New Guidance on Use of Nonstatin Cholesterol-Lowering Drugs

July 08, 2016

The American College of Cardiology (ACC) has released an "Expert Consensus Decision Pathway" document on the role of nonstatin therapies for low-density lipoprotein (LDL) cholesterol lowering in the management of cardiovascular disease risk.

Chair of the document's writing committee, Donald M. Lloyd-Jones, MD, Northwestern University Clinical and Translational Sciences Institute, Chicago, Illinois, explained to Medscape Medical News that the document has been issued to advise on the use of several nonstatin medications that have recently been the subject of new clinical trials.

"Since 2013 when the ACC/AHA [American Heart Association] last updated the cholesterol guidelines, there have been a number of new trials published with additional data on at least three new classes of cholesterol lowering medication. It has been a particularly active period. So we have issued this update to help clinicians introduce this new data into clinical practice," he said.

The document, which was published in the July 5 issue of the Journal of the American College of Cardiology (JACC), is endorsed by the National Lipid Association.

The three major new datasets all involved adding new drugs on top of statins in patients at high risk for cardiovascular disease. They are:

  • HPS THRIVE: showing no additional benefit and possible harm of adding niacin on top of statins.

  • IMPROVE-IT: showing modest benefit and safety of ezetimibe on top of statins.

  • PCSK9 monoclonal antibodies: short-term outcomes data in patients at very high risk.

Dr Lloyd-Jones said, "We have produced 7 different algorithms for patients with cardiovascular disease or comorbidities: high-risk patients more likely to consider expensive new drugs."

In the JACC paper, the authors explain that the algorithms endorse the four evidence-based statin benefit groups identified in the 2013 ACC/AHA cholesterol guidelines and assume that the patient is currently taking or has attempted to take a statin, given that this is the most effective initial therapy.

They add: "Recommendations attempt to provide practical guidance for clinicians and patients regarding the use of nonstatin therapies to further reduce atherosclerotic cardiovascular disease risk in situations not covered by the guidelines."

Dr Lloyd-Jones reported that the document includes two different algorithms for familial hypercholesterolemia (FH), "in which we recommend a lower threshold for use of PCSK9 drugs." It also includes recommendations for patients with diabetes and other high-risk groups who do not already have cardiovascular disease.

"In all these groups who are at high risk, we recommend that if LDL has not been reduced by 50% with lifestyle and statins then other drugs can be considered."

While ezetimibe is considered appropriate for high-risk primary prevention, there is not enough data on efficacy or safety of PCSK9 to recommend use in primary prevention, he said.

"Our feeling about the PCSK9 inhibitors is that they should be reserved for the highest-risk patients, those with ACS [acute coronary syndrome] who can't tolerate statins. If they have FH, our feeling was these patients should go straight to PCSK9 inhibitors; otherwise they should try ezetimibe first. If they were regular secondary prevention patients without FH, then ezetimibe should be considered first."

The authors conclude that these recommendations should help clinicians frame discussions with patients about treatment decisions. They will also provide a roadmap for the next set of guidelines, together with new data from several other trials due to be reported in the next couple of years. These include longer-term results with PCSK9 agents and anacetrapib.

A summary of the Consensus Decision Pathway makes the following points:

  • The 2013 ACC/AHA cholesterol guideline identified four major statin benefit groups for atherosclerotic cardiovascular disease (ASCVD) risk-reduction: (1) patients age 21 years or older with clinical ASCVD; (2) adults age 21 years or older with LDL cholesterol level of at least 190 mg/dL (not due to secondary modifiable causes); (3) adults aged 40 to 75 years without ASCVD but with diabetes and an LDL cholesterol level of 70 to 189 mg/dL; and (4) adults aged 40 to 75 years without ASCVD or diabetes who have an LDL cholesterol level of 70 to 189 mg/dL and an estimated 10-year risk for ASCVD of 7.5% or greater, as determined by the Pooled Cohort Equations.

  • Recommendations in the 2013 guideline included using high- or moderate-intensity statin therapy for primary and secondary prevention scenarios, with dose adjustments as necessary for adverse effects, advanced age, drug-drug interactions, or comorbidities. The current Expert Consensus Decision Pathways rely on the evidence base established by the 2013 guideline and incorporate newer clinical trial data on niacin, ezetimibe, and the recently approved PCSK9 inhibitors (alirocumab and evolocumab).

  • The 2013 guideline provided a framework for addition of non-statin therapies that the current Expert Consensus Panel has used to provide more detailed recommendations for specific patient scenarios. The Expert Consensus Panel addressed three questions:

    1. In what patient populations should nonstatin therapies be considered?

    2. In what situations should nonstatin therapies be considered (ie, when is the amount of LDL cholesterol lowering [percentage LDL cholesterol reduction or LDL cholesterol range achieved on therapy] less than anticipated, less than desired, or inadequate?), and which treatment options should be considered in patients who are truly statin intolerant?

    3. If nonstatin therapies are to be added, which agents or therapies should be considered and in what order? All pathways for nonstatin therapy recommendations include assuring that the patient is following a healthy lifestyle.

  • Consistent with the recommendations of the 2013 guideline, fasting LDL cholesterol levels should be regularly assessed after initiation of lipid-lowering treatment and every 3 to 12 months thereafter as indicated.

  • The approach to suspected statin intolerance should include temporary discontinuation of statin therapy, lower dosing, rechallenge (preferably with two to three statins of differing metabolic pathways), and intermittent (one to three times weekly) dosing of long half-life statins.

  • In selected high-risk patients, such as those with existing ASCVD or LDL cholesterol level of 190 mg/dL or greater, use of nonstatins may be considered if maximally tolerated statin therapy has not achieved greater than 50% reduction in LDL cholesterol from baseline.

  • The pathways also provide guidance on other factors that should be considered regarding the addition of nonstatin therapies, including the absolute LDL cholesterol level achieved, the extent of available scientific evidence for safety and tolerability, potential for drug-drug interactions, efficacy of additional LDL cholesterol lowering in ASCVD event reduction, cost, convenience and medication storage, pill burden, route of administration, potential to jeopardize adherence to evidence-based therapies, and importantly, patient preferences.

  • The Expert Consensus Panel emphasizes that LDL cholesterol levels are not firm triggers for adding medication, but they are factors that may be considered within the broader context of an individual patient's clinical situation.

  • Referral to a lipid specialist and registered dietitian may be considered for higher-risk patients with statin intolerance and is strongly encouraged for patients with FH.

  • Ezetimibe is the first nonstatin medication that should be considered in most of the patient scenarios, given its safety and tolerability, as well as demonstrated, though modest, efficacy when added to moderate-dose statin in one trial of patients with acute coronary syndrome.

  • Bile acid sequestrants (BAS) may be considered as second-line therapy for patients in whom ezetimibe is not tolerated, but they should be avoided in patients with triglycerides greater than 300 mg/dL.

  • Alirocumab and evolocumab may be considered if the goals of therapy have not been achieved on maximally tolerated statin and ezetimibe in higher-risk patients with clinical ASCVD or FH. Given the lack of long-term safety and efficacy data on these agents, they are not recommended for use in primary prevention patients in the absence of FH.

  • For patients with homozygous hypercholesterolemia, referral to a lipid specialist is strongly recommended with statins, and nonstatins including ezetimibe, BAS, with consideration for use of lomitapide, mipomersen, and LDL apheresis as necessary. LDL apheresis is also approved for heterozygous FH.

J Am Coll Cardiol. 2016;68:92-125. Full text

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