310101

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 #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

(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 eight-

month 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




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 high-

intensity 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 high-

intensity 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

Conclusion Consider ezetimibe as a statin add-on for high-

risk patients who cant tolerate a high-intensity statin dose, or for high-risk patients who dont get the expected 50% LDL reduction with a high-

intensity 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.

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 Definition

A High-quality randomized controlled trial (RCT)

High-quality meta-analysis (quantitative

systematic review)

B Nonrandomized clinical trial

Nonquantitative systematic review

Lower quality RCT

Clinical cohort study

Case-control study

Historical control

Epidemiologic study

C Consensus

Expert opinion

D Anecdotal evidence

In vitro or animal study 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 Detail-

Document: Melanie Cupp, Pharm.D., BCPS

References 1. 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.

2. 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.

3. 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;29:151-67.

4. 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;161:471-77.

5. FDA statement on the AIM-HIGH trial. May 26, 2011. http://www.fda.gov/Drugs/DrugSafety/Post marketDrugSafetyInformationforPatientsandProviders/ucm256841.htm. (Accessed December 1, 2014).

6. 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.


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/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm194964.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 Suggested Approach

Should I still screen patients

for high cholesterol?

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?

Continued

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





Can I still use Framingham,

continued

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 75 years of age.

Should patients 21 to





Should patients

21 to 75 years of age without additional risk factors.

10 If additional risk factors are present, a high-

intensity 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





How should patients already

on a statin be managed? Ensure most patients with atherosclerotic cardiovascular disease or LDL 190 mg/dL or higher are getting a high-

intensity 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





What is the role of

nonstatins,

continued

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


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 Definition

A High-quality randomized controlled trial (RCT)

High-quality meta-analysis (quantitative

systematic review)

B Nonrandomized clinical trial

Nonquantitative systematic review

Lower quality RCT

Clinical cohort study

Case-control study

Historical control

Epidemiologic study

C Consensus

Expert opinion

D Anecdotal evidence

In vitro or animal study 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 Detail-

Document: Melanie Cupp, Pharm.D., BCPS

References 1. 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.

2. American Heart Association. 2013 Prevention Guidelines Tools. CV Risk Calculator. http://my.americanheart.org/cvriskcalculator. (Accessed April 12, 2015).

3. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25 Suppl 2):S49-73.

4. PL Detail-Document, Common Cardiovascular Risk Calculators. Pharmacists Letter/Prescribers Letter. January 2014.

5. Yancy CW, Harrington RA, Robinson JG. New cholesterol guidelines and CV risk calculator: controversy clarified. Medscape. January 29, 2014. http://www.medscape.com/viewarticle/819542_3. (Accessed April 12, 2015).

6. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25 Suppl 2):S76-99.

7. Stone NJ, Robinson JG, Lichtenstein AH, et al. Treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: synopsis of the 2013 American College of Cardiology/American Heart Association cholesterol guideline. Ann Intern Med 2014;160:339-43.

8. Muntner P, Colantonio LD, Cushman M, et al. Validation of the atherosclerotic cardiovascular disease Pooled Cohort risk equations. JAMA

2014;311:1406-15. 9. Tjia J, Briesacher BA, Peterson D, et al. Use of

medications of questionable benefit in advanced dementia. JAMA Intern Med 2014;174:1763-71.

10. American Diabetes Association. Standards of medical care in diabetes-2015. Diabetes Care 2015;38(Suppl 1):S1-94. http://professional.diabetes.org/admin/UserFiles/0%20-%20Sean/Documents/January%20Supplement%20Combined_Final.pdf. (Accessed April 7, 2015).

11. PL Detail-Document, Ezetimibes Role in Cardiovascular Risk Reduction. Pharmacists Letter/Prescribers Letter. January 2015.

12. Kutner JS, Blatchford PJ, Taylor DH, et al. Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial. JAMA Intern Med 2015 Mar 23. doi:10.1001/jamainternmed.2015.0289. [Epub ahead of print].

13. Cook NR, Ridker PM. Further insight into the cardiovascular risk calculator: the roles of statins, revascularizations, and underascertainment in the Womens Health Study. JAMA Intern Med 2014;174:1964-71.

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