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Health Care Guideline:

Lipid Management in Adults

Eleventh Edition

October 2009

I ICSINSTITUTE FOR CLINICAL

SYS TEMS IMPROVEMENT

The information contained in this ICSI Health Care Guideline is intended primarily for health profes-

sionals and the following expert audiences:

physicians,nurses,andotherhealthcareprofessionalandproviderorganizations;

healthplans,healthsystems,healthcareorganizations,hospitalsand integratedhealthcare

deliverysystems;

healthcareteachinginstitutions;

healthcareinformationtechnologydepartments;

medicalspecialtyandprofessionalsocieties;

researchers;

federal,stateandlocalgovernmenthealthcarepolicymakersandspecialists;and

employeebenetmanagers.

ThisICSIHealthCareGuidelineshouldnotbeconstruedasmedicaladviceormedicalopinionrelatedto

anyspecicfactsorcircumstances.Ifyouarenotoneoftheexpertaudienceslistedaboveyouareurged

toconsultahealthcareprofessionalregardingyourownsituationandanyspecicmedicalquestions

youmayhave.Inaddition,youshouldseekassistancefromahealthcareprofessionalininterpreting

thisICSIHealthCareGuidelineandapplyingitinyourindividualcase.

ThisICSIHealthCareGuidelineisdesignedtoassistcliniciansbyprovidingananalyticalframework

fortheevaluationandtreatmentofpatients,andisnotintendedeithertoreplaceaclinician'sjudgmentortoestablishaprotocolforallpatientswithaparticularcondition.AnICSIHealthCareGuideline

rarelywillestablishtheonlyapproachtoaproblem.

CopiesofthisICSIHealthCareGuidelinemaybedistributedbyanyorganizationtotheorganization's

employeesbut,exceptasprovidedbelow,maynotbedistributedoutsideoftheorganizationwithout

thepriorwrittenconsentoftheInstituteforClinicalSystemsImprovement,Inc.Iftheorganizationis

alegallyconstitutedmedicalgroup,theICSIHealthCareGuidelinemaybeusedbythemedicalgroup

in any of the following ways:

copiesmaybeprovidedtoanyoneinvolvedinthemedicalgroup'sprocessfordevelopingand

implementingclinicalguidelines;

the ICSI Health Care Guideline may be adopted or adapted for use within the medical grouponly,providedthatICSIreceivesappropriateattributiononallwrittenorelectronicdocuments;

and

copiesmaybeprovidedtopatientsandtheclinicianswhomanagetheircare,iftheICSIHealth

CareGuidelineisincorporatedintothemedicalgroup'sclinicalguidelineprogram.

AllothercopyrightrightsinthisICSIHealthCareGuidelinearereservedbytheInstituteforClinical

SystemsImprovement.TheInstituteforClinicalSystemsImprovementassumesnoliabilityforany

adaptationsorrevisionsormodicationsmadetothisICSIHealthCareGuideline.

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CHD or CHD equivalentand/or 10 -year risk> 20% LDL goal < 100 CHD goal consider < 70Initiate statin therapyand establish LDL goals

Laboratorymonitoring in3-12 months

Evaluation andmanagement of elevatedtriglycerides and/or low

HDL

LDL goal met?

9

Drug therapy Statin therapy management Aspirin/supplements

A

8

A

2+ risk factors and10-year CHD risk10-20%!LDL goal < 100!Initiate drug therapy

if LDL > 130 (optionalif LDL 100 -129)

6

2+ risk factors and10-year CHD risk < 10%!LDL goal < 130!Consider drug therapy

if LDL > 160 (optionalif LDL 130-159)

5

A

A

0-1 risk factor and 10-yearCHD risk < 10%!LDL goal < 160!Consider drug therapy if

LDL > 190 (optional if LDL160-189)

4

Address adherenceand lifestyle

modifications

10

HDL > 40and triglycerides

< 200?

11 14

A

12

A

7

no

no

Patient has dyslipidemiaor is at high risk for

coronary heart disease(CHD)

1

A

Calculate 10-year riskfor CHD or add upcardiac risk factors

3

A

yes

Health maintenance

13

A

yes

Initiate lifestylemodifications

2

A

Adjunctive measures See Annotation #2

15

Follow-up

16

A

A

Health Care Guideline:

Lipid Management in Adults

Eleventh Edition

October 2009

www.icsi.org

I ICSINSTITUTE FOR CLINICAL

SYS TEMS IMPROVEMENT

Copyright 2009 by Institute for Clinical Systems Improvement 1

A = Annotation

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Institute for Clinical Systems Improvement

www.icsi.org

2

Algorithms and Annotations .......................................................................................1-42

Algorithm ...........................................................................................................................1

Foreword

Scope and Target Population ......................................................................................... 3

Clinical Highlights and Recommendations .................................................................. 3

Priority Aims ................................................................................................................. 3

Key Implementation Recommendations ....................................................................... 3

Related ICSI Scientic Documents .............................................................................. 4Disclosure of Potential Conict of Interest................................................................... 4

Introduction to ICSI Document Development.............................................................. 4

Description of Evidence Grading.................................................................................. 5

Annotations ................................................................................................................... 6-17

Appendices .................................................................................................................. 18-42

Appendix A Omega-3 Fatty Acids ...................................................................... 18-19

Appendix B Identied Secondary Causes and Conditions Associatedwith Hyperlipidemia ...............................................................................................20

Appendix C Drug Companion Document........................................................... 21-41Appendix D NCEP Recommendations on Strategies to Improve Adherence ..........42

Supporting Evidence....................................................................................................43-65

Brief Description of Evidence Grading............................................................................44

References ...................................................................................................................45-50

Conclusion Grading Worksheets .................................................................................51-65

Conclusion Grading Worksheet A Annotation #8 (Risk Factors

and Lipid-Lowering Therapy) ...........................................................................51-58

Conclusion Grading Worksheet B Annotation #8

(History of CHD) ..............................................................................................59-65

Support for Implementation ..................................................................................... 66-72

Priority Aims and Suggested Measures ............................................................................ 67

Measurement Specications .................................................................................. 68-69

Key Implementation Recommendations .......................................................................... 70

Knowledge Resources ...................................................................................................... 70

Resources Available.......................................................................................................... 71

Shared Decision-Making Resources ................................................................................ 72

Table of Contents

Lipid Management in AdultsEleventh Edition/October 2009

Work Group LeaderTony Woolley, MD

Internal Medicine, Park

Nicollet Health ServicesWork Group MembersCardiology

Stephen Kopecky, MD

Mayo Clinic

Thomas Kottke, MD

HealthPartners Medical

Group

Family Medicine

Patrick O'Connor, MD

HealthPartners Medical

Group

Health Education

Susan Hanson, RDPark Nicollet Health

Services

Internal Medicine

William Conroy, MDPark Nicollet Health

Services

Denise Dupras, MDMayo Clinic

Phillip Kofron, MD, MPH

Park Nicollet Health

Services

Robert Needham, MDLakeview Clinic

Nursing

Deb J. Johnson, MSN

Marsheld Clinic

Pharmacy

Mikel K. Bofenkamp,

PharmD

Park Nicollet Health

Services

Sarah Groen, PharmDHealthPartners Medical

Group

FacilitatorsKathy Cummings, RN, BSN,

MA

ICSI

Linda Setterlund, MS, CPHQICSI

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Foreword

Scope and Target Population

This guideline describes the treatment of adults age 20 and older who are dyslipidemic.

Clinical Highlights and Recommendations

Initiate a statin with patients who have a history of CHD or CHD risk equivalent. (Annotation #8)

Establish lipid goals based on risk level. (Annotation #3)

Instruct patients on healthy lifestyle and adjunctive measures. (Annotation #2)

Patient adherence with recommended therapy should be reinforced during scheduled follow-up. (Anno-

tations #13, 16)

LDL goal less than 70 can be considered for patients with established CAD, non-cardiac atherosclerosis

or coronary artery disease equivalent. (Annotation #9)

Priority Aims

1. Increase the percentage of patients with CHD or whose 10-year risk is greater than 20% who are on a

statin.

2. Improve the percentage of patients with or without CHD who meet their lipid treatment goals.

3. Increase adherence with adjunctive treatment of patients with CHD or CHD risk equivalent through

education.

4. Improve the percentage of patients on lipid-lowering medication who receive regular follow-up care

for lipid disorder.

5. Increase the percent of patients on lipid-lowering therapy who remain on therapy.

Key Implementation Recommendations

The following system changes were identied by the guideline work group as key strategies for health care

systems to incorporate in support of the implementation of this guideline.

General Implementation Principles

Prior to implementation, it is important to consider current organizational infrastructure that addresses the

following:

1. System and process design

2. Training and education

3. Culture and the need to shift values, beliefs and behaviors of the organization.


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Related ICSI Scientic Documents

Guidelines

Diagnosis and Treatment of Chest Pain and Acute Coronary Syndrome (ACS)

Heart Failure in Adults

Hypertension

Diagnosis and Treatment Management of Type 2 Diabetes Mellitus

Stable Coronary Artery Disease

Preventive Services for Adults

Primary Prevention of Chronic Disease

Disclosure of Potential Conict of Interest

ICSI has adopted a policy of transparency, disclosing potential conict and competing interests of all indi-viduals who participate in the development, revision and approval of ICSI documents (guidelines, order

sets and protocols). This applies to all work groups (guidelines, order sets and protocols) and committees(Committee on Evidence-Based Practice, Cardiovascular Steering Committee, Women's Health Steering

Committee, Preventive & Health Maintenance Steering Committee and Respiratory Steering Committee).

Participants must disclose any potential conict and competing interests they or their dependents (spouse,

dependent children, or others claimed as dependents) may have with any organization with commercial,

proprietary, or political interests relevant to the topics covered by ICSI documents. Such disclosures will

be shared with all individuals who prepare, review and approve ICSI documents.

Steven L. Kopecky MD is a consultant for Bayer, Fibrex, ParinGenix, Pinnacle Care, Prime Therapeutics

and has received grant research support from AtherGenics, Integrium and Reliant.

Patrick J. O'Connor MD has received research funding from AHRQ, NHLBI, NIPPIS and NIA. All grant

monies go to the HealthPartners Research Foundation. He also is a member of American Diabetes Asso-

ciation.

No work group members have potential conicts of interest to disclose.

Introduction to ICSI Document Development

This document was developed and/or revised by a multidisciplinary work group utilizing a dened process

for literature search and review, document development and revision, as well as obtaining input from and

responding to ICSI members.

For a description of ICSI's development and revision process, please see the Development and Revision

Process for Guidelines, Order Sets and Protocols at http://www.icsi.org.

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Evidence Grading System

A. Primary Reports of New Data Collection:

Class A: Randomized, controlled trial

Class B: Cohort study

Class C: Non-randomized trial with concurrent or historical controls

Case-control study

Study of sensitivity and specicity of a diagnostic test

Population-based descriptive study

Class D: Cross-sectional study

Case series

Case report

B. ReportsthatSynthesizeorReectUponCollectionsofPrimaryReports:

Class M: Meta-analysis

Systematic reviewDecision analysis

Cost-effectiveness analysis

Class R: Consensus statement

Consensus report

Narrative review

Class X: Medical opinion

Citations are listed in the guideline utilizing the format of(Author, YYYY [report class]). A full explanation

of ICSI's Evidence Grading System can be found at http://www.icsi.org.

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Algorithm Annotations

1. Patient Has Dyslipidemia or Is at High Risk for Coronary Heart

Disease (CHD) Secondary causes of abnormal lipid levels should be considered and treated when appropriate.

Patients with a history of non-coronary atherosclerosis (including carotid occlusive vascular disease,

abdominal aortic aneurysm, or peripheral vascular disease) or who have diabetes are at high risk for

CHD and are considered CHD risk equivalent.

See Appendix B, "Identied Secondary Causes and Conditions Associated with Hyperlipidemia."

2. Initiate Lifestyle ModicationsDiet and exercise are the cornerstones of treatment for asymptomatic patients with dyslipidemia (Stefanick,

1998 [A]). Patients with an elevated LDL-cholesterol level should begin the Therapeutic Lifestyle Changes

program and an individualized program of regular exercise. A diet low in saturated and transfats, and high

in soluble ber, consideration given to adding 2 grams plant sterol/stanol is recommended.

Patients who are overweight should be advised to reduce their calorie intake to achieve weight

loss.

Patients should follow the diet and exercise program for a reasonable amount of time to determinewhether their LDL-cholesterol level is lowered to the target range. For many asymptomatic patients,

a diet and exercise program is sufcient.

Lifestyle modications include diet; aerobic exercise; weight management; smoking cessation; evaluation

of alcohol consumption; and a nutritional supplement containing sitostanol ester, a saturated derivative of a

plant seed oil (EPA-DHA). The addtion of two grams plant sterol/stanol can effectively lower LDL. To avoid

unintended toxic effects from vitamins, patients should be cautioned not to exceed recommended doses.

Vitamin E supplements should not be used. Studies have shown no benet in preventing clinical outcomes,

and smaller studies suggest a blunting of the benet from antidyslipidemic medications on HDL-C and

angiographic progression of vascular disease (Brown, 2001 [A]; Cheung, 2001 [A]).

Please refer to Appendix A, "Omega-3 Fatty Acids," and Appendix C, "Drug Companion Document," for

additional information.

Other management strategies, therapeutic lifestyle change (TLC), may include the following.

Diet

The evidence in the literature and the NCEP Adult Treatment Panel Consensus Position suggest that adults

with elevated lipids, CHD or CHD risk equivalent should be following the ATP III Therapeutic Lifestyle

Changes (TLC) diet or something more aggressive.

The TLC diet lowers saturated fat to less than 7% of calories avoiding trans fat, limiting dietary cholesterol

to less than 200 mg/day and adds dietary options such as 2 grams/day plant stanols/sterols and at least

5-10 grams/day viscous soluble ber to enhance LDL lowering, and has an increased emphasis on weightmanagement and physical activity.

It is desirable to have the assessment and education for these individuals carried out by a registered dieti-

tian when possible (Arntzenius, 1985 [B]; Blankenhorn, 1990 [B]; LaRosa, 1990 [R]; Ornish, 1990 [A];

Schuler, 1992 [A]; Stefanick, 1998[A]; Summary of the Second Report of the National Cholesterol Educa-

tion Program, 1993 [R]).


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Aerobic exercise

Many cross-sectional studies demonstrate a more favorable lipoprotein prole in men and women who aremore active and physically t when compared to those who are sedentary.

The strongest evidence comes from the National Runner's Health Study (NRHS), which included men and

women who responded to a questionnaire assessing health habits. Lipid data was obtained from physiciansand compared to running distance. Increasing distance correlated with increased benecial lipid effects,

including decreases in LDL-cholesterol and triglycerides, along with an increase in HDL-cholesterol.

These effects were also correlated with the "leanness" of the individual (Berg, 1994 [R]; Pronk, 1993 [R];

Stefanick, 1998 [A]).

The evidence from cross-sectional studies in men suggest that aerobic exercise may induce an increase of5%-10% in HDL-cholesterol, primarily the HDL2 subfraction, and decrease the triglycerides. Additionally,

some studies found a decrease in LDL-cholesterol and total cholesterol. These changes are dependent on the

intensity and frequency of physical activity. Short-term studies show that baseline tness affects the lipid

response to exercise. Changes in lipids induced by a single exercise session persist about 48 hours, which

has implications for the timing of lipid testing (Williams, 1997 [D]).

Interpretation of the data from some studies of exercise in women is complicated by the lack of controlof the hormonal status. In the NRHS study of women runners, HDL-cholesterol increased irrespective ofmenstrual status. Interestingly, women using oral contraceptives in this study had a blunted increase in

HDL-cholesterol induced by exercise. Not only whether an individual is menopausal, but also the timing

of the studies relative to the menstrual cycle affect the outcome. Cross-sectional studies continue to show

a benecial effect in HDL-cholesterol; however, interventional studies in pre- and postmenopausal women

fail to consistently show a signicant change in HDL-cholesterol (Taylor, 1993 [R]; Williams, 1996 [D]).

Weight management

Overweight and obesity increase the risk for cardiovascular disease and adversely affect plasma lipids.

Each 1 kg increase in body weight has been observed to increase plasma triglycerides by 1.04% and decreaseHDL-cholesterol by 0.83%.

Conversely, decreases in body weight and body fat are associated with favorable changes in cardiovascular

risk factors, including increased HDL-cholesterol concentrations and decreased total cholesterol, LDL-cho-

lesterol and triglyceride concentrations. Every 1 kg decrease in body weight has been observed to decrease

triglycerides by 0.77%-0.87% and increase HDL-cholesterol by about 1%.

Weight management should be considered an important component of interventions intended to maximize

lipid management and reduce risk of cardiovascular disease (Denke, 1999 [R]).

Smoking cessation

As well as being an independent risk factor for the development of CHD, cigarette smoking is associatedwith changes in the lipoprotein distribution and other metabolic factors that promote atherogenesis.

Nicotine stimulation of sympathetic nervous system activity results in elevation of plasma free fatty acidsand very low density lipoproteins. Smoking also clearly reduces HDL-cholesterol and may reduce HDL-

cholesterol antiatherogenic effects by altering its composition.

Smoking cessation trials have documented a signicant rise in HDL-cholesterol after smoking cessation.

Cigarette smoking in women is associated with earlier menopause and lower estrogen levels, which contribute

to an increased CHD risk (Billimoria, 1975 [C]; McBride,1992 [R]; Schefer, 1992 [C]).

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Evaluation of alcohol consumption

Light to moderate consumption of alcohol has been associated with lower coronary heart disease rates.

This is dened as no more than one drink per day for women or two drinks per day for men. One drink is

dened as twelve ounces of regular beer, ve ounces of wine or one and one-half ounce of distilled spirits

(80 proof).

Alcohol may help protect against heart disease by raising levels of HDL-cholesterol. Risks for CHD, hyper-

triglyceridemia, pancreatitis, hypertension and cardiomyopathy may increase in women who consume morethan one drink per day and for men who consume more than two drinks per day.

Alcohol consumption should be avoided by women who are pregnant or trying to conceive, individuals

operating a motor vehicle or other equipment, individuals taking prescription or non-prescription medication,

recovering alcoholics, and those with a history of chemical dependency. Most authorities do not recommend

initiation of alcohol consumption for non-drinkers with lipid disorders (Criqui, 1990 [R]; Jackson, 1993

[R]; Klatsky, 1981 [B]; Rimm, 1996 [R]).

Sterol and stanol ester nutritional supplement

Clinical studies in men and women with Type 2 diabetes mellitus, hyperlipidemia, and known CHD have

shown that sitostanol ester, a saturated derivative of a plant sterol, can lower total cholesterol and LDL-cholesterol approximately 10%.

It has no signicant effect on HDL-cholesterol and triglyceride levels.

The primary mechanism is blockage of cholesterol absorption. One small randomized study of women

demonstrated an additive effect of sitostanol in combination with simvistatin. Caution should be exercised in

patients on medications because of limited information about drug interactions(Grundy, 2005 [R]; Gylling,

1994 [C]; Gylling, 1997 [A]; Miettinen, 1995 [A]; Vanhanen, 1993 [A]).

Fish oil (EPA-DHA)

Omega-3 fats are found in some fatty sh and in some plant sources, such as walnuts, canola and soybean oils,

and axseed. They do not affect LDL levels but may help protect the heart in other ways. In some studies,people who ate sh had a reduced death rate from heart disease. It is possible that this is related to the effects

of omega-3 fats, which may help prevent blood clots from forming and inammation from affecting artery

walls. Omega-3 fats also may reduce the risk for heart rhythm problems and, at high doses, reduce triglyc-

eride levels. Studies have suggested that omega-3 fats reduce the risk for heart attack and death from heart

disease for those who already have heart disease (National Cholesterol Education Program, 2001 [R]).

The recommended daily amount of omega-3 fatty acids in patients with dyslipidemia is 1 gram of EPA/DHA

by capsule supplement, or by eating at least two servings per week of fatty sh. Studies show that 1.5 gramsof ALA or more per day from plant sources is associated with a 40%-65% reduced risk of death from cardiac

events. The amounts of omega-3 fatty acids in various foods are found in the table in Appendix A, "Omega-3

Fatty Acids." Plant-based sources of omega-3 fatty acids would be ground ax seed, ax seed oil, walnut

oil, canola oil and soybean oil. Fish meals can be difcult for patients to maintain, and there are issues of

potential environmental contaminants including mercury, PCBs, dioxin and others. Because of this, capsulesupplements may be preferred, although there is no uniformity of EPA/DHA content or purity. Patients should

consult their health providers or nutritionists regarding this issue (Kris-Etherton, 2002 [R]).

Dietary and non-dietary intake of n-3 polyunsaturated fatty acids may reduce overall mortality and sudden

death in patients with stable CAD (Bucher, 2002 [M]).

See the ICSI Stable Coronary Artery Disease guideline for more information.


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3. Calculate 10-Year Risk for CHD or Add Up Cardiac Risk FactorsThe National Cholesterol Education Program Adult Treatment Panel III (ATP III) denes high risk as a net

of two or more (CHD) risk factors, which leads to more vigorous intervention (National Cholesterol Educa-

tion Program, 2001[R]). Identied risk factors are:

Age 45 years or older for men; age 55 years or older for women. CHD rates are higher in the elderlythan in the young, and in men more than in women of the same age.

A family history of premature CHD, dened as denite myocardial infarction (MI) or sudden death

before age 55 in the father or a male primary relative, or before age 65 in the mother or a female

primary relative.

Currently smoking.

Hypertension, dened as blood pressure greater than 140/90 mmHg (conrmed by measurement

on several occasions) or current use of any antihypertensive medication.

Low HDL-cholesterol level (less than 40 mg/dL).

Emerging nontraditional risk factors such as C-reactive protein (CRP) and total homocysteine have been

shown to have some predictive values in screening vascular disease. The value of screening for these risk

factors is not yet known.

A cardiac risk calculator based on the Framingham study can be accessed through the following Web site:

http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof

Obesity and physical inactivity are not listed as risk factors, but should be considered as targets for interven-

tion. Obesity operates through other risk factors (hypertension, hyperlipidemia, decreased HDL-cholesterol

and diabetes mellitus).

If HDL-cholesterol is 60 mg/dL or higher, one risk factor may be subtracted because high HDL-cholesterol

levels decrease CHD risk. (For example, if a patient has three risk factors but his or her HDL-cholesterollevel is 60 mg/dL or higher, one risk factor is subtracted, leaving a total of two risk factors.)

Family history

Family history of coronary artery disease was identied as a risk factor by the National Cholesterol Educa-

tion Program (NCEP) in an attempt to screen for heterozygous familial hypercholesterolemia, as well as

other genetically predisposed populations to coronary disease. Heterozygous familial hypercholesterolemia

affects 1 in 500 persons in the United States, with the risk of death from coronary artery disease increased

almost fourfold between the ages of 20 and 74. (Myocardial infarction leading to sudden death often occurs

in these men in their 30s or 40s, and by age 50, 80 percent of males have ischemic heart disease.) Withoutintervention, approximately 50%-75% of men with heterozygous familial hypercholesterolemia will have

a myocardial infarction by age 60. Thompson showed the prevalence of coronary disease in men at age 35

equalled that in women at age 40 in contrast to the typical 10-year lag between men and women.

(Bild, 1993 [R]; Goldstein, 1989 [R]; Scientic Steering Committee on behalf of the Simon Broome Register

Group,1991 [R]; Thompson, 1989 [R]; Williams, 1986 [D]; Yamamoto, 1989 [D])

C-reactive protein (CRP), if measured by high-density lipoprotein, may have an independent value as a

predictor of cardiovascular disease risk and independent value in identifying patients with normal lipids

who could benet from treatment (Albert, 2002 [C]).


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8. Drug TherapyThe decision to begin drug therapy must be based on a clinical discussion with the patient in which the

evidence-based outcome data, possible side effects, and cost are weighed.

No primary prevention studies have addressed pharmacologic lipid treatment in persons at low risk for CHD,

and there is no evidence to support drug treatment in this population. In particular, the incidence of CHD inmen under 40 and premenopausal women is very low, and drug treatment in these groups is discouraged.

Primary prevention studies of pharmacologic lipid lowering have not shown a decrease in mortality,

although most studies have shown about a 30% reduction in CHD events. Study populations have consisted

predominately of middle-aged men, some with other risk factors. Similar benet in higher-risk women can

be assumed but has not been demonstrated.

The LDL threshold for drug therapy is consistent with ATP-III. However, in particular cases, drug therapy

may be considered at LDL thresholds 30 mg/dL lower than noted in Annotation boxes #4-7.

Please refer to Appendix C, "Drug Companion Document."

Table 7: Absolute Risk Reduction and Number Needed to Treat (NNT) with Pharmacologic Lipid

Lowering

10-year* risk for

CHD

Events

prevented/1,000

patients treated

NNT to prevent one

event over five years

35% 105 9.5

30% 90 11

25% 75 13

20% 60 17

15% 45 19

10% 30 335% 15 67

2.5% 7.5 133

The NNT can be presented to the patient as the number of people who would have to take medication for

ve years to prevent a non-fatal heart attack. (The major primary prevention studies have been four- to six-

year studies.) For example, if the NNT is 13, then 1 of 13 patients would benet from treatment and 12 of

13 would not.

* Assumes 30% risk reduction


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Table 8: Primary Prevention for CHD

Therapy Population NNT over 5 years Trial

Statin Men > 45 40 WOSCOPS

Statin Men > 45 and HTN 24 WOSCOPS

Statin Men > 45 and FHx 23 WOSCOPS

Statin Men > 45/Women > 55 with

HDL-cholesterol

< 50, LDL-cholesterol

> 130

50

AFCAPS

Aspirin Men > 50 63 NEJM 321:129, 1989

* The literature supports a dose of aspirin between 81 mg and 162 mg.

(Downs, 1998 [A]; Frick, 1987 [A]; Levy, 1993 [R]; Lipid Research Clinics Program, 1984 [A]; Shepherd,

1995 [A]; Physicians Health Study, 1989 [A]; Ridker, 2008 [A]; West of Scotland Coronary Prevention

Group, 1998 [A])

Statin Therapy Management

Patients with risk factors for coronary heart disease but no history of disease who receive lipid-lowering

therapy are likely to experience a decreased risk of coronary heart disease. [Conclusion Grade I: See

Conclusion Grading Worksheet A Annotation #8 (Risk Factors and Lipid-Lowering Therapy)] (ALLHAT,

2002 [A]; Downs, 1998 [A]; Frick, 1987 [A]; Heart Protection Study Collaborative Group, 2002 [A]; Lipid

Research Clinics Program, 1984 [A]; Pignone, 2000 [M]; Sever, 2003[A]; Shepherd, 2002 [A]; Shepherd,

1995 [A]).

Patients with a history of coronary disease (including unstable angina and acute myocardial infarction) often

benet from treatment with a statin. Studies have consistently shown a decrease in risk of death from coro-

nary heart disease [Conclusion Grade I: See Conclusion Grading Worksheet B Annotation #8 (History of

CHD)] (Cannon, 2004 [A]; Goldberg, 1998 [A]; Heart Protection Collaborative Study, 2002 [A]; LaRosa,

1999 [M]; LIPID Study Group, 1998 [A]; Nissen, 2004 [A]; Scandinavian Simvastatin Survival StudyGroup, 1994 [A]; Shepherd, 2002 [A]).

Specic statin and dose should be selected based on cost and amount of lipid-lowering required. SeeAppendix C, "Drug Companion Document," for additional information.

Thus, for care of patients with established CHD or CHD risk equivalent (which includes occlusive carotid

disease, peripheral vascular disease, abdominal aortic aneurysm, or diabetes), the use of statin therapy is

recommended.

Bedtime or evening dose of statin is more effective (higher cholesterol synthesis).

To maximize absorption, lovastatin needs to be taken with food, but lovastatin SR should be taken

on an empty stomach.

Use of brates in conjunction with thiazolidinediones may cause an major decrease in HDL levels insome patients. It may be advisable to check an HDL value 1-2 months after initiating this combina-

tion of medications (Mymin, 2009 [D]; Normen, 2004 [D]).

Dosage adjustments should not be made more often than every four weeks after a fasting lipid

panel.

Please consult manufacturer's product label insert, PDR, etc., for full prescribing information.


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Safety Considerations in Prescribing Statins in Primary Care Settings

DO

c Check baseline renal function and thyroid function (TSH) prior to initiating statin therapy.

c Check ALT or AST levels prior to prescribing a statin and after any planned increase in statin dose.

c Consider the potential for drug-drug interactions when prescribing statins. Vitamin E intake may reduce

the benet of statins.

c Be alert for patient characteristics that may increase the risk for myopathy during statin therapy, such as

advanced age (particularly elderly women), renal or liver impairment, diabetes with evidence of hepatic

fatty changes, hypothyroidism, drugs of abuse (amphetamines, phencyclidine, heroin, cocaine), surgery,

trauma, ischemia-reperfusion, debilitated status, excessive alcohol intake, heavy exercise.

c Provide patient education regarding recognition and reporting of symptoms of myopathy during statin

therapy.

c Counsel patients to discontinue statin therapy during a short course of a macrolide or ketolide antibiotic

(e.g., azithromycin, clarithromycin, erythromycin, or telithromycin).c Suspect myopathy when a statin-treated patient complains of unexplained, generalized muscle pain,

tenderness or weakness. Joint pain, nocturnal leg cramps, or localized pain are not symptoms of

myopathy.

c Check CK levels when a patient reports symptoms of myopathy.

c If CK levels are less than ve times upper limit of normal, repeat measurement in one week.

c If CK levels are elevated to ve times upper limit of normal or greater, discontinue statin therapy and

monitor serum CK levels.

c Assess for signs of dehydration or renal compromise in patients with myopathy.

c Consider referral for patients requiring combination lipid-lowering therapy, or document the need forthis therapy, such as lack of response to monotherapy in a high-risk patient.

c When adding a statin to the regimen of a patient already receiving a brate, initiate at the lowest starting

dose of statin.

c Consider the differences in pharmacokinetic proles among statins, particularly in patients requiring

long-term therapy with drugs that are CYP3A4 substrates, inhibitors or both.

DON'T

c Prescribe statin-brate combination therapy in patients with the following conditions: impaired liver or

renal function (creatinine level greater than 2.0 mg/dL), cyclosporine or tacrolimus therapy, long-term

macrolide antibiotic therapy or azole antifungal therapy, advanced age (greater than 70 years), skeletal

muscle conditions.

c Prescribe high-dose statin therapy for elderly patients and patients with renal insufciency, or in combi-

nation with brates or cyclosporine.

c Vitamin E may reduce the benet of statins or of statin-niacin combination therapy. Vitamin E does notappear to reduce the risk of major cardiovascular events.


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c Use of brates in conjunction with thiazolidinediones may cause an major decrease in HDL levels in

some patients. It may be advisable to check an HDL value 1-2 months after initiating this combination

of medications.

(Ballantyne, 2003 [R]; Heart Protection Study Collaborative Group, 2002 [A])

Statin Safety and the Muscle

Denitions

Myalgia

Myalgia is dened as pain or soreness and/or weakness in skeletal muscles in the absence of serum creatinine

elevation. Symptoms of myalgia are quite variable and include cramping, pain, aches, tenderness, soreness,stiffness, heaviness, and weakness either at rest or only during physical exertion. Muscle cramping at night

only is not likely statin related.

Myopathy

Myopathy is dened as complaints of myalgia, plus elevation in serum CK (creatinine kinase) greater than

10 times the upper limit of normal (ULN).

Rhabdomyolysis

Rhabdomyolysis is dened as CK elevation > 10,000 U/L, in accord with the denition currently used by

the FDA, regardless of whether the patient has experienced a change in renal function, because such a CK

level places the patient at high risk for acute renal failure. A second component is CK > 10X the ULN withworsening renal function and/or a requirement for medical intervention with intravenous hydration therapy,

along with myalgia.

Incidence

Incidence of muscle symptoms or signs (CK = creatinine kinase elevations) is the most prevalent and

important adverse effect of statin therapy. The occurrence of serious muscle toxicity with currently marketed

statins is rare.

Myopathy occurs in ve patients per 100,000 person-years (in clinical trials, the rate is 1.5%-3.0%, most

often without CK elevation and at an equivalent rate in patients given placebo). In the practice setting, the

range is 0.3%-33%. The higher rate may occur partly because statin-intolerant patients and high-risk patientsare likely to be excluded from clinical trials.

Rhabdomyolysis occurs in 1.6 patients per 100,000 person-years.

Recommendations regarding statin safety and muscle symptoms

1. Muscle symptoms or increased CK due to statin therapy is rare. Rule out other causes including

increased physical activity, trauma, falls, accidents, seizure, shaking chills, hypothyroidism, infec-

tions, carbon monoxide poisoning, polymyositis, dematomyositis, alcohol abuse and drug abuse

(cocaine, amphetamines, heroin or PCP).

2. Baseline pretreatment CK levels are not necessary except in high-risk patients. Risk factors for

muscle toxicity include advanced age and frailty, small body frame, deteriorating renal function,

infection, untreated hypothyroidism, interacting drugs, perioperative patients and alcohol abuse.

3. It is not necessary to measure CK levels in asymptomatic patients during treatment. Marked increases

are rare and usually related to physical exertion or other causes.


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4. Patient education regarding the muscle symptoms to watch for and report is essential for all patients

taking statins.

5. Measure CK levels in symptomatic patients to help decide whether to continue therapy or alter

dose.

6. Discontinue statin in patients with intolerable muscle symptoms with or without CK elevation whenother etiologies are ruled out.

Once asymptomatic, resume the same or different statin at the same or lower dose. Recurrence ofsymptoms with multiple statins and doses requires initiation of other lipid-altering therapy.

Patient counseling regarding intensication of therapeutic lifestyle changes (reduced intake of

saturated fats and cholesterol, increased physical activity, and weight control) should be an integral

part of management in all patients with statin-associated intolerable muscle symptoms.

7. If patient is asymptomatic or has tolerable muscle complaints but CK less than 10X the ULN,

continue statin at same or lower dose while monitoring symptoms.

8. If patient develops rhabdomyolysis (CK greater than 10,000 IU/L or CK greater than 10X the ULN

with elevation in serum creatinine, OR requiring IV hydration therapy), stop statin. Hospitalizationmay be required. Once recovered, the risk vs. benet of therapy should be carefully reconsidered.

(Jacobson, 2008 [R]; McKenney, 2006 [R])

PatientsUnabletoUseStatinTherapy

Myalgias are common in patients with statins; however, the cause and effect relationship is unclear. We

recommend trying other statins or lowering the dose. Consider a 10- to 14-day vacation from statins and

see if the myaligia symptoms abate as a diagnostic maneuver. The evidence is inconclusive at this time for

treating myalgia with Vitamin D and coenzyme Q.

If patients are intolerant to a statin, clinicians are encouraged to have the patient try the other statins in

reduced doses before ruling out all statins.

If patients are unable to take a statin, then bile-acid sequestrants, niacin, bric acid derivatives or brates,

and ezetimibe are available. In the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT),cholestyramine 24 grams/day showed a 10% reduction in risk of fatal and non-fatal MI. Adherence in this

study varied, but a linear relationship was seen with reduction in CHD risk corresponding to cholestyramine

dose and reduction in LDL-cholesterol (Lipid Research Clinics Program, 1984 [A]).

In the Coronary Drug Project, niacin 3 grams/day reduced mortality 11% over placebo. There are also studies

with angiographic endpoints that showed benets of bile-acid sequestrants alone and in combination with

niacin (Coronary Drug Project Research Group, The, 1975 [A]).

The VA-HIT trial, utilizing gembrozil 600 mg twice daily, showed a 22% reduction in the combined inci -

dence of CHD death and non-fatal MI.

The ENHANCE study evaluated simvastin with and without ezetimibe on carotid intima-media thicknessin familia hyperlipidemic patients and did not nd a signicant difference after 24 months in this surrogate

endpoint, though the LDL was signicantly lower with combination therapy (Kastelein, 2005 [A]).

The SEAS study, while not showing a difference in aortic stenosis progression with combination therapy,

did show a signicant reduction in the secondary endpoint of non-fatal ischemic events in the simvastin/

ezetimibe-treated group compared to placebo after 52 months (Rossebo, 2008 [A]).


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Aspirin

Aspirin irreversibly inhibits platelet cyclooxygenase and impairs platelet aggregation in doses as low as60 mg every other day. A clinical history of bleeding diathesis, active ulcer disease or aspirin allergy is a

major contraindication. Dosage appears unimportant, usually ranging from 60 mg every other day up to

325 mg daily.

Secondary prevention

Secondary prevention trials with aspirin have demonstrated reduced cardiovascular and cerebrovascular

endpoints. A meta-analysis of over 70,000 patients with arterial disease or risk factors for arterial disease

reported a 25% decrease in vascular events and an 18% decrease in vascular deaths with aspirin-based

antiplatelet therapy (Antiplatelet Trialists' Collaboration, 1994 [M]).

Primary prevention

Primary prevention studies in patients not selected for cardiovascular risk factors have shown minimal

benet. Some studies have shown reduced non-fatal myocardial infarction, but this was not supported by

meta-analysis (Eidelman, 2003 [M]; Hayden, 2002 [M]; Nowak, 2003 [R]).

Patients with hyperlipidemia are at intermediate risk and may derive greater benet from aspirin than thelower-risk populations studied in primary prevention trials. The recommendation for aspirin in hyperlipi-

demic patients is supported by this reasoning, and by the low cost and risk of this therapy (Manson, 1991

[B]; Peto, 1988 [A]).

9. LDL Goal Met?Patients with coronary heart disease (CHD) have an LDL goal of less than 70 mg/dL. A recent trial provides

evidence that intensive statin therapy to reduce LDL-cholesterol levels below 100 mg/dL showed substantialclinical benet in patients with stable CAD (LaRosa, 2005 [A]).

If lipid goals are not met, it is important to intensify therapy until goals are reached. Lipid treatment is

intensied within four months of an abnormal LDL value less than 20% of the time. This problem, referred

to as "clinical inertia," is a major obstacle to improved lipid management.

Clinical inertia is dened as failure to intensify therapy at an ofce visit when the patient is above his/

her evidence-based goal. Studies at HPRF (HealthPartners Research Foundation) suggest that in high-risk

patients such as those with diabetes or heart disease, clinical inertia may be found at over half the ofce

visits (Phillips, 2001 [R]).

Organized efforts to use decision-support tools with or without electronic medical records may help reducethe problem of clinical inertia.

10. Address Adherence and Lifestyle ModicationsPoor adherence can limit the effectiveness of therapies. In asymptomatic conditions such as hyperlipidemia,

this can be especially problematic. Long-term adherence to drug therapy for chronic conditions is estimatedto be only about 50%. Adherence in clinical trials is often much higher, due to multiple factors including

patient selection, close monitoring and educational efforts of medical staff.

Some factors associated with poor adherence are number of drugs, complexity and frequency of drug admin-

istration, adverse side effects, asymptomatic conditions, cost and psychosocial problems.

The rst step is to identify potential adherence. Some signs of non-adherence include missed visits, inability

to reach by phone, medication rell history, rescheduling of appointments, complaints about ofce visits,

impatience during visits, failure to achieve therapeutic goals, and change in health care provider(s).


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Suggested ways to improve adherence include asking about compliance in a non-threatening way at each

visit; simplication of the drug regimen (frequency and complexity); reminder systems; drug-count devices;

pill minders; involvement of family or friends; a health care team approach including nurses, dietitians,

pharmacists and educators, in addition to physicians; written instructions; and educating the patient about the

medications, including potential adverse effects, importance of therapy, realistic goals, necessity of lifelong

treatment, and importance of continued attention to non-pharmacologic therapy (i.e., diet, exercise).

Additionally, the doctor-patient relationship can play a key role in improving compliance, in part throughthe physician's efforts to understand the patient's perspective on compliance.

Assess the patient's knowledge of his/her medication and medical condition:

"Can you explain why you are taking this medication?"

"How do you take your medication (with food or on an empty stomach; in the morning or the

evening)?"

Assess the patient's medication administration process:

"Many patients have difculty remembering to take their medication. From what you recall, have youever had trouble remembering to take your medications?"

"How do you remember to take your medication each day? Do you use a reminder device such as a

pillbox or alarm?"

Assess the patient's barriers to adherence:

"What is the most difcult task for you in reaching your cholesterol goal?"

"Are you comfortable with your ability to follow the treatment plan that we have designed for you?"

"Are you experiencing any unusual symptoms that you fear may be due to your medication?"

"Is the cost of your medications interfering with your treatment?"For more information on adherence please refer to Appendix D, "NCEP Recommendations on Strategies

to Improve Adherence."

(Insull, 1997 [R]; Morris, 1993 [R]; Nichols-English, 2000 [R]; Riesen, 2004 [R])

LifestyleModications

With the patient, review key lifestyle changes and set priorities and goals. Reinforce lifestyle modications

as described in Annotation #2, "Initiate Lifestyle Modication."

12. Laboratory Monitoring in 3-12 months

Obtain a fasting lipid panel or lipid panel with direct LDL and transaminase as indicated (or see drug insertor drug companion) (McKenney, 2001b [R]).

Refer to Appendix C, "Drug Companion Document."

13. Health MaintenanceHealth maintenance includes periodic monitoring, risk factor modication, and reinforcement of adjunctive

measures (see Annotation #2, "Initiate Lifestyle Modications").


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14. Evaluation and Management of Elevated Triglycerides and/or Low

HDLThe link between triglycerides and CHD is complex and may be explained by the association of high triglyc-erides, low HDL-cholesterol and unusually atherogenic LDL-cholesterol. Elevated triglycerides also often

reect an increase in triglyceride-rich remnant lipoproteins that have atherogenic potential.Patients with primarily triglyceride elevation and normal or moderately elevated cholesterol are candidates

for treatment if there is evidence of cholesterol-rich VLDL and IDL particles, typically found in patients

with triglyceride levels between 200 and 499 mg/dL and occasionally between 500 and 1,000 mg/dL. If

triglycerides are greater than 500, triglyceride-lowering drugs become rst-line therapy. The clinician may

wish to consider the use of statin therapy. This is especially true if there is a strong family history of CHDand dyslipidemia, such as familial combined hyperlipidemia, or if the patient has evidence of atherosclerotic

disease. Treatment can also be supported in diabetics with or without low HDL-cholesterol.

Patients with very high triglycerides (greater than 1,000 mg/dL) are at increased risk of hepatomegaly,

splenomegaly, hepatic steatosis and pancreatitis and are candidates for dietary and drug therapy. Patients

with fasting triglycerides less than 1,000 mg/dL are at less immediate risk of pancreatitis. After ruling out

or controlling for secondary causes (e.g., diabetes mellitus, hypothyroidism, chronic renal failure, alcoholabuse, hormone replacement therapy and/or oral contraceptives), the National Institutes of Health recom-

mend dietary measures for initial management of borderline and high triglycerides (please see Appendix B,"Identied Secondary Causes and Conditions Associated with Hyperlipidemia," for additional secondary

causes). If dietary and lifestyle modication (weight reduction if needed, decrease in alcohol, increase physical

activity, smoking cessation) does not lower triglycerides to desired level, then drug therapy is indicated. (See

Appendix A, "Omega-3 Fatty Acids," and Appendix C, "Drug Companion Document.")

Uncontrolled glucose levels in patients with diabetes mellitus contribute to hypertriglyceridemia. Glucose

levels in patients with diabetes should be under control to bring triglyceride levels under control.

When triglycerides are over 400 mg/dL, the LDL-cholesterol cannot be calculated and a direct measure of

LDL, where available, is preferred. Although the LDL-cholesterol can be calculated when the triglycerides

are moderately elevated (200-400 mg/dL), keep in mind that the LDL-cholesterol may be underestimateddue to the Friedenwald equation.

LDL-cholesterol = Total cholesterol minus HDL-cholesterol minus (triglyceride divided by 5).

Non-HDL-cholesterol becomes a secondary target when triglycerides are 200-499. The non-HDL target is 30

mg/dL higher than the LDL target. Non-HDL-cholesterol is calculated by the formula non-HDL- cholesterol

= T-cholesterol minus HDL-cholesterol.

(Grundy, 1998 [R]; McKenney, 2001b [R]; National Cholesterol Education Program, 2001 [R])

16. Follow-upCoronary risk status and a lipid prole should be obtained at least annually (McKenney, 2001b [R]; National

Cholesterol Education Program, 2001 [R]).


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Omega-3 Fatty Acids

Omega-3 fatty acids are found in sh oil and in some vegetable oils, nuts, seeds and soy. You can get omega-3

fatty acids from some foods or from over-the-counter and prescription supplements. Fish oil contains two

important omega-3 fatty acids: EPA (eicosapentanoic acid) and DHA (docosahexanoic acid). Plant sourcesprovide ALA (alpha-linolenic acid). Studies of EPA and DHA, suggest that:

doses of up to 1 gram per day reduce risk of heart attacks in high-risk patients, and

doses of up to 3 grams per day lower serum triglyceride levels.

Tips for Getting More Omega-3 Fatty Acids

Use vegetable oils that are high in omega-3 fatty acids. Examples are canola oil, soybean oil,axseed oil and walnut oil.

Select sh from the chart below and eat at least 7 ounces per week. Prepare sh by grilling, baking,

broiling or poaching.

Add walnuts or ground axseed to cereals, yogurt and salads. Whole axseeds will not work aswell they simply pass through the body undigested.

Substitute ground axseed for fat (butter or oil) in baked products. Try using 3 tablespoons of

ground axseed instead of 1 tablespoon of oil.

Snack on edamame (steamed soybeans, sold fresh or frozen).

Omega-3 fatty acid supplements should be refrigerated and eaten with food. This will reduce the

possibility of a mild shy aftertaste.

Fish Sources of Omega-3 Fatty Acids

Serving Size: 3.5 ounces, cooked

Safety Note: Pregnant and nursing women and young children should avoid shark,

swordfish, king mackerel and tilefish. These contain high levels of mercury. Albacore tuna

has more mercury than canned light tuna. Albacore tuna should be limited to no more than 6ounces per week.

Fish EPA + DHA content (g/Serving) Calories/Serving

Farmed salmon 2.15 206

Atlantic herring 2.01 203

Wild salmon 1.84 182

Sardines, canned in tomato sauce 1.35 186

Atlantic mackerel 1.20 262

Farmed rainbow trout 1.15 169Wild rainbow trout 0.980 150

White tuna, canned in water 0.860 128

Halibut 0.470 140

Shrimp 0.320 99

Fresh yellowfin tuna 0.280 139

Light tuna, canned in water 0.270 116

Atlantic cod 0.160 105

Appendix A Omega-3 Fatty Acids

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Lipid Management in AdultsAppendix A Omega-3 Fatty Acids Eleventh Edition/October 2009

Plant Sources of Omega-3 Fatty Acids

Food Amount Omega-3 fatty

acids (g/serving)

Fiber

(g/serving)

Calories/Serving

Flaxseed oil 1 tablespoon 7.249 n/a 120

Ground flaxseed 1 tablespoon 1.597 1.9 37

English walnuts 1 tablespoon(7 halves)

1.290 0.9 93

Soy oil 1 tablespoon 0.940 n/a 120

Canola oil 1 tablespoon 0.862 n/a 120

Tofu, raw, firm 1/2 cup 0.733 2.9 183

Green soybeans, cooked 1/2 cup 0.319 3.8 127

Navy beans, cooked 1 cup 0.213 19.1 255

Wheat germ 1/4 cup 0.208 3.8 104

Avocado, raw 1 cup sliced 0.182 9.8 234Black walnuts 1 tablespoon

(7 halves)0.155 0.5 48

Kidney beans, canned 1 cup 0.125 19.1 210

Baked beans, canned 1 cup 0.104 10.4 239

2006 American Dietetic Association Disorders of Lipid Metabolism Tool Kit.Sources: www.nal.usda.gov/fnic/foodcomp/search, www.nutritiondata.com, U.S. Food and DrugAdministration. What you need to know about mercury in fish and shellfish. FDA/CFSAN Consumer

Advisory EPA-823-R-04-005. March 2004.http://www.cfsan.fda.gov/~dms/admehg3.html.

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Appendix B Identied Secondary Causes and Conditions

Associated with HyperlipidemiaCholesterol Triglyceride HDL-Cholesterol

Drugs

Antihypertensives:Thiazides Increase IncreaseLoop diuretic Decrease

Beta-blockers Increase Increase/DecreaseHormones:

Glucocorticoids Increase IncreaseAnabolic steroids Increase Increase

Oral contraceptives Increase/Decrease Increase Increase/DecreaseEstrogens Decrease Increase IncreaseProgestins Increase DecreaseGrowth hormone Increase

Others:Amiodarone IncreaseIsotretinoin Increase Increase Decrease

Cyclosporine Increase

Diseases/Conditions

Metabolic/Endocrine:Diabetes (esp NIDDM) Increase Increase DecreaseHypothyroidism Increase IncreaseAnorexia nervosa IncreaseObesity Increase Increase Decrease

Pregnancy Increase IncreaseAcromegaly Increase

Hyperuricemia/gout Increase DecreaseLiver Disorders:

Hepatocellular Increase DecreaseCholestasis Increase Decrease

Renal Diseases:

Nephrotic syndrome Increase Increase DecreaseChronic renal ailure Increase/Decrease Increase/Decrease Decrease

Others:SLE Increase IncreaseRheumatoid arthritis Decrease Decrease IncreasePancreatitis Increase

Dietary Factors

Alcohol abuse Increase IncreaseHigh-at diet Increase Increase

Low-at diet Decrease Decrease DecreaseHigh-cholesterol diet Increase

Weight gain IncreaseVery high-ber diet Decrease

(McKenney, 2001b [R]; Stone, 1994 [R])


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Appendix C Drug Companion Document

This document may provide assistance to the clinician initiating and providing

ongoing pharmacologic management of the dyslipidemic patient.

It includes the following informational pieces:

Treatment options for dyslipidemia

Drug discussions on the following medications (in order of discussion):

Statins

Fibric acid derivatives / Fibrates

Niacin

Ethyl esters of omega-3 fatty acidsSelective cholesterol absorption inhibitor

Bile-acid sequestrants

Table outlining medications, lipid effects, contraindications, drug interac-

tions, potential side effects, dosing considerations, and required moni-

toring.

Please note: Information provided is not all-inclusive, and providers should

consult manufacturer's product labeling insert, PDR, etc., for full prescribing

information.


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* Niacin can elevate glucose in patients with diabetes. Review the drug education sheet with the patient when initiating niacin

therapy.

** TLC therapeutic lifestyle change

*** Although not FDA-labeled, use of gembrozil is supported by the VA-HIT Study.

If considering combination therapy or alternative agents, suggest lipid clinic consultation.

Appendix C Drug Companion Document Lipid Management in AdultsTreatment Options for Dyslipidemia Eleventh Edition/October 2009

Type ofDyslipidemia

Lipid Subfractions Primary Therapy Secondary Therapy

LDL HDL Trigl.Incr ! 40 > 200

StatinNiacin*

Omega-3 fatty acids

High LDL-Cholesterol and

Triglycerides

LDL HDL Trigl.Incr < 40 > 200

Weight loss Physical activity Discontinue smoking No alcohol Improve diabetes

mellitus control TLC**

Statin

Fibric acids

Niacin*

Omega-3 fatty acidsEzetimide

LDL HDLIncr ! 40

StatinFibric acidsNiacin*EzetimideBile acid sequestrant

High LDL-Cholesterol

LDL HDLIncr < 40

Weight loss Physical activity TLC** Discontinue smoking

StatinFibric acidsNiacin*Bile acid sequestrantEzetimide

Isolated LowHDL-Cholesterol

HDL < 40LDL is normal

Physical activity Discontinue smoking

(drug recommendations fortreatment remain controversialexcept in CHD)Fibric acids***StatinNiacin*

HighTriglycerides

Weight loss Discontinue smoking No alcohol Improve diabetes

mellitus control TLC** Physical activity

Fibric acidsNiacin*Omega-3 fatty acids

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**Approximate mean change from baseline. Note: the +/- sign applies to both numbers.

***BAS = Bile-Acid Sequestrant

Reducing LDL-cholesterol (LDL-C) levels is the primary approach to lowering risk of CHD in both primary and secondary

prevention. In some patients, triglycerides may be elevated along with LDL-C, so reducing triglycerides and increasingHDL-cholesterol (HDL-C) may also be desirable. Selection of drug therapy is dependent on several factors including

lipoprotein levels and percent reduction needed to attain goal; concurrent drug therapies that could increase the risk of

side effects occuring with specic lipid-lowering drugs; and presence of other medical disorders that may affect drug

metabolism, increase risk of side effects or be adversely affected by a specic lipid-lowering drug.

Monotherapy

Statins are the drugs of choice for lowering LDL-cholesterol, and aggressive treatment with statins should be pursued.

Statins also have a modest effect on reducing triglycerides and increasing HDL-cholesterol. Several studies with clinical

endpoints support use of statins in primary and secondary prevention.

If a patient is intolerant to a statin, clinicians are encouraged to have the patient try the other statins before ruling them

all out. This is especially important in secondary prevention. In the Heart Protection Study, there was no signicant

difference between the simvastatin 40 mg and placebo groups, in the number of patients with elevations of serum

transaminases or unexplained muscle aches or weakness.

If patients are unable to take statins, then bile-acid sequestrants, niacin, bric acids and ezetimibe can be used.

The secondary-prevention VA-HIT trial utilizing gembrozil 600 mg twice daily in patients with normal LDL-choles-

terol, low HDL-cholesterol and triglycerides less than or equal to 300 mg/dL showed a 22% reduction in the combined

incidence of CHD death and non-fatal MI. Almost 50% of this study population had evidence of metabolic syndrome ordiabetes, and they showed the greatest benet. Fibric acids have a variable effect on LDL-cholesterol. Fenobrate may

be more effective at lowering LDL-cholesterol than gembrozil. They are usually reserved for hypertriglyceridemia or

for an isolated low HDL-cholesterol.

In the Coronary Drug Project, a large-scale secondary prevention trial, niacin 3 grams/day reduced mortality 11% over

placebo. Niacin has a favorable effect on LDL-cholesterol, triglycerides and HDL-cholesterol and is good for mixed

hyperlipidemia. Niacin has a greater effect on HDL-cholesterol than other currently available lipid medications. To

improve tolerability and compliance, doses of niacin need to be titrated.

Ezetimibe mainly reduces LDL-cholesterol, with minimal effect on triglycerides or HDL-cholesterol. No clinical outcomestudies are currently available, but ezetimibe appears useful for reducing LDL-cholesterol in patients who cannot take

a statin and in combination with other LDL-reducing medications.


Treatment Options for Dyslipidemia

Lipid Disorder Monotherapy % LDL HDL Trig Combination Therapy % LDL** HDL** Trig

Hypercholesterolemia

Increase LDL, normaltrig, normal HDL

StatinEzetimibeNiacin

BAS***

-25 to 63-18-6 to 25

-15 to 30

Statin + EzetimibeStatin + NiacinStatin + BAS***

Statin + Niacin + BAS***Niacin + BAS***

-46 to 61-36 to 42-45 to 64

-66-25 to 55

+16 to 27

Combined Hyperlipidemia

Increase LDL, increasetrig, and normal or lowHDL

StatinFibric AcidsNiacin

-25 to 45+10 to -28-6 to 25

+5 to 15+5 to 35+8 to 38

-5 to 37-10 to 50-30 to 50

Statin + Fibric AcidsNiacin + StatinNiacin + Fibric AcidsNiacin + BAS***

-20 to 35-36 to -42

-25 to 55

+16 to 27-35-15 to 45-20 to 37

Hypertriglyceridemia StatinFibric AcidsNiacin

+5-10-30 to 50-10 to 50

Niacin + Fibric Acids

Isolated low HDL Fibric AcidsStatinsNiacin

+6 to 12+5 to 10+5 to 35

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In the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), participants were to take cholestyramine

12 gm twice daily, but compliance varied. A linear relationship was seen with reduction in CHD risk corresponding to

cholestyramine dose and reduction in LDL-cholesterol. A 19% reduction in risk of fatal and non-fatal MI was seen in

patients taking cholestyramine 24 gm/day. The bile-acid sequestrants reduce LDL-cholesterol, but they can increase

triglycerides so should only be used as monotherapy in patients with baseline triglycerides less than or equal to 200

mg/dL.Combination therapy

Although combination therapy is not supported by outcome-based studies, some high-risk patients will require combi-

nation therapy. Most likely, these patients will have CHD. Using low doses of two complementary agents can often

reduce LDL-cholesterol to a greater extent than a higher dose of either agent, such as when a statin is combined with

either ezetimibe or a bile-acid sequestrant, with fewer side effects and possibly less cost. In very resistant cases, triple

therapy may be needed.

In patients with mixed hyperlipidemia (increased LDL-cholesterol and triglycerides), the primary goal is decreasing

LDL-cholesterol. A high triglyceride (200-499 mg/dL) with hypercholesterolemia signals a relatively high risk of CHD.These patients often have a low HDL-cholesterol. Combination of a cholesterol-lowering drug with a triglyceride-

lowering drug to achieve the non-HDL-cholesterol goal may be most warranted in patients with established coronary

artery disease who are at very high risk of recurrent coronary events. Combining nicotinic acid with a statin is favorable

for improving LDL-cholesterol, HDL-cholesterol and triglycerides. Use of bric acids leads to effective decrease in

triglycerides and increased HDL-cholesterol, but effect on LDL-cholesterol is varied.

An increased incidence of severe myopathy has been reported when a statin was combined with nicotinic acid or bric

acids. Most of these cases involved a high dose of the statin in patients with reduced renal function. When these combi-

nations were evaluated in patients with normal renal and liver function in controlled clinical trials, myopathy rarelyoccurred (incidence of approximately 0.12%). In general, these combinations need not be avoided, but careful patient

selection, monitoring and education are required. These combinations should generally be avoided in patients with acute

or serious chronic illness (especially chronic renal disease), patients undergoing surgery or in patients who are already

receiving cyclosporine, macrolide antibiotics, nefazodone, azole antifungal agents, or protease inhibitors.

Rosuvastatin dose does not need to be decreased when co-administered with fenobrate, because co-administration of

fenobrate (67 mg three times daily) with rosuvastatin (10 mg) resulted in no signicant changes in plasma concentra-

tions of rosuvastatin or fenobrate.

In general, the combination of a statin and a brate raises the risk of myopathy and rhabdomyolysis. There may be alower incidence of myopathy with fenobrate compared to gembrozil. Clinical trials have established that the concur-

rent use of gembrozil and statins results in an increased area under the curve (AUC), elimination half-life and serum

peak concentration of the statin. Fenobrate does not adversely affect either the metabolism or pharmacokinetics of the

statins, making it a more appropriate choice.

There have been several studies with small numbers of carefully selected patients that have shown brates (including

gembrozil) can be used safely with statins (incidence of myopathy was approximately 0.12%). There may be a poten-

tial difference in risk of myopathy between gembrozil and fenobrate when combined with statins. Gembrozil hasbeen shown to increase plasma levels of simvastatin acid, lovastatin and rosuvastatin, while fenobrate has no effect on

plasma levels of rosuvastatin. Simvastatin, lovastatin and rosuvastatin all have labeled dose restrictions when combined

with gembrozil, while pravastatin, atorvastatin and uvastatin do not.

Renal function should be assessed along with a baseline creatinine kinase (CK). Patients must be asked to report promptly

any unexplained muscle aches or weakness, especially if malaise or fever is present, u-like symptoms (without upper

respiratory infection) or brownish urine. If these symptoms occur, repeat the CK and rule out non-drug causes, e.g.,

recent increased or unusually vigorous exercise. If CK is rapidly rising or 10 times the upper limit of normal, both drugsshould be discontinued until the symptoms subside and CK returns to normal.


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Please consult manufacturer's product labeling insert, or PDR for full prescribing information.

(Backman, 2000 [A]; Downs, 1998 [A]; Dujovne, 2002 [C]; Gagne, 2002[C]; Goldberg, 1998[A]; Grundy, 1998 [R];

Heart Protection Study Collaborative Group, 2002 [A]; Jacobson, 2006 [R]; Lipid Research Clinics Program, 1984

[A]; McKenney, 2002 [R]; McKenney, 2001a [R]; Scandinavian Simvastatin Survival Study Group, 1994 [A]; Schrott,

1995 [A]; Shek, 2001 [R])


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Appendix C Drug Companion Document Lipid Management in AdultsStatins Eleventh Edition/October 2009

Six statins are available: atorvastatin, uvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin.

Efcacy

Substantial reductions in LDL-cholesterol of 25%-60%. This is dose-dependent, with the greatest effect

seen at the starting dose, and an additional 6%-7% reduction with each doubling of the dose.

Reductions in triglycerides are possible with all statins but are dependent on the baseline triglyceride

level, the LDL-cholesterol-lowering potency of the statin, and the dose utilized.

The Scandinavian Simvastatin Survival Study (4S) trial reported reductions of 30%-45% in deaths due

to CHD, cardiovascular disease and all causes after 4.5 years treatment with simvastatin in patients withCHD. This was shown in men, women and elderly (Scandinavian Simvastatin Survival Study Group,

1994 [A]).

The Heart Protection Study, utilizing 40 mg of simvastatin, reported a 24% reduction in rst occurrence

of major vascular events (non-fatal MI or coronary death, non-fatal or fatal stroke, coronary or non-

coronary revascularization) in a wide range of high-risk individuals, 40-80 years of age, regardless of

baseline cholesterol levels (Heart Protection Study Collaborative Group, 2002 [A]).

The West of Scotland trial reported a 31% reduction in risk of non-fatal MI or death from CHD in menwith hypercholesterolemia and no history of MI who were treated using 40 mg of pravastatin daily (West

of Scotland Coronary Prevention Group, 1998 [A]).

The CARE study, using 40 mg of pravastatin daily, showed a 24% reduction in major coronary events in

men and women with a mean LDL-cholesterol of 139 mg/dL who had survived a myocardial infarction

(Goldberg, 1998 [A]).

In AFCAPS/TexCAPS, treatment with lovastatin 20-40 mg daily resulted in a 37% reduction in the risk

of rst major coronary events. This reduction occurred in men and women without clinically evident

atherosclerotic cardiovascular disease, with average LDL-cholesterol (mean 150 mg/dL) and below-average HDL-cholesterol (mean 36 mg/dL in men and 40 mg/dL in women) (Downs, 1998 [A]).

The PROVE-IT trial, comparing pravastatin 40 mg (mean LDL-chol 95 mg/dL) versus atorvastatin 80mg (mean LDL-cholesterol 62 mg/dL) in patients following acute coronary syndrome, reported a 25%

reduction in the risk of death, MI or urgent revascularization in the atorvastatin group (Cannon, 2004

[A]).

Safety

Asymptomatic increases in serum transaminases to greater than three times the upper limit of normal

(ULN) on two consecutive lab tests is estimated to occur in 0.1 to 2 percent of patients (incidence issimilar to patients treated with placebo). Elevations are usually transient and may normalize even with

continued therapy or may not reoccur even with reintroduction of the same statin and dose. Nonetheless,

patients should be closely monitored until the transaminases have normalized. The FDA contraindicated

statin use in patients with cholestasis and active liver disease. It is not known whether statins worsen the

outcome in patients with chronic transaminase elevations due to Hepatitis B or C. There is no evidencethat they are harmful in patients with fatty liver due to obesity. The use of statins in patients with chronic

liver disease depends on the clinical judgment of risk versus benet.

Use with caution at reduced dosages in patients with primary biliary cirrhosis.

Dipstick-positive proteinuria and microscopic hematuria have been seen in rosuvastatin-treated patients.

The incidence appears to increase with dose escalation. These increases were generally transient and

not associated with worsening renal function. The clinical signicance of this is unknown, but a dose

reduction should be considered in patients on 40 mg/day with unexplained persistent proteinuria on

routine urinalysis testing.

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Characterized by muscle aches, soreness, weakness and signicant elevation in creatinine kinase (CK)

or a CK level generally 10 times the upper limit of normal (ULN), myopathy appears dose dependent

and is rare with monotherapy (0.1 percent). The percentage of patients in placebo-controlled trials with

non-specic muscle aches or joint pains without signicant increases in CK was similar in both statin

and placebo groups. Nonetheless, patients can develop clinically signicant myopathy, and failure to

recognize it and discontinue the statin can lead to rhabdomyolysis, myoglobinuria and renal necrosis.

Risk of myopathy appears increased in patients with impaired renal insufciency. Older patients maybe more susceptible, and it is most likely to occur in patients with complex medical problems and/or on

multiple medications. Risk appears increased in patients who are receiving a bric acid, niacin or drugs

that inhibit the cytochrome P450 enzyme, particularly 3A4, which is the major metabolizing enzyme

of lovastatin, simvastatin and atorvastatin. Expression of this enzyme varies among individuals 10- to

40-fold, and the afnity of substrates to inhibit this enzyme also varies. Thus it is difcult to predict

when a signicant interaction will occur, but providers need to be aware of the potential. Some inhibitorsof 3A4 include (list is not all-inclusive) macrolide antibiotics*, azole antifungals**, protease inhibitors,

cyclosporine, tacrolimus, dexamethasone, danazol, testosterone, propoxyphene, quinidine, nefazodone,

pimozide, uoxetine, uvoxamine, verapamil, diltiazem, nifedipine, nicardipine, sildenal, amiodarone,

zarlukast, and grapefruit juice.

Fluvastatin and to a small extent rosuvastatin are metabolized by the 2C9 isoenzyme. Potential inter-

actions may occur when they are given along with medications that are also metabolized by the 2C9

isoenzyme (e.g., oral anticoagulants, phenytoin, oral sulfonylureas, NSAIDs) or those that inhibit the

2C9 isoenzyme (e.g., uconazole**, oral miconazole, gembrozil).

Controlled clinical trials with bric acids have failed to document a substantial risk of myopathy in

patients with normal renal function. Some key points for combination with a bric acid include:

Establish that the patient has normal renal and thyroid function.

Establish that there is no other potential drug interaction that could increase the blood level of

the statin or bric acid.

Limit the initial statin dose to the starting or intermediate dose. The dose of statin can then beincreased cautiously if needed.

Teach the patient to recognize and report promptly symptoms of muscle soreness, tenderness,pain or brownish urine.

Obtain a baseline CK blood level prior to initiating combination therapy. The CK should be

repeated if a patient reports symptoms suggestive of myopathy.

If a patient experiences these muscle symptoms, with or without CK elevations, rule out

common causes such as exercise or strenuous work. Advise moderation in activity for patients

who experience this nding during combination therapy.

Discontinue combination therapy if a CK of ve times the upper limit of normal or greater

occurs in a patient with muscle symptoms. Wait for the symptoms to resolve and CK to returnto normal before reinstituting therapy with either drug and use a lower dose of the drug(s).

If a patient experiences muscle symptoms with either no elevation in CK level or a moderate

elevation (i.e., three to less than ve times the upper limit of normal), monitor the patient's

symptoms and CK levels until symptoms resolve and CK level returns to normal or until the

clinical situation worsens to the point described above and discontinue both drugs.


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When combined with cyclosporine, only low doses of statins should be used. FDA-labeled dosing for

combination with cyclosporine is 10-20 mg of lovastatin and pravastatin***, 5 mg of rosuvastatin and

5 to 10 mg of simvastatin.

In two reported cases, possibly associated with macrolide antibiotics, rhabdomyolysis occurred after

completion of a course of clarithromycin and azithromycin in patients who had been taking lovastatin

40 mg/day for 5 years. Both patients had been receiving diltiazem and low-dose prednisone and one

had renal insufciency. If at all possible, macrolide antibiotics should be avoided in patients on a statin,especially if the patient has renal insufciency or is already on another drug known to increase the risk

of myopathy. If a macrolide antibiotic cannot be avoided, consideration should be given to temporarily

discontinuing the statin, reducing the dose of the statin, or if long-term therapy with the macrolide is

needed, change to pravastatin or uvastatin.

If treatment with systemic azole antifungals** (ketoconazole, itraconazole, miconazole, uconazole

greater than or equal to 200 mg/day) is necessary, then the statin should be temporarily discontinued

during treatment or changed to pravastatin.

Grapefruit juice is a known inhibitor of the 3A4 isoenzyme in the gut wall. Consumption of more than 1

quart of juice per day has caused dramatic increases of 12- to 15-fold of the AUC and Cmax of lovastatin,

whereas consumption of 8 ounces of juice per day has caused a twofold increase in the AUC and Cmax

of lovastatin. Patients taking statins that are metabolized by the 3A 4 isoenzyme should be advised to

limit consumption of grapefruit to no more than 8 ounces of juice or one-half fruit per day.

Studies of verapamil combined with simvastatin and diltiazem combined with lovastatin have shown a

four- to vefold increase in mean AUC and three- to fourfold increase in mean Cmax of the parent drug.

If a patient is on diltiazem or verapamil, then the statin should be initiated with the recommended startingdose, and increased only if warranted. Alternatively, pravastatin and uvastatin could be used.

Major surgery is a known risk factor for rhabdomyolysis. Consider temporarily stopping the statin until

the patient is home and ambulatory.

Regardless of statin used, patients must be told to report promptly any unexplained muscle aches or weak-

ness, especially if malaise or fever is present, or u-like symptoms (without upper respiratory infection)or brown urine. If these symptoms occur and myopathy is suspected, the lipid-lowering medication(s)

should be temporarily discontinued, and a medical evaluation including CK is recommended.

* Azithromycin, dirithromycin do not inhibit CYP450 3A4. Azithromycin has been implicated ina case of lovastatin-induced rhabdomyolysis.

** Fluconazole in doses greater than or equal to 200 mg/day may inhibit clearance of statins metabo-

lized by CYP450 3A4. Fluconazole and miconazole are potent inhibitors of CYP450 2C9 and may

affect clearance of uvastatin. Fluconazole has been shown to have a clinically insignicant effect

on rosuvastatin clearance.

*** Pravastatin and rosuvastatin are not signicantly metabolized by CYP450 3A4, but a study in

heart transplant (HT) patients on cyclosporine showed their respective AUCs were 20-fold higher

and 7-fold higher vs. the control group.


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Drug LDL-Cholesterol Reduction Cost per 30 Tablets

Fluvastatin 20 mg (B) 22% $$$$Pravastatin 10 mg (G) 22% $Lovastatin 20 mg (G) 27% $Fluvastatin 40 mg (B) 25% $$$$Simvastatin 5 mg (G) 26% $Simvastatin 10 mg (G) 30% $Lovastatin 40 mg (G) 33% $$Pravastatin 20 mg (G) 32% $$Pravstatin 40 mg (G) 34% $$Fluvastatin XL 80 mg (B) 35% $$$$$Pravastatin 80 mg (G) 37% $$$$$Simvastatin 20 mg (G) 38% $$Atorvastatin 10 mg (B) 39% $$$$Simvastatin 40 mg (G) 41% $$Atorvastatin 20 mg (B) 43% $$$$$Rosuvastatin 5 mg (B) 45% $$$$$Ezetimibe 10

mg/Simvastatin 10 mg (B)

45% $$$$$Simvastatin 80 mg (G) 47% $$Atorvastatin 40 mg (B) 50% $$$$$Rosuvastatin 10 mg (B) 52% $$$$$Ezetimibe 10mg/Simvastatin 20 mg (B)

52% $$$$$Rosuvastatin 20 mg (B) 55% $$$$$Ezetimibe 10mg/Simvastatin 40 mg (B)

55% $$$$$Atorvastatin 80 mg (B) 60% $$$$$Ezetimibe 10

mg/Simvastatin 80 mg (B)

60% $$$$$Rosuvastatin 40 mg (B) 63% $$$$$

Legend Cost Legend

(B) = Brand name only available $ = $0-$25

(G) = Generic available (cost of generic listed) $$ = $25.01-$50

$$$ = $50.01-$75

$$$$ = $75.01-$100$$$$$ = > $100

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Statins Dose LimitationsAtorvastatin Cyclosporine:

Not to exceed 10 mg dailyFluvastatin Severe renal impairment:

Doses above 40 mg daily have not been studied

Lovastatin Severe renal impairment:

Doses above 20 mg daily should be used cautiously

Cyclosporine:

10 mg daily to start, not to exceed 20 mg daily

Fibrates or niacin (greater than or equal to 1

gm/day):

Not to exceed 20 mg dail

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