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ACC Issues New Guidelines on Nonstatin Lipid-Lowering

Drugs CME / ABIM MOC / CE
News Author: Sue Hughes
CME Author: Charles P. Vega, MD
Posted: 8/17/2016

Clinical Context
The 2013 guidelines regarding lipid management from the American Heart Association (AHA) and the American
College of Cardiology (ACC) engendered significant debate and confusion. However, at their core, the
recommendations identified 4 high-risk groups who could experience a net health benefit with statin therapy,
and the guidelines also discriminated as to which patients should receive moderate- or high-intensity treatment
with statins.
The guidelines also clearly discouraged the use of nonstatin medications to treat lipids in order to prevent
atherosclerotic cardiovascular disease (ASCVD). However, these recommendations predated the approval of
the proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors, which have been demonstrated to dramatically
reduce serum levels of low-density lipoprotein (LDL) cholesterol beyond the change associated with statins
alone. PCSK9 inhibitors currently carry indications for the treatment of familial hypercholesterolemia syndromes
and among patients who require additional lowering of LDL cholesterol levels.
Now, controversy rages again regarding the best strategy to reduce patients' cardiovascular risk. The current
consensus statement from the ACC provides recommendations on the use of nonstatin treatments of high LDL
cholesterol levels.

Synopsis and Perspective

The ACC has released an "Expert Consensus Decision Pathway" document on the role of nonstatin therapies
for 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 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 3 major new datasets all involved adding new drugs in addition to statins for 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 in addition to 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 article, the authors explain that the algorithms endorse the 4 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 ASCVD risk in situations not covered by the guidelines."
Dr Lloyd-Jones reported that the document includes 2 different algorithms for familial hypercholesterolemia, "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."
Although ezetimibe is considered appropriate for high-risk primary prevention, there are 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 [familial hypercholesterolemia], 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 4 major statin benefit groups for ASCVD risk
reduction: (1) patients 21 years or older with clinical ASCVD; (2) adults 21 years or older with LDL
cholesterol level of at least 190 mg/dL (not due to secondary modifiable causes); (3) adults 40 to 75
years old without ASCVD but with diabetes and an LDL cholesterol level of 70 to 189 mg/dL; and (4)
adults 40 to 75 years old 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 nonstatin therapies that the current Expert
Consensus Panel has used to provide more detailed recommendations for specific patient scenarios.
The Expert Consensus Panel addressed 3 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 2-3 statins of differing metabolic pathways), and
intermittent (1-3 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 a greater than 50% reduction in LDL cholesterol levels from baseline.

The pathways also provide guidance on other factors that should be considered regarding the addition
of nonstatin therapies. Such factors include 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 familial hypercholesterolemia.

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 a trial of patients with acute coronary syndrome.

Bile acid sequestrants may be considered as second-line therapy for patients in whom ezetimibe is not
tolerated, but they should be avoided in patients with triglyceride levels 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 familial
hypercholesterolemia. 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 familial
hypercholesterolemia.

For patients with homozygous hypercholesterolemia, referral to a lipid specialist is strongly

recommended with statins, and nonstatins including ezetimibe, bile acid sequestrants, with
consideration for use of lomitapide, mipomersen, and LDL apheresis as necessary. LDL apheresis is
also approved for heterozygous familial hypercholesterolemia.

J Am Coll Cardiol. 2016;68:92-125.[1]

Guideline Highlights

Nonadherence to statin therapy frequently results in elevated LDL cholesterol levels and
cardiovascular risk. Adherence to statins can be assessed with a lipid panel after 4 to 12 weeks of
statin therapy.

There is not a universal definition for statin intolerance, but statin intolerance is usually manifest as
moderate to severe muscle pain that subsides on discontinuation of statins and occurs consistently
after the application of 2 to 3 different statins, including one at a low dose.

Alternate-day statin dosing should be considered in cases of statin intolerance.

High-intensity treatment with statins should be expected to reduce LDL cholesterol levels by at least
50%, whereas moderate-intensity statin therapy should reduce LDL cholesterol levels by 30% to 50%.

Among patients with a history of ASCVD who experience a suboptimal reduction in LDL cholesterol
levels while taking a high-intensity statin, ezetimibe is recommended as the first-line add-on drug given
its safety profile and evidence in reducing ASCVD events when combined with simvastatin.

PCSK9 inhibitors may be prescribed for these patients if the LDL cholesterol response remains
inadequate and/or if the patient experiences statin intolerance.

However, PCSK9 inhibitors may be considered first-line additions to statins when the baseline LDL
cholesterol level is at least 190 mg/dL. These patients are much more likely to have familial

hypercholesterolemia, and consideration should be given to referral to a lipid specialist as well as

cascade screening to detect affected family members.

In cases of patients without ASCVD who have a baseline LDL cholesterol level of 190 mg/dL or more
and do fail to have an adequate response to high-intensity treatment with statins, clinicians may
consider initiation of either ezetimibe or a PCSK9 inhibitor.

For patients between 40 and 75 years old who have diabetes but no history of ASCVD and whose
baseline LDL cholesterol level is between 70 and 189 mg/dL, ezetimibe is considered a first-line drug
when high-intensity statins fail. Bile acid sequestrants are a second-line option.

Adults between 40 and 75 years old whose sole risk factor is a calculated 10-year ASCVD risk of 7.5%
or more should receive moderate-intensity statin therapy. If this treatment fails to achieve its goal, then
high-intensity statins should be initiated. If LDL cholesterol levels remain persistently elevated,
ezetimibe may be considered, with bile acid sequestrants as a second choice.

The panel recommends against the use of PCSK9 inhibitors among patients receiving hemodialysis or
in patients with symptomatic heart failure.

Clinical Implications

The current guidelines from the ACC recommend ezetimibe as first-line treatment for failure to achieve
treatment goals with statins among patients with high LDL cholesterol levels but no cardiovascular risk,
except for a 10-year calculated ASCVD risk of 7.5% or more.

The current ACC guidelines also generally recommend ezetimibe as first-line treatment for patients
with ASCVD who fail to achieve an adequate response to high-intensity statin therapy.

Implications for the Healthcare Team: The ACC guidelines emphasize that statins are the preferred
option to treat high LDL cholesterol levels with the goal of ASCVD prevention, and the healthcare team
should take every step to ensure that patients are adherent to statins at the right dose before
considering adding other agents that affect LDL cholesterol levels.

CME Test
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/qna/processor/41027?show
article/867002_print
41027 StandAlone=true&formType=INTERNAL
true

To receive AMA PRA Category 1 Credit, you must receive a minimum score of 75% on the post-test.
3

INTERNAL

316549

You are seeing a 64-year-old man without a history of ASCVD or diabetes. He has an LDL
cholesterol level of 158 mg/dL and a 10-year calculated ASCVD risk of 11.3%. He is initiated with
moderate-intensity statin therapy, and then a high-intensity statin, but his LDL cholesterol level
declines by only 22%. According to the current recommendations from the ACC, what is part of the
best practice for this patient at this time?
RADIOBUTTON

Continue taking a high-intensity statin alone

Consider adding ezetimibe
Consider adding a PCSK9 inhibitor
Consider adding a bile acid sequestrant
316551

Unfortunately, before you can see the patient again to discuss his LDL cholesterol treatment, he has
a non-ST elevation myocardial infarction. According to the current ACC recommendations, what is
the best option for him now?
RADIOBUTTON

Continue with high-intensity statin alone

Consider adding ezetimibe
Consider adding a PCSK9 inhibitor
Consider adding a bile acid sequestrant
Save and Proceed

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;68:92-125.
http://content.onlinejacc.org/article.aspx?
articleid=2510936&_ga=1.242276683.831055067.1428269375. Accessed July 8, 2016.

This article is a CME / ABIM MOC / CE certified activity. To earn credit for this activity
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