefit groups:

1. Adult patients older than 21 years of age with clinical atherosclerotic cardiovascular disease (ASCVD).

2. Adults older than 21 years of age with low-density lipoprotein cholesterol (LDL-C) above 190 mg/dL.

3. Adults aged 40-75 years without ASCVD but with diabetes and with LDL-C 70-189 mg/dL.

4. Adults aged 40-75 years without either ASCVD or diabetes, with LDL-C 70-189 mg/dL and an estimated 10-year risk for ASCVD of over 7.5% as determined by the Pooled Cohort Equations.

At the time of the 2013 guidelines, there was little evidence to recommend the use of medications other than statins.

Recent evidence

The IMPROVE-IT trial¹ was a double-blind, randomized trial involving 18,144 men and women who were older than 50 years and hospitalized for an acute coronary syndrome within the preceding 10 days. They were randomized to either simvastatin plus ezetimibe or simvastatin plus placebo. The primary endpoints were a composite of death from cardiovascular disease, a major coronary event (nonfatal MI, unstable angina requiring admission, or coronary revascularization), or nonfatal stroke. At 1 year, the mean LDL was 69.9 mg/dL in the simvastatin-monotherapy group and 53.2 mg/dL in the simvastatin-ezetimibe group (P under .001), representing a 24% decrease in LDL between the two groups. The rate of the primary endpoints was significantly lower in the simvastatin plus ezetimibe group with a hazard ratio of 0.936 (P = .016). The risk of MI was significantly decreased with an HR of 0.87 (P = .002), and the risk of ischemic stroke significantly decreased with an HR of 0.79 (P = .008). Prespecified safety endpoints showed no significant difference between the two groups.

The FOURIER trial² examined the PCSK-9 inhibitor, evolocumab. FOURIER was a randomized, double-blind, placebo-controlled study involving 27,564 patients with atherosclerotic cardiovascular disease and LDL levels of 70 mg/dL or higher who were receiving statin therapy (at least atorvastatin 20 mg or equivalent with/without ezetimibe). Patients were between 45 and 80 years old with a history of history of MI, nonhemorrhagic stroke, or symptomatic peripheral artery disease. Patients were randomized to receive subcutaneous injections of evolocumab or matching placebo. The primary endpoints were similar to that of IMPROVE-IT: a composite of cardiovascular death, myocardial infarction, stroke, unstable angina hospitalization, and coronary revascularization. The median LDL on entry was 92 mg/dL for both groups. At 48 weeks, the evolocumab group showed a 59% decrease in LDL, compared with placebo, with a decrease in median LDL from 92 mg/dL to 30 mg/dL. The primary endpoint occurred in 9.8% of the evolocumab group and 11.3% in the placebo group for a hazard ratio of 0.85 (P less than .001) representing a total risk reduction of 13.2%. The risk of MI or stroke and need for revascularization were significantly lower values in the evolocumab group, compared with placebo. Cardiovascular death did not show significant changes. There was no significant difference in rate of serious events.

The ODYSSEY trial³ reported on another PCSK-9 inhibitor, alirocumab, in a randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an ACS in the prior 12 months. At the median follow-up (2.8 years), the LDL of the alirocumab group was 53.3 mg/dL, compared with 101.4 mg/dL in the placebo group. The primary endpoints for cardiovascular risks were similar to those in the FOURIER trial: a risk of 9.5% in the alirocumab group and 11.1% in the placebo group for a total risk reduction of 14.4%. This suggests the class of PCSK-9 inhibitors have a strong correlation with reducing LDL levels 54%-59% and reducing major cardiac adverse events by 13%-15%.
 

Recommendations

The American College of Cardiology released a focused update that integrated the new evidence regarding the use of nonstatin therapy. The current focused update recommends an overall 50% or greater reduction in LDL for patients with clinical ASCVD. If this reduction is not achieved, ACC suggests that one consider the addition of nonstatin therapy with either ezetimibe or a PCSK-9 inhibitor.4 If a patient requires less than 25% additional LDL reduction, consider ezetimibe; if a patient requires more than 25% additional LDL reduction, consider a PCSK-9 inhibitor. Specifically, the guideline states: “If the patient still has less than 50% reduction in LDL-C (and may consider LDL-C above 70 mg/dL or non–HDL-C above 100 mg/dL), the patient and clinician should enter into a discussion focused on shared decision making regarding the addition of a nonstatin medication to the current regimen.”

The other group that is mentioned in the recommendations, with an acknowledgment that the evidence for benefit in primary prevention is not available, is individuals who have an LDL above 190 mg/dL even while compliant with a maximally effective statin regimen. The guidelines make further but less strong recommendations about a number of risk groups, but the largest and strongest change, based on strong evidence, is the recommendation to consider nonstatin therapy in individuals with established ASCVD, as described above.
 

Bottom line

Recent trials show significant reductions in LDL, leading to significant reductions in cardiovascular endpoints with ezetimibe and PCSK-9 inhibitors. This has led to an additional ACC recommendation to consider the use of nonstatin therapy in addition to maximal statin therapy in selected patients with established cardiovascular disease.

References

1. Cannon C et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-97.

2. Sabatine M et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-22.

3. ODYSSEY Outcomes: Results suggest use of PCSK9 inhibitor reduces CV events, LDL-C in ACS patients. Article from American College of Cardiology. ACC News Story. 2018 Mar 10.

4. Lloyd-Jones DM et al. 2017 Focused update of the 2016 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology task force on expert consensus decision pathways. J Am Coll Cardiol. 2017 Oct 3;70(14):1785-1822. Epub 2017 Sep 5.

Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Plako is a second-year resident in the family medicine residency program at Abington Jefferson Hospital.

Importance

While statins remain the foundation for treating high cholesterol in order to reduce cardiovascular risk, new evidence has lead to important revisions in the American Heart Association’s recommendations for treatment of hypercholesterolemia in patients at very high cardiovascular risk (secondary prevention) with the addition of specific nonstatin agents. We will briefly review the AHA 2013 guideline recommendations, the relevant new information, and the updated AHA recommendations.

American Heart Association 2013 guidelines

The 2013 American College of Cardiology/AHA cholesterol guidelines recommend either high- or moderate-intensity statin therapy for patients in the four statin benefit groups:

1. Adult patients older than 21 years of age with clinical atherosclerotic cardiovascular disease (ASCVD).

2. Adults older than 21 years of age with low-density lipoprotein cholesterol (LDL-C) above 190 mg/dL.

3. Adults aged 40-75 years without ASCVD but with diabetes and with LDL-C 70-189 mg/dL.

4. Adults aged 40-75 years without either ASCVD or diabetes, with LDL-C 70-189 mg/dL and an estimated 10-year risk for ASCVD of over 7.5% as determined by the Pooled Cohort Equations.

At the time of the 2013 guidelines, there was little evidence to recommend the use of medications other than statins.

Recent evidence

The IMPROVE-IT trial¹ was a double-blind, randomized trial involving 18,144 men and women who were older than 50 years and hospitalized for an acute coronary syndrome within the preceding 10 days. They were randomized to either simvastatin plus ezetimibe or simvastatin plus placebo. The primary endpoints were a composite of death from cardiovascular disease, a major coronary event (nonfatal MI, unstable angina requiring admission, or coronary revascularization), or nonfatal stroke. At 1 year, the mean LDL was 69.9 mg/dL in the simvastatin-monotherapy group and 53.2 mg/dL in the simvastatin-ezetimibe group (P under .001), representing a 24% decrease in LDL between the two groups. The rate of the primary endpoints was significantly lower in the simvastatin plus ezetimibe group with a hazard ratio of 0.936 (P = .016). The risk of MI was significantly decreased with an HR of 0.87 (P = .002), and the risk of ischemic stroke significantly decreased with an HR of 0.79 (P = .008). Prespecified safety endpoints showed no significant difference between the two groups.

The FOURIER trial² examined the PCSK-9 inhibitor, evolocumab. FOURIER was a randomized, double-blind, placebo-controlled study involving 27,564 patients with atherosclerotic cardiovascular disease and LDL levels of 70 mg/dL or higher who were receiving statin therapy (at least atorvastatin 20 mg or equivalent with/without ezetimibe). Patients were between 45 and 80 years old with a history of history of MI, nonhemorrhagic stroke, or symptomatic peripheral artery disease. Patients were randomized to receive subcutaneous injections of evolocumab or matching placebo. The primary endpoints were similar to that of IMPROVE-IT: a composite of cardiovascular death, myocardial infarction, stroke, unstable angina hospitalization, and coronary revascularization. The median LDL on entry was 92 mg/dL for both groups. At 48 weeks, the evolocumab group showed a 59% decrease in LDL, compared with placebo, with a decrease in median LDL from 92 mg/dL to 30 mg/dL. The primary endpoint occurred in 9.8% of the evolocumab group and 11.3% in the placebo group for a hazard ratio of 0.85 (P less than .001) representing a total risk reduction of 13.2%. The risk of MI or stroke and need for revascularization were significantly lower values in the evolocumab group, compared with placebo. Cardiovascular death did not show significant changes. There was no significant difference in rate of serious events.

The ODYSSEY trial³ reported on another PCSK-9 inhibitor, alirocumab, in a randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an ACS in the prior 12 months. At the median follow-up (2.8 years), the LDL of the alirocumab group was 53.3 mg/dL, compared with 101.4 mg/dL in the placebo group. The primary endpoints for cardiovascular risks were similar to those in the FOURIER trial: a risk of 9.5% in the alirocumab group and 11.1% in the placebo group for a total risk reduction of 14.4%. This suggests the class of PCSK-9 inhibitors have a strong correlation with reducing LDL levels 54%-59% and reducing major cardiac adverse events by 13%-15%.
 

Recommendations

The American College of Cardiology released a focused update that integrated the new evidence regarding the use of nonstatin therapy. The current focused update recommends an overall 50% or greater reduction in LDL for patients with clinical ASCVD. If this reduction is not achieved, ACC suggests that one consider the addition of nonstatin therapy with either ezetimibe or a PCSK-9 inhibitor.4 If a patient requires less than 25% additional LDL reduction, consider ezetimibe; if a patient requires more than 25% additional LDL reduction, consider a PCSK-9 inhibitor. Specifically, the guideline states: “If the patient still has less than 50% reduction in LDL-C (and may consider LDL-C above 70 mg/dL or non–HDL-C above 100 mg/dL), the patient and clinician should enter into a discussion focused on shared decision making regarding the addition of a nonstatin medication to the current regimen.”

The other group that is mentioned in the recommendations, with an acknowledgment that the evidence for benefit in primary prevention is not available, is individuals who have an LDL above 190 mg/dL even while compliant with a maximally effective statin regimen. The guidelines make further but less strong recommendations about a number of risk groups, but the largest and strongest change, based on strong evidence, is the recommendation to consider nonstatin therapy in individuals with established ASCVD, as described above.
 

Bottom line

Recent trials show significant reductions in LDL, leading to significant reductions in cardiovascular endpoints with ezetimibe and PCSK-9 inhibitors. This has led to an additional ACC recommendation to consider the use of nonstatin therapy in addition to maximal statin therapy in selected patients with established cardiovascular disease.

References

1. Cannon C et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-97.

2. Sabatine M et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-22.

3. ODYSSEY Outcomes: Results suggest use of PCSK9 inhibitor reduces CV events, LDL-C in ACS patients. Article from American College of Cardiology. ACC News Story. 2018 Mar 10.

4. Lloyd-Jones DM et al. 2017 Focused update of the 2016 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology task force on expert consensus decision pathways. J Am Coll Cardiol. 2017 Oct 3;70(14):1785-1822. Epub 2017 Sep 5.

Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Plako is a second-year resident in the family medicine residency program at Abington Jefferson Hospital.