2016 ACC Guidelines for Nonstatin Therapies: An In-Depth Guide

Patients will be asking whether they are candidates for the new proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, and new guidelines published by the American College of Cardiology (ACC) can help pharmacists determine and explain the role of these new therapies.¹

Since the 2013 publication of the original ACC/American Heart Association (AHA) guidelines for treatment of blood cholesterol, the FDA has approved several nonstatin therapies, including the PCSK9 inhibitors alirocumab (Praluent) and evolocumab (Repatha). Additionally, new evidence, such as the results of the IMPROVE-IT trial, has proven the benefits of the nonstatin therapy ezetimibe (Zetia). Ongoing trials are assessing the cardiovascular benefits of 3 PCSK9 inhibitors: alirocumab, evolocumab, and a third agent still in development: bococizumab.^2,3

To address new evidence supporting therapies such as ezetimibe and PCSK9 inhibitors, the ACC published guidance for use of nonstatin therapies in March 2016. In addition to clarifying the role of ezetimibe and PCSK9 inhibitors in patients with hyperlipidemia, the guidelines define the place of bile acids sequestrants and dietary adjuncts, such as phytosterol and soluble dietary fiber supplements, in patients without familial forms of hypercholesterolemia.¹

A Brief Review of the 2013 Guidelines

The 2013 ACC/AHA guidelines recommended the use of statins in 4 patient groups²:

• Patients with clinical atherosclerotic cardiovascular disease (ASCVD).
• Patients with low-density lipoprotein cholesterol (LDL-C) levels of 190 mg/dL or higher (not due to secondary modifiable causes,⁴ such as medications, metabolic disorders, underlying disease, or poor diet).
• Patients aged 40 to 75 years without ASCVD, but with type 2 diabetes mellitus (T2DM) and an LDL-C level of 70 mg/dL to 189 mg/dL.
• Patients aged 40 to 75 years without ASCVD or T2DM, but with an LDL-C level of 70 mg/dL to 189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher (estimated using the pooled risk cohort equation).⁵

The 2013 ACC/AHA guidelines subdivided statin therapy into high- and moderate-intensity therapy, with high-intensity therapy sufficient to attain a ≥50% reduction in LDL-C, and moderate-intensity therapy sufficient to reduce LDL-C by 30% to <50% (Table 1^1,2).

Table 1: Statin Therapy by Treatment Intensity^1,2

High-intensity statin therapy intended to lower LDL-C by ≥50%

Moderate-intensity statin therapy intended to lower LDL-C by 30% to <50%

Atorvastatin 40 to 80 mg daily

Rosuvastatin 20 to 40 mg daily

Atorvastatin 10 to 20 mg daily

Rosuvastatin 5 to 10 mg daily

Simvastatin 20 to 40 mg daily

Pravastatin 40 to 80 mg daily

Lovastatin 40 mg daily

Fluvastatin (extended-release) 80 mg daily

Fluvastatin 40 mg twice daily

Pitavastatin 2 to 4 mg daily

Although high-intensity therapy is desirable for the majority of patients, moderate-intensity therapy is considered sufficient for 2 patient groups²:

• Patients older than 75 years.
• Patients aged 40 to 75 years with LDL-C levels <190 mg/dL, no existing ASCVD, and a 10-year risk of ASCVD <7.5%.

ASCVD risk equivalents and conditions that define ASCVD with comorbidities are listed in Table 2^1,2. Of note, the 10-year risk of ASCVD is calculated using the pooled risk cohort equation.^1,2,5

Table 2: Conditions That Define Clinical ASCVD^1,2

Conditions That Define ASCVD

Acute coronary syndrome

History of myocardial infarction

Stable or unstable angina

Coronary or other arterial revascularization

Stroke

Transient ischemic attack

Peripheral arterial disease presumed to be of atherosclerotic origin

Conditions That Define ASCVD with Comorbidities

Diabetes

Recent ASCVD event (<3 months ago)

ASCVD event while already taking a statin

Poorly controlled other major ASCVD risk factors

Elevated lipoprotein(a)

Patient with chronic kidney disease not on hemodialysis

^{Note: A patient with ASCVD taking a statin defines a patient taking a statin for secondary prevention.}

The Role of Nonstatin Therapy

For patients who cannot achieve a ≥50% LDL-C reduction or a 30% to <50% LDL-C reduction with statins and dietary interventions (including fiber supplements and phytosterol supplements), the new ACC guidelines recommend the use of several nonstatin therapies, depending on the patient group under consideration (Table 3¹). These therapies including ezetimibe, bile acid sequestrants, and PCSK9 inhibitors (Table 4¹).

Table 3: Nonstatin Therapies for Patients Without Familial Hypercholesterolemia¹

In patients taking statins for primary prevention:

In patients taking statins for secondary prevention:

Were the patient’s baseline LDL-C levels ≥190 mg/dL?

If yes, the patient is classified among:

• Patients without clinical ASCVD with baseline LDL-C levels ≥190 mg/dL not due to secondary causes taking a statin for primary prevention

If no, ask:

Does the patient have diabetes, and is the patient aged 40 to 75 years?

If yes, the patient is classified among:

• Patients aged 40 to 75 years without clinical ASCVD, but with diabetes and baseline LDL-C levels 70 to 189 mg/dL taking a statin for primary prevention

If no, ask:

Does the patient have a 10-year ASCVD risk ≥7.5% based on the pooled cohort equation, and is the patient aged 40 to 75 years?

If yes, the patient is classified among:

• Patients aged 40 to 75 years without clinical ASCVD or diabetes, but with baseline LDL-C levels 70 to 189 mg/dL and a 10-year ASCVD risk ≥7.5% taking a statin for primary prevention

Does the patient have clinical ASCVD with comorbidities?

If yes, the patient is classified among:

• Patients with clinical ASCVD with comorbidities who are taking a statin for secondary prevention

If no, ask:

Was the patient’s baseline LDL-C level ≥190 mg/dL?

If yes, the patient is classified among:

• Patients with clinical ASCVD with baseline LDL-C levels ≥190 mg/dL who are taking a statin for secondary prevention

If no, the patient is classified among:

• Patients with stable clinical ASCVD without comorbidities who are taking a statin for secondary prevention

Critically, under the new treatment guidelines, PCSK9 inhibitors are not recommended for all patient groups. Only patients taking maximally tolerated statin therapy who have clinical ASCVD, or patients without clinical ASCVD and baseline LDL-C levels ≥190 mg/dL are potential candidates. Additionally, except in patients with a baseline LDL-C level ≥190 mg/dL, ezetimibe should be considered before the use of a PCSK9 inhibitor.¹

Bile acid sequestrants are generally reserved as an option in patients who are intolerant to or have an inadequate response with ezetimibe and have a fasting triglyceride level <300 mg/dL. Of note, the modest hypoglycemic effect of the specific bile acid sequestrant colesevelam may be desirable in patients with T2DM.¹

Niacin is not listed as a nonstatin treatment option in any of the 6 patient subgroups who qualify for nonstatin therapy. Researchers pointed to current evidence showing no clinical benefit for the use of niacin and the potential for substantial harm with concurrent use of niacin and statins.¹

Table 4: Treatment Approach in 6 Patient Groups¹

Patient Population

Goal

Pharmacologic Options^a

Patients with stable clinical ASCVD without comorbidities who are taking a statin for secondary prevention

≥50% reduction in LDL-C, or optionally, an LDL-C level <100 mg/dL (provided that the patient is on a maximally tolerated statin)

Ezetimibe should be used first, with later consideration of a PCSK9 inhibitor alone or in combination with ezetimibe

Patients with clinical ASCVD with comorbidities who are taking a statin for secondary prevention

≥50% reduction in LDL-C, or optionally, an LDL-C level <70 mg/dL or non—HDL-C level <100 mg/dL (provided that the patient is on a maximally tolerated statin)

Ezetimibe should be used first, with later consideration of a PCSK9 inhibitor alone or in combination with ezetimibe

Patients with clinical ASCVD with baseline LDL-C levels ≥190 mg/dL who are taking a statin for secondary prevention

≥50% reduction in LDL-C, or optionally, an LDL-C level <70 mg/dL (provided that the patient is on a maximally tolerated statin)

Patients initiating nonstatin therapy have the option of initiating a PCSK9 inhibitor or ezetimibe. Bile acid sequestrants are a second-line option after ezetimibe in patients who are intolerant to ezetimibe and have triglyceride levels <300 mg/dL.

Patients without clinical ASCVD, but with baseline LDL-C levels ≥190 mg/dL not due to secondary causes taking a statin for primary prevention

≥50% reduction in LDL-C, or optionally, an LDL-C level <100 mg/dL (provided the patient is on a maximally tolerated statin)

Patients initiating nonstatin therapy have the option of initiating a PCSK9 inhibitor or ezetimibe. Bile acid sequestrants are a second-line option after ezetimibe in patients who are intolerant to ezetimibe and have triglyceride levels <300 mg/dL.

Patients aged 40 to 75 years without clinical ASCVD, but with diabetes and baseline LDL-C levels 70 to 189 mg/dL taking a statin for primary prevention

≥50% reduction in LDL-C, or optionally, an LDL-C level <100 mg/dL or non—HDLC level <130 mg/dL (provided the patient is on a maximally tolerated statin)

Patients have the option of initiating either ezetimibe (preferred) or bile acid sequestrants as a second-line option after ezetimibe in those who are intolerant to ezetimibe and have triglyceride levels <300 mg/dL. If bile acid sequestrants are used, colesevelam should be considered due to its modest HbA1C-reducing effects.

Patients aged 40 to 75 years without clinical ASCVD or diabetes, but with baseline LDL-C levels 70 to 189 mg/dL, and a 10-year ASCVD risk ≥7.5% taking a statin for primary prevention

<30% reduction in LDL-C, or optionally, if they do not have an LDL-C level <100 mg/dL on a moderate-intensity statin

OR

If patients have high-risk markers^b

After attempting high-intensity statin therapy, patients have the option of initiating either ezetimibe (preferred) or bile acid sequestrants as a second-line option after ezetimibe in those who are intolerant to ezetimibe and have triglyceride levels <300 mg/dL.

^aNote that these pharmacologic options are only a consideration after intensifying lifestyle therapy (including consideration of fiber supplements and phytosterol supplements), evaluation of patients for statin intolerance, a discussion of nonstatin therapies (including the potential drug-drug interactions), consideration of patient attitudes, and in some cases, referral to a lipidologist.

^bHigh-risk markers include an ASCVD risk ≥20%, a primary LDL-C level ≥160 mg/dL at baseline, poorly controlled other major ASCVD risk factors, a family history of premature ASCVD with or without elevated Lp(a), evidence of accelerated subclinical atherosclerosis, elevated hs-CRP, or other risk-modifying conditions (eg, CKD, HIV, and chronic inflammatory disorders).

Patients with Familial Hypercholesterolemia

In addition to PCSK9 inhibitors, ezetimibe, bile acid sequestrants, and dietary adjuncts, the panel addressed the role of treatments for patients with familial hypercholesterolemia, including mipomersen, lomitapide, and LDL apheresis. For patients with confirmed or suspected familial hypercholesterolemia, specialist management is the most appropriate treatment strategy.¹

Importantly, treatments such as lomitapide and mipomersen, which are only indicated for use in patients with familial forms of hypercholesterolemia, should be administered under the care of a lipid specialist and are not included in the treatment algorithms detailed in the 2016 ACC guidelines.¹

Conclusions

The ACC’s 2016 nonstatin therapy guidelines have far-reaching implications for the management of cardiovascular disease and the extent of the use of advanced specialty products such as PSCK9 inhibitors in patients without familial hypercholesterolemia.¹

For many patients, the nonstatin therapy guidelines recommend the use of ezetimibe before attempting treatment with a PCSK9 inhibitor. For some groups—including patients without clinical ASCVD and those with a baseline LDL-C level <190 mg/dL&mdash;the PCSK9 inhibitor option is not present in treatment algorithms at all.¹

By emphasizing treatment adherence, dietary measures, and shared decision-making, the new guidelines will help clarify the place that advanced nonstatin therapies such as PCSK9 inhibitors hold in therapy, and also limit the use of these therapies to qualifying patient groups who have the greatest need for advanced options.

Key Practice Points

• In most patients, dietary measures, including the use of phytosterol and fiber supplements should be considered before initiating nonstatin treatments.
• Patients have ASCVD if they have 1 or more of the following: acute coronary syndrome, angina (stable or unstable), peripheral arterial disease presumed to be of atherosclerotic origin, or a history of myocardial infarction, stroke, transient ischemic attack, or arterial revascularization procedure (coronary or other).
• Although ezetimibe is an option for all patient groups, it should be considered the first-line nonstatin therapy in patients with ASCVD and a baseline LDL-C level <190 mg/dL.
• Bile acid sequestrants may be considered as second-line therapy after ezetimibe in patients with fasting triglyceride levels <300 mg/dL.
• The following patient groups are candidates for PCSK9 inhibitor therapy: Patients with clinical ASCVD. Patients without clinical ASCVD with a baseline LDL-C level ≥190 mg/dL.
• Use of the specific bile acid sequestrant colesevelam may be desirable in patients with T2DM due to its modest hypoglycemic effect.
• Niacin is no longer recommended in combination with statins in any patient group due to potential harms and lack of clinical benefit.
• These guidelines do not provide specific guidance for patients with familial forms of hypocholesterolemia, but they mention that these patients should be treated by specialists.

References

1. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016 Mar 28. pii: S0735-1097(16)32398-1. doi: 10.1016/j.jacc.2016.03.519. [Epub ahead of print]

2. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):2889-2934. doi: 10.1016/j.jacc.2013.11.002. Epub 2013 Nov 12.

3. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387-2397. doi: 10.1056/NEJMoa1410489. Epub 2015 Jun

4. Stone NJ. Secondary causes of hyperlipidemia. Med Clin North Am. 1994;78(1):117-141.

5. ASCVD Risk Estimator. http://tools.acc.org/ASCVD-Risk-Estimator/. Published 2014. Accessed May 2016.