PL Detail-Document #310101

This PL Detail-Document gives subscribers

additional insight related to the Recommendations published in

PHARMACISTS LETTER / PRESCRIBERS LETTER

January 2015

Ezetimibes Role in Cardiovascular Risk Reduction

Background
The primary target of lipid-lowering therapy is
LDL because there is a strong relationship
between elevated LDL and coronary heart
disease.1-3 Statins are the drugs of choice for
cardiac risk reduction due to their proven
benefits.1,3 Moderate doses of statins, which
primarily target LDL, decrease cardiovascular
morbidity and mortality by 25% to 35% with five
years use.2,4
When patients cant take a statin, or dont
achieve the LDL-lowering effects seen in statin
clinical trials, use of a nonstatin is usually
contemplated. However, the benefit/risk ratio of
these medications, especially when added to a
statin, is generally marginal or even
unfavorable.1,5,6 Several studies have examined
the efficacy of ezetimibe (Zetia [U.S.], Ezetrol
[Canada]) or ezetimibe plus simvastatin (Vytorin
[U.S.] for improving surrogate or clinical
outcomes in patients with dyslipidemia or other
cardiovascular risk factors.
But the recent
IMPROVE-IT study is the first to show that
adding ezetimibe to a statin can further reduce
cardiovascular risk. This article reviews these
studies and discusses potential therapeutic niches
for ezetimibe.

Ezetimibe Imaging Studies

ENHANCE (Effect of Combination Ezetimibe
and High-Dose Simvastatin vs Simvastatin Alone
on the Atherosclerotic Process in Patients with
Heterozygous Familial Hypercholesterolemia)
was the first large trial designed to assess the
effects of combination lipid-lowering therapy
compared to statin monotherapy on the
progression of atherosclerosis.
ENHANCE
compared simvastatin 80 mg/ezetimibe 10 mg to
simvastatin 80 mg. Over 700 patients were
enrolled. ENHANCE included patients between
the ages of 30 and 75 years (mean 46 years) with
a baseline LDL >210 mg/dL (>5.4 mmol/L). The
primary endpoint was change in mean carotid

artery intima-media thickness (CA IMT). CA

IMT is a measurement of plaque build-up, and is a
surrogate marker for cardiovascular events. CA
IMT was measured using ultrasound at baseline,
six months, 12 months, 18 months, and
24 months. The percent change in baseline in
lipid parameters was a secondary endpoint. After
two years, combination therapy did not reduce
atherosclerotic
progression
more
than
monotherapy, despite being more effective at
lowering LDL (58% vs 41%, p<0.01). Although
there did not seem to be a difference in
cardiovascular events between the treatment
groups, the study was underpowered to detect
such as difference. Adverse effects were similar
between groups.7
ARBITER 6-HALTS (Arterial Biology for the
Investigation of the Treatment Effects of
Reducing Cholesterol 6-HDL and LDL Treatment
Strategies) had a primary endpoint similar to
ENHANCE.
ARBITER 6-HALTS included
patients with coronary heart disease or a coronary
heart disease risk equivalent (e.g., diabetes, 10year Framingham risk score of 20% or more, etc)
who were on long-term statin therapy. Subjects
were required to have measurements of LDL-C
<100 mg/dL (<2.6 mmol/L) and HDL-C
<50 mg/dL (<1.3 mmol/L) (men) or <55 mg/dL
(1.4 mmol/L) (women) within three months prior
to enrollment. There were 363 patients enrolled
in the study. Study subjects were randomly
assigned to receive either extended-release niacin
at a target dose of 2000 mg per day or ezetimibe
10 mg daily. The drugs were given in an openlabel fashion. (Note that only 75% of the patients
assigned to niacin reached the target dose.) The
primary endpoint of the study was the difference
between groups in the change in CA IMT from
baseline to 14 months. There were four secondary
endpoints: change in lipid values; a composite
endpoint
of
heart
attack,
myocardial
revascularization, hospital admission for acute
coronary syndrome, and death from coronary
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(PL Detail-Document #310101: Page 2 of 4)

heart disease; discontinuation of study drug

because of adverse effects; and health-related
quality of life. The study was stopped short of
finishing because of a difference in efficacy.
There were 14-month endpoint data available for
only 208 patients, or 57% of total enrollment.
Regarding the primary endpoint, niacin was better
than ezetimibe at reducing CA IMT at both eightmonth and 14-month follow-up. There was a
significant reduction in CA IMT from baseline
with niacin, but there was not a significant change
in CA IMT from baseline with ezetimibe.
Ezetimibe was better than niacin at lowering LDL
(p=0.01). Niacin was better than ezetimibe at
increasing HDL-C (p<0.001). A significantly
larger number of subjects experienced the
composite outcome of cardiovascular events in the
ezetimibe group in comparison with the niacin
group (5% vs 1%, p=0.04). (Note that the study
was not powered to show a difference in clinical
outcomes.) There was no significant difference in
the number of subjects who left the study because
of side effects from the drugs. There was also no
significant difference between groups in healthrelated quality of life at baseline or at 14 months.8

Ezetimibe Outcome Studies

Preliminary data suggested that lipid-lowering
treatment might reduce progression of aortic
stenosis. Based on this data, and the association
between aortic stenosis and cardiovascular events,
the SEAS trial compared simvastatin 40 mg plus
ezetimibe 10 mg to placebo in over 1800 patients
with mild-to-moderate aortic stenosis but without
known coronary disease. The drugs did not affect
the primary composite endpoint of major
cardiovascular events (e.g., nonfatal heart attack,
revascularization, ischemic stroke, aortic valve
replacement). They also did not affect the need
for aortic valve replacement. Fewer patients had
ischemic cardiovascular events in the treatment
group (HR 0.78, 95% CI 0.63 to 0.97, p=0.02),
but there was a higher risk of cancer in the
treatment group (11.1% vs 7.5%, p=0.01).9 After
analyzing the data, the FDA concluded, in part,
that: ezetimibe did not increase cancer risk in
animals in preclinical studies; cancer risk did not
increase over time, as would be expected if the
drug caused growth of pre-existing cancers; it is
not likely that the drug would cause the myriad
cancers that presented; and the study was not
designed to assess cancer risk.10

Chronic kidney disease is associated with

cardiovascular risk. The primary prevention
SHARP trial (Study of Heart and Renal
Protection) was designed to assess the safety and
efficacy of simvastatin plus ezetimibe in patients
with moderate to severe renal disease. The
primary outcome measure was first major
atherosclerotic event (nonfatal heart attack,
coronary
death,
ischemic
stroke,
or
revascularization).
Because of concern for
myopathy with high-dose statins in renal disease,
the study compared just 20 mg of simvastatin plus
ezetimibe 10 mg to placebo. Over 9000 patients
were randomized. Median follow-up was almost
five years. Treatment safely reduced the risk of
the primary endpoint regardless of renal disease
severity. There was no indication of increased
cancer risk.11
In the as-yet unpublished IMPROVE-IT study,
ezetimibe 10 mg plus simvastatin 40 mg was
compared to simvastatin 40 mg alone in a very
high-risk secondary prevention population: recent
hospitalization for acute coronary syndrome. The
combination modestly reduced cardiovascular
events (a composite endpoint of cardiovascular
death, heart attack, unstable angina requiring
hospitalization, revascularization, or stroke) over
simvastatin alone, without more side effects. The
primary endpoint was reached in 32.7% of the
combination group and in 34.7% of the
simvastatin monotherapy group (p=0.016).
Treating 50 patients with the combination for
seven years will prevent one cardiovascular event
compared to simvastatin alone (i.e., absolute risk
reduction 2%). The parts of the composite
endpoint that had the most impact on reducing it
were heart attack and stroke, which were nonfatal
endpoints. All-cause mortality was not affected.
Combination therapy dropped LDL from a mean
of 95 mg/dL (2.5 mmol/L) to 53 mg/dL
(1.4 mmol/L), compared to 70 mg/dL
(1.8 mmol/L) with simvastatin alone.12

Commentary
Last years new U.S. cholesterol guidelines
represented a paradigm shift in the treatment of
dyslipidemia. Moderate- or high-dose statins
were recommended based on cardiac risk, and
LDL was no longer the therapeutic target. This
was based on the fact that statin clinical outcome
trials used fixed statin doses, and did not target an
LDL goal.1 But not all experts agreed, and those
More. . .

Copyright 2015 by Therapeutic Research Center

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(PL Detail-Document #310101: Page 3 of 4)

experts now cite IMPROVE-IT as support for

their backing of a lower is better strategy in
which LDL goals are targeted.12 However, per the
new U.S. guidelines, simvastatin 40 mg is a
moderate-intensity statin, and is not commonly
used for secondary prevention.1,12 For secondary
prevention in adults 75 years and younger, a highintensity statin (e.g., atorvastatin 80 mg or 40 mg
[if 80 mg not tolerated] once daily or rosuvastatin
20 or 40 mg once daily) is recommended.1
Unfortunately, IMPROVE-IT did not test the
safety and efficacy of adding ezetimibe to a highintensity statin, or compare the combination to a
high-intensity statin alone.12 Others point out that
IMPROVE-IT did not reduce mortality, and
benefit was modest.12 IMPROVE-IT was not
designed to compare the benefits of specific LDL
targets. But it does support the concept put forth
in the guidelines that lower is better with proven
therapyshown to provide incremental benefit
thats safe.12
Several high-quality studies support specific
statin doses for reducing cardiovascular morbidity
and mortalilty.1

Levels of Evidence
In accordance with the trend towards Evidence-Based
Medicine, we are citing the LEVEL OF EVIDENCE
for the statements we publish.
Level
A

C
D

Adapted from Siwek J, et al. How to write an evidence-based

clinical review article. Am Fam Physician 2002;65:251-8.

Project Leader in preparation of this PL DetailDocument: Melanie Cupp, Pharm.D., BCPS

References
1.

Conclusion
Consider ezetimibe as a statin add-on for highrisk patients who cant tolerate a high-intensity
statin dose, or for high-risk patients who dont get
the expected 50% LDL reduction with a highintensity statin [Evidence level C; expert
opinion].1 IMPROVE-IT shows that ezetimibe
can provide modest benefit when added to a
moderate dose statin in a high-risk secondary
prevention population, particularly in regard to
heart attack and stroke prevention.12 Less benefit
might be expected in a lower-risk population.
U.S. subscribers can get our PL Chart, Lipid
Treatment FAQ, for practical pointers on helping
patients manage their cholesterol.
Canadian
subscribers, see our PL Chart, Canadian
Cardiovascular
Society
Dyslipidemia
Recommendations, for a summary of the 2012
guidelines.
Users of this PL Detail-Document are cautioned to use their
own professional judgment and consult any other necessary
or appropriate sources prior to making clinical judgments
based on the content of this document. Our editors have
researched the information with input from experts,
government agencies, and national organizations.
Information and internet links in this article were current as
of the date of publication.

Definition
High-quality randomized controlled trial (RCT)
High-quality meta-analysis (quantitative
systematic review)
Nonrandomized clinical trial
Nonquantitative systematic review
Lower quality RCT
Clinical cohort study
Case-control study
Historical control
Epidemiologic study
Consensus
Expert opinion
Anecdotal evidence
In vitro or animal study

2.

3.

4.

5.

6.

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. Circulation 2014;129(25
Suppl 2):S1-45.
Grundy SM, Cleeman JI, Merz CN, et al.
Implications of recent clinical trials for the National
Cholesterol Education Program Adult Treatment
Panel III guidelines. Circulation 2004;110:227-39.
Anderson TJ, Gregoire J, Hegele RA, et al. 2012
update of the Canadian Cardiovascular Society
guidelines for the diagnosis and treatment of
dyslipidemia for the prevention of cardiovascular
disease in the adult. Can J Cardiol 2013;29:15167.
The AIM-HIGH Investigators. The role of niacin in
raising high-density lipoprotein cholesterol to
reduce cardiovascular events in patients with
atherosclerotic
cardiovascular
disease
and
optimally treated low-density lipoprotein cholesterol
rationale and study design. The Atherothrombosis
Intervention in Metabolic syndrome with low
HDL/high triglycerides: Impact on Global Health
outcomes (AIM-HIGH). Am Heart J 2011;161:47177.
FDA statement on the AIM-HIGH trial. May 26,
2011.
http://www.fda.gov/Drugs/DrugSafety/Post
marketDrugSafetyInformationforPatientsandProvid
ers/ucm256841.htm.
(Accessed December 1,
2014).
Anderson TJ, Boden WE, Desvigne-Nickens P, et
al. Safety profile of extended-release niacin in the
AIM-HIGH trial. N Engl J Med 2014;371:288-90.

More. . .
Copyright 2015 by Therapeutic Research Center
3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
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(PL Detail-Document #310101: Page 4 of 4)

7.

PL Detail-Document, Does Ezetimibe ENHANCE

Lipid Therapy?
More Information from the
ENHANCE Trial. Pharmacists Letter/Prescribers
Letter. May 2008.
8. PL Detail-Document, Ezetimibe vs. Niacin for
Atherosclerosis: the ARBITER 6-HALTS study.
Pharmacists Letter/Prescribers Letter. December
2009.
9. Rossebo AB, Pedersen TR, Borman K, et al.
Intensive lipid lowering with simvastatin and
ezetimibe in aortic stenosis.
N Engl J Med
2008;359:1343-56.
10. FDA.
Follow-up to the August 2008 early
communication about an ongoing safety review of
ezetimibe/simvastatin (marketed as Vytorin),
simvastatin (marketed as Zocor) and ezetimibe
(marketed as Zetia)-FDA investigates a report from
the SEAS trial.
December 22, 2009.

http://www.fda.gov/Drugs/DrugSafety/PostmarketD
rugSafetyInformationforPatientsandProviders/Drug
SafetyInformationforHeathcareProfessionals/ucm1
94964.htm. (Accessed December 1, 2014).
11. Baigent C, Landray MJ, Reith C, et al. The effects
of lowering LDL cholesterol with simvastatin plus
ezetimibe in patients with chronic kidney disease
(Study of Heart and Renal Protection):
a
randomised placebo-controlled trial.
Lancet
2011;377:2181-92.
12. ORiordan M. IMPROVE-IT: Modest benefit when
adding ezetimibe to statins in post-ACS patients.
November
21,
2014.
http://www.medscape.com/viewarticle/835030?nlid
=70146_2562&src=wnl_edit_medp_card&spon=2.
(Accessed December 1, 2014).

Cite this document as follows: PL Detail-Document, Ezetimibes Role in Cardiovascular Risk Reduction.
Pharmacists Letter/Prescribers Letter. January 2015.

Evidence and Recommendations You Can Trust

3120 West March Lane, Stockton, CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249
Copyright 2015 by Therapeutic Research Center

Subscribers to the Letter can get PL Detail-Documents, like this one,

on any topic covered in any issue by going to www.PharmacistsLetter.com,
www.PrescribersLetter.com, or www.PharmacyTechniciansLetter.com

PL Detail-Document #310506
This PL Detail-Document gives subscribers
additional insight related to the Recommendations published in

PHARMACISTS LETTER / PRESCRIBERS LETTER

May 2015

Lipid Treatment FAQs

The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) lipid guidelines represent a paradigm shift in the treatment
of dyslipidemia. The 2015 American Diabetes Association Standards of Medical Care in Diabetes make similar recommendations. The guidelines
focus on reducing cardiovascular risk using moderate- or high-intensity statins. (See our PL Chart, 2013 ACC/AHA Cholesterol Guidelines, for a
list of high- and moderate-intensity statins.) Familiar tools such as LDL targets, nonstatin lipid medications, and the Framingham risk calculator
have fallen by the wayside for the most part. The chart below addresses common questions that arise in practice concerning the new thinking about
treatment of lipids.
Clinical Question
Should I still screen patients
for high cholesterol?

Suggested Approach
Assess traditional cardiovascular risk factors (e.g., lipids, blood pressure, diabetes) every four to six years in patients
20 to 79 years of age without atherosclerotic cardiovascular disease.2,6
Patients will be treated based on cardiovascular risk (see next box), not just lipid levels.1

How do I assess
cardiovascular risk to help
decide if a patient needs a
statin for primary
prevention?

For estimation of 10-year cardiovascular disease risk in patients 40 to 75 years of age without cardiovascular
disease, not receiving cholesterol-lowering therapy, with LDL 70 to 189 mg/dL, use the Pooled Cohort Equations
Cardiovascular Risk Calculator, available at http://my.americanheart.org/cvriskcalculator.1,2
This new calculator was introduced in the 2013 guidelines.
Evidence suggests that predicted risk with the new calculator and observed risk are similar.8
Obtain the patients age, sex, race, total and HDL cholesterol, systolic blood pressure, antihypertensive use,
presence of diabetes, and smoking status.2
Plug this information into the calculator. The 10-year cardiovascular risk can be used to help you determine
whether the patient needs a statin (see first box on next page).
Not all experts agree with its use. For example, the new calculator may overestimate risk in women. 13 See Can I
still use Framingham? below for information about alternative calculators.

Can I still use Framingham?

Use the Pooled Cohort Equations Cardiovascular Risk Calculator (the new calculator) for most patients.
The Pooled Cohort Equations Cardiovascular Risk Calculator was developed to be more clinically useful and
generalizable than Framingham.3

Framingham was based on data from whites, and was less precise in patients with diabetes. 4 For
development of the new calculator, large, diverse, contemporary, community-based, primary
prevention cohorts were used.3 Some of the Framingham cohorts were included.3 While Framingham

Continued

More. . .
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(PL Detail-Document #310506: Page 2 of 6)

Clinical Question
Can I still use Framingham,
continued

Suggested Approach
calculated the risk of coronary heart disease, the risk determined with the new calculator is the risk of
hard cardiovascular outcomes: coronary death, nonfatal MI, and fatal and nonfatal stroke. 3 These are
clinically relevant outcomes.3 Risk estimated with the new calculator does not include risk of
coronary heart disease alone, risk of revascularization, or risk of heart failure.3 The new calculator is
intended for use in both black and white men and women, with and without diabetes.3
Consider other risk calculators if they were developed in a patient population that more closely matches the patient
in question.5 For example, risk in a healthy, non-diabetic female nurse might be best represented by the Reynolds
Risk Score.5
See our PL Chart, Common Cardiovascular Risk Calculators, to help you choose the most appropriate calculator for
a given patient.

Who do I treat, and how?

First, determine which of the four statin benefit groups the patient fits into. This determines whether the patient
should be considered for high- or moderate-intensity statin therapy. The benefit groups and statin dosing are
delineated in our PL Chart, 2013 ACC/AHA Cholesterol Guidelines.
Briefly, a statin is recommended for patients with clinical atherosclerotic heart disease, LDL 190 mg/dL or
higher, or diabetes and age 40 to 75 years. For other patients age 40 to 75 years with an LDL of 70 to 189
mg/dL, 10-year cardiovascular risk determines if a statin is appropriate. In these patients, a 10-year risk of
7.5% is the point where the benefit of statins appears to exceed the risk.1
Discuss the benefits and risks of statin therapy with the patient BEFORE starting a statin, especially for
primary prevention.1
Start with the target dose in most patients; there is no proof that up-titrating improves tolerability.
It is prudent to use cautious dosing in patients more prone to statin side effects: those over 75 years of age,
those with a history of statin intolerance, and those taking interacting medications.7

What if a patient doesnt fit

into one of the four benefit
groups (see above)?

If there is clinical suspicion that such a patient may benefit from a statin, additional factors can be taken into
consideration.1 These are listed in footnote a at the end of the chart. See discussions below on patients <40 years
of age and those >75 years of age.

Should patients 21 to <40

years of age receive a statin?

A high-intensity statin (e.g., atorvastatin 80 mg) is recommended for patients with cardiovascular disease.1
A high-intensity statin is recommended for patients with LDL 190 mg/dL or higher.1
If a patient has diabetes, but no cardiovascular disease and LDL <190 mg/dL, individualize. Consider additional
factors (see footnote a). Discuss statin risks and benefits, lifestyle changes, and risk factor management.1
The American Diabetes Association suggests a high- or moderate-intensity statin for diabetes patients with
additional risk factors.10

Continued

More. . .
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(PL Detail-Document #310506: Page 3 of 6)

Clinical Question
Should patients
21 to <40 years of age
receive a statin,
continued

Which patients with diabetes

should receive a statin?

How should patients over

75 years of age be managed?

Suggested Approach
Discuss lifestyle changes (e.g., smoking cessation) and manage risk factors (e.g., control hypertension, diabetes).1,7
Patients with multiple risk factors or a single strong risk factor (see footnote a at the end of the chart) may opt to
try at least a moderate-intensity statin for primary prevention based on statin risks/benefits, and patient preferences.1
Use the Pooled Cohort Equations Cardiovascular Risk Calculator as a tool when discussing risk with patients. The
calculator provides lifetime risk calculation for 20 to 59-year-olds; 10-year risk may underestimate lifetime risk in
young patients.1,2
Ensure women taking a statin do not become pregnant.
For patients with cardiovascular disease, use high-intensity statin for most patients who can tolerate it.1,10 See
discussion below about patients over 75 years of age.1
For patients 40 to 75 years of age, with LDL 70 to 189 mg/dL (1.8 to 4.9 mmol/L) and an estimated 10-year risk of
atherosclerotic cardiovascular disease of less than 7.5%, use a moderate-intensity statin.1
American Diabetes Association guidelines suggest considering a moderate-intensity statin for patients 40 to
75 years of age without additional risk factors.10
American Diabetes Association guidelines suggest considering a high-intensity statin for patients ages 40 to
75 years with additional risk factors.10
The American Diabetes Association guidelines suggest a high- or moderate-intensity statin for patients <40 years
with additional risk factors.10
The American Diabetes Association guidelines suggest considering a moderate-intensity statin in diabetes patients
>75 years of age without additional risk factors.10 If additional risk factors are present, consider high-intensity.10
For secondary prevention, use a moderate-intensity statin.1
If the patient is already taking a high-intensity statin and tolerating it well, it can be continued.1
American Diabetes Association guidelines recommend a high-intensity statin for diabetes patients of all ages
with cardiovascular disease.10
For primary prevention, consider comorbidities, potential for harm, patient preferences and priorities, and 10-year
cardiovascular risk.1
The Pooled Cohort Equations Cardiovascular Risk Calculator can be used in patients 75 to 79 years of age.1
See footnote a for a list of factors to consider.
The American Diabetes Association guidelines suggest considering a moderate-intensity statin in diabetes
patients >75 years of age without additional risk factors.10 If additional risk factors are present, a highintensity statin can be considered.10
Discuss lifestyle changes (e.g., smoking cessation) and manage risk factors (e.g., control hypertension and
diabetes).1,7
If a statin is chosen, a high- or moderate-intensity statin is preferred.1
Consider stopping statins in patients with life expectancy <1 year, or advanced dementia.9,12
More. . .
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(PL Detail-Document #310506: Page 4 of 6)

Clinical Question
How should patients already
on a statin be managed?

Suggested Approach
Ensure most patients with atherosclerotic cardiovascular disease or LDL 190 mg/dL or higher are getting a highintensity statin.
For primary prevention patients, do not use the patients on-treatment lipid values in the calculator. If a patient is
already taking a cholesterol medication, use their pretreatment lipid values.4
Lipid treatment was not common in the cohorts used to develop the equation.3
If pretreatment lipids are not available, keep in mind that the risk calculator is only one piece of information used in
the decision to start a statin for primary prevention.5 Consider patient preferences, potential for harm, and potential
for benefit.5 Factors to consider besides those included in the risk calculator are listed in footnote a.
An alternative is to shoot for an LDL <100 mg/dL, based on statin outcome trials, especially in high-risk patients.7

How do I explain the new

thinking about lipids to
patients?
How should statin patients
be monitored?

Explain that studies looking at statin benefits used specific doses, and did not adjust therapy to meet specific
cholesterol goals.

What is the role of

nonstatins?

Continued

Check fasting lipid panel four to 12 weeks after statin initiation, then every three to 12 months. 1
If the LDL drop is less than expected, check adherence to the statin and lifestyle interventions. Expected
LDL reductions for each statin dose are delineated in our PL Chart, 2013 ACC/AHA Cholesterol Guidelines.
Consider statin dose reduction if two consecutive LDL measurements are less than 40 mg/dL.1
Check ALT (alanine aminotransferase) at baseline. Repeat only if symptoms of hepatotoxicity occur. 1
Document any pre-existing muscle symptoms before starting a statin to establish a baseline.1
Consider checking creatine kinase at baseline in patients at increased risk for myopathy (e.g., drug
interactions, etc). Repeat only if symptomatic.1
If severe muscle symptoms or fatigue of unknown cause develops, hold the statin and check creatine kinase,
creatinine, and urinalysis to rule out rhabdomyolysis.1
Do not routinely use nonstatins. Re-evaluate need in patients already on them.
The addition of a nonstatin to a statin has not been proven to further reduce cardiovascular mortality;
therefore, nonstatins are no longer routinely recommended.1,11
Adding a nonstatin to achieve a specific LDL goal could result in reduction in the statin to a suboptimal dose.1
Reinforce statin adherence and lifestyle changes and check for secondary causes before adding a nonstatin. 1
For patients who cannot tolerate the recommended statin dose or who do not achieve the expected statin response
and are high-risk at baseline (i.e., LDL 190 mg/dL or higher, diabetes, clinical atherosclerotic or cardiovascular
disease), consider a nonstatin [Evidence level C; expert opinion].1
For high-risk patients who cant tolerate a high-intensity statin, or who dont get the expected 50% LDL reduction,
suggest adding ezetimibe to a moderate-intensity statin. Theres no proof that adding other nonstatins (fibrates, etc)
More. . .
Copyright 2015 by Therapeutic Research Center
3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
www.PharmacistsLetter.com ~ www.PrescribersLetter.com ~ www.PharmacyTechniciansLetter.com

(PL Detail-Document #310506: Page 5 of 6)

Clinical Question
What is the role of
nonstatins,
continued

Suggested Approach
to a statin improves outcomes, and niacin worsens glycemic control.11
For triglycerides of 500 mg/dL or higher, an omega-3 fatty acid, niacin, or fenofibrate can be used.1
Do not add gemfibrozil to a statin.1

a. Additional factors to consider:1

LDL 160 mg/dL or higher or other evidence of genetic hyperlipidemia.

Cardiovascular disease onset in a first-degree male relative before age 55, or in a first-degree female relative before age 65.

High-sensitivity C-reactive protein 2 mg/L or higher.

Ankle-brachial index <0.9.

Elevated lifetime risk of atherosclerotic cardiovascular disease.

Coronary artery calcium (CAC) score 300 Agatston units or higher, or 75th percentile or higher for age, gender, and ethnicity.

Statin adverse effects.

Statin drug interactions.

Patient preferences.

Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making
clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national
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More. . .
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(PL Detail-Document #310506: Page 6 of 6)

5.

Levels of Evidence
In accordance with the trend towards Evidence-Based
Medicine, we are citing the LEVEL OF EVIDENCE
for the statements we publish.
Level
A

C
D

Definition
High-quality randomized controlled trial (RCT)
High-quality meta-analysis (quantitative
systematic review)
Nonrandomized clinical trial
Nonquantitative systematic review
Lower quality RCT
Clinical cohort study
Case-control study
Historical control
Epidemiologic study
Consensus
Expert opinion
Anecdotal evidence
In vitro or animal study

6.

7.

8.

Adapted from Siwek J, et al. How to write an evidence-based clinical

review article. Am Fam Physician 2002;65:251-8.

9.

Project Leader in preparation of this PL DetailDocument: Melanie Cupp, Pharm.D., BCPS

10.

References
1.

2.

3.

4.

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Cite this document as follows: PL Detail-Document, Lipid Treatment FAQs. Pharmacists Letter/Prescribers
Letter. May 2015.

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