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PL Detail-Document #300101 −This PL Detail-Document gives subscribers

additional insight related to the Recommendations published in−

PHARMACIST’S LETTER / PRESCRIBER’S LETTER

January 2014

More. . . Copyright © 2014 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

2013 ACC/AHA Cholesterol Guidelines

The 2013 American Heart Association (AHA)/American College of Cardiology (ACC) lipid guidelines represent a paradigm shift in the treatment of

dyslipidemia. These guidelines focus on reducing cardiovascular risk using proven interventions. Per the new guidelines, patients receive high- or

moderate-dose statin therapy, depending on which of four “statin benefit groups” they fit into. The guidelines introduce a new risk calculator for

estimation of 10-year cardiovascular disease risk. This calculator can be used to determine if a high- or moderate-dose statin is appropriate for

primary prevention. Unlike previous guidelines, the 2013 guidelines do not recommend titrating the statin dose to achieve a specific LDL target.

This is because randomized controlled trials have demonstrated cardiovascular risk reduction using specific statin doses, not LDL targets. Treating to

a given target may result in statin undertreatment if an evidence-based statin dose is not used, or overtreatment. The addition of a nonstatin has not

been proven to further reduce cardiovascular risk; therefore, nonstatins are no longer routinely recommended. The table below provides a summary

of these guidelines, with an emphasis on pharmacotherapy.

--Information in table is from reference 1 unless otherwise denoted.--

Who should be

assessed for

cardiovascular risk,

and how?

For patients without atherosclerotic cardiovascular disease:

• Assess traditional risk factors (e.g., lipids, blood pressure, diabetes) every four to six years in patients 20 to 79 years

of age.2,3

• In patients 40 to 75 years of age not receiving cholesterol-lowering therapy, and with LDL 70 to 189 mg/dL

(1.8 to 4.9 mmol/L), also estimate 10-year risk using the Pooled Cohort Equations Cardiovascular Risk

Calculator, available at http://my.americanheart.org/cvriskcalculator. Get an app from iTunes (for iPhone, iPad, and

iPod), or Google Play (for Android).

What lifestyle

changes are

recommended to

reduce

cardiovascular

risk?

Adhere to a heart-healthy diet:

• Eat vegetables, fruits, whole grain, low-fat dairy, poultry, fish, beans, nontropical vegetable oils, and nuts, but avoid

red meat (i.e., Mediterranean-style diet, DASH [Dietary Approaches to Stop Hypertension] diet).2

• Limit sugary drinks and sweets.2

• Limit saturated and trans fat to 5% to 6% of calories.2

• Limit sodium intake to 2400 mg daily (about one teaspoon table salt [kosher/sea salt have less sodium per teaspoon]).2

• For adults who would benefit from blood pressure lowering, further reduction to1500 mg daily is ideal. Combine

sodium restriction with the DASH diet.2

Exercise regularly:

• Engage in moderate-to-vigorous aerobic activity for at least 40 minutes (on average) three to four times each week.2

Avoid tobacco.

Maintain a healthy weight.

(PL Detail-Document #300101: of 5)



Who should be

treated with a

statin?

There are four major statin benefit groups:

• Patients with clinical atherosclerotic cardiovascular disease.

• Patients with LDL 190 mg/dL (5 mmol/L) or higher.

• Patients age 40 to 75 years of age with diabetes (but without clinical atherosclerotic cardiovascular disease) and LDL

70 to 189 mg/dL (1.8 to 4.9 mmol/L).

• Patients without clinical atherosclerotic cardiovascular disease or diabetes with LDL 70 to 189 mg/dL

(1.8 to 4.9 mmol/L), with an estimated 10-year risk of atherosclerotic cardiovascular disease of 7.5% or higher.

If a patient does not fit into one of the four statin benefit groups (e.g., LDL 70 to 189 mg/dL [1.8 to 4.9 mmol/L] with 10-year

risk 5% to 7.5%) , but there is clinical suspicion that they may benefit from a statin, additional factors can be taken into

consideration:

• 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/dL or higher.

• Ankle-brachial index <0.9.

• Elevated lifetime risk of atherosclerotic cardiovascular disease.

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

ethnicity.

• Statin adverse effects.

• Statin drug interactions.

• Patient preferences.

What are the

pharmacologic

treatment options?

Continued…

Pharmacotherapy

Use for…

High-dose Statin (average LDL reduction about

50% or higher):a

• Atorvastatin 80 mg once daily (40 mg if

80 mg not tolerated).

• Rosuvastatin 20 mg to 40 mg once daily.b

• Secondary prevention in adults 75 years of age and younger. (Level A)

• Primary prevention in adults with LDL 190 mg/dL (5 mmol/L) or

higher. (Level A)

• Primary prevention in adults 40 to 75 years of age with LDL 70 to

189 mg/dL (1.8 to 4.9 mmol/L) and an estimated 10-year risk of

atherosclerotic cardiovascular disease of 7.5% or higher (moderate-

dose also an option). (Level A)

• Primary prevention in diabetes patients 40 to 75 years of age with

LDL 70 to 189 mg/dL (1.8 to 4.9 mmol/L) and an estimated 10-year

risk of atherosclerotic cardiovascular disease of 7.5% or higher.

(Level C)




Pharmacologic treatment options,

continued

Pharmacotherapy

Use for…

Moderate-dose Statin (average LDL reduction about

30 to <50%):a

• Atorvastatin 10 to 20 mg once daily.b

• Fluvastatin 40 mg twice daily or 80 mg

(XL) once daily.b

• Lovastatin 40 mg once daily.

• Pitavastatin 2 to 4 mg once daily.b

• Pravastatin 40 to 80 mg once daily.b

• Rosuvastatin 5 to 10 mg once daily.b

• Simvastatin 20 to 40 mg once daily.

• Secondary prevention in adults older than 75 years. (Level A)

• Patients who cannot tolerate a high-dose statin.

• Primary prevention in adults 40 to 75 years of age with LDL 70 to

189 mg/dL (1.8 to 4.9 mmol/L) and an estimated 10-year risk of

atherosclerotic cardiovascular disease of 7.5% or higher (high-dose

also an option). (Level A)

• Primary prevention in diabetes patients 40 to 75 years of age, with

LDL 70 to 189 mg/dL (1.8 to 4.9 mmol/L) and an estimated 10-year

risk of atherosclerotic cardiovascular disease of less than 7.5%.

(Level A)

Low-dose Statin (average LDL reduction <30%):a

• Fluvastatin 20 to 40 mg once daily.b

• Lovastatin 20 mg once daily.

• Pitavastatin 1 mg once daily.b

• Pravastatin 10 to 20 mg once daily.

• Simvastatin 10 mg once daily.b

• For patients who cannot tolerate a high- or moderate-dose statin.

Nonstatin

• Reinforce statin adherence and lifestyle

changes, and check for secondary causes

before adding a nonstatin.

• Do not add gemfibrozil to statin therapy.

• No proof adding a nonstatin to a statin

further reduces cardiovascular risk.

• Triglycerides 500 mg/dL or higher (use omega-3 fatty acids [e.g.,

fish oil], niacin, or fenofibrate).

• Patients who cannot tolerate the recommended statin dose or do not

achieve the expected statin response and are high-risk (i.e., patient

with LDL 190 mg/dL [5 mmol/L] or higher at baseline, diabetes, or

clinical atherosclerotic cardiovascular disease).

How is statin

therapy

monitored?

Continued…

• Check ALT (alanine aminotransferase) at baseline. Repeat only if symptoms of hepatotoxicity occur.

• Document any pre-existing muscle symptoms before starting a statin to establish a baseline.

• Consider checking creatine kinase at baseline in patients at increased risk for myopathy (e.g., drug interactions, etc).

Repeat only if symptomatic.

• If severe muscle symptoms or fatigue of unknown cause develop, hold the statin and check creatinine and urinalysis to

rule-out rhabdomyolysis.




Statin monitoring,

continued • Check fasting lipid panel four to 12 weeks after statin initiation, then every three to 12 months.

• Check adherence to statin and lifestyle interventions if LDL drop less than expected.

• Consider statin dose reduction if two consecutive LDL measurements are less than 40 mg/dL (1.03 mmol/L).

• Monitor for new-onset diabetes per diabetes screening guidelines.

a. Doses listed are for patients with normal renal function not taking an interacting medication. See our PL Chart, Characteristics of the

Various Statins, for renal dosing and select drug interactions. High-dose, moderate-dose, and low-dose statin designations are categorical

only. Actual statin percent LDL-lowering may vary in practice.

b. Atorvastatin 20 mg, fluvastatin extended-release (XL) 80 mg, fluvastatin 20 to 40 mg, pitavastatin, pravastatin 80 mg, rosuvastatin 5 mg and

40 mg, and simvastatin 10 mg are FDA-approved but lack evidence from randomized-controlled trials for reduction in major cardiovascular

events.

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 J, 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 2013 Nov 12 [Epub ahead of print];doi:10.1161/01.cir.0000437738.63853.7a.

2. 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 2013 Nov 12 [Epub ahead of print];doi:10.1161/01.cir.0000437740.48606.d1.

3. American Heart Association. 2013 Prevention Guidelines Tools. CV Risk Calculator. http://my.americanheart.org/cvriskcalculator. (Accessed November 23, 2013).

Cite this document as follows: PL Detail-Document, 2013 AHA/ACC Lipid Guidelines. Pharmacist’s

Letter/Prescriber’s Letter. January 2014.

Evidence and Recommendations You Can Trust…

3120 West March Lane, Stockton, CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Copyright 2014 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 #280502 −This Detail-Document accompanies the related article published in−

PHARMACIST’S LETTER / PRESCRIBER’S LETTER May 2012


Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 www.pharmacistsletter.com ~ www.prescribersletter.com ~ www.pharmacytechniciansletter.com

Characteristics of the Various Statins

―Based on U.S. product labeling and relevant studies. Canadian product information given if differs significantly (e.g., more conservative) from U.S. (Full update

November 2013)―

View our helpful PL Chart, Non-Statin Lipid-Lowering Agents

Druga Potency (average

decrease in

LDL)1,2,8

Renal

Considerations

Liver Function

Monitoringc

Selected Drug Interactions

Cost/month

(U.S./

Canada)b

Atorvastatin

(Lipitor, generics)

10 mg: 35-39%

20 mg: 43%

40 mg: 50%

80 mg: 55-60%

No dose

adjustment

necessary for

reduced renal

function.

(Use 10 mg

daily in patients

with renal

disease per

Canadian

labelling.)

Check liver function

tests at baseline and

when clinically

indicated.4

Metabolized by CYP3A4, but less than

lovastatin and simvastatin. Some drugs

that significantly inhibit its metabolism

through CYP3A4 inhibition include

amiodarone, erythromycin,

clarithromycin, telithromycin,

itraconazole & other azoles, nefazodone,

protease inhibitors, cyclosporine, and

grapefruit juice; atorvastatin dose

reduction or discontinuation may be

recommended. Consider cautious dosing

with niacin or fibrates (avoid

gemfibrozil). Rifampin may increase or

decrease levels, depending on timing.

10 mg:

$7.08

(generic)/

$10.17

(generic)

Fluvastatin

(Lescol, generics;

Lescol XL)

20 mg: 22%

40 mg: 25%

80 mg: 35%

(as XL product)

In severe renal

impairment, use

daily doses over

40 mg with

caution.

(Canadian

labelling

recommends not

using if CrCl

<30 mL/min.)


tests at baseline (and

8 weeks after initiation

or dosage increase, per

Canadian labelling) and

when clinically

indicated.4

Metabolized primarily by CYP2C9. Few

significant interactions with 2C9

inhibitors.3 May be less likely to be

involved in drug interactions. Use with

phenytoin or glyburide can increase

levels of both drugs. Consider dose

reduction with niacin. Caution with

fibrates (avoid gemfibrozil). Max dose

20 mg twice daily with cyclosporine or

fluconazole. Rifampin decreases levels.

80 mg XL:

$162.24/

$49.39

http://www.pharmacistsletter.com/

http://www.prescribersletter.com/

(PL Detail-Document #280502: Page 2 of 9)




decrease in

LDL)1,2,8

Renal

Considerations

Liver Function

Monitoringc


Cost/month

(U.S./

Canada)b

Lovastatin

(Mevacor, generics)

10 mg: 21%

20 mg: 24-27%

40 mg: 30-31%

80 mg: 40-42%

(as 40 mg BID)

If CrCl

<30 mL/min,

use daily doses

over

20 mg with

caution.



periodically, per

Canadian labelling

[more frequent with

40 mg or more]) and

when clinically

indicated.4

Metabolized by CYP3A4.

Contraindicated with strong CYP3A4

inhibitors including erythromycin,


itraconazole, ketoconazole,

posaconazole, voriconazole, protease

inhibitors, and nefazodone. Avoid

grapefruit and cyclosporine

(cyclosporine contraindicated [Canada]).

Do not exceed 40 mg daily with

amiodarone. Do not exceed 20 mg daily

with diltiazem, verapamil, danazol,

dronedarone, or niacin >1000 mg/day

(Canada), or 40 mg daily with extended-

release niacin (Niaspan). Consider dose

reduction with ranolazine. Caution with

fibrates (avoid gemfibrozil; do not

exceed 20 mg daily with fibrates

[Canada]).

40 mg:

$<5

(generic)/

$29.11

(generic)

Pitavastatin

(Livalo) (U.S. only)

1 mg: 29%

2 mg: 36-39%

4 mg: 41-45%

For glomerular

filtration rate

(GFR) 15-59

mL/min/1.73m2,

including

hemodialysis,

initial daily dose

is 1 mg, max

daily dose is

2 mg.



when clinically

indicated.4

Not significantly metabolized by

cytochrome P450 and may be less likely

to be involved in drug interactions.

Contraindicated with cyclosporine.

Limit dose to 1 mg daily with

erythromycin or 2 mg daily with

rifampin. Consider dosage reduction

with niacin. Caution with fibrates (avoid

gemfibrozil).

2 mg:

$150







decrease in

LDL)1,2,8

Renal

Considerations

Liver Function

Monitoringc


Cost/month

(U.S./

Canada)b

Pravastatin

(Pravachol, generics)

10 mg: 22%

20 mg: 29%

40 mg: 34%

80 mg: 37%

In significant

renal

impairment,

start with 10 mg

daily.

(Canadian

labelling advises

caution with

daily doses

of 40 mg or

more in renal

impairment.)



12 weeks after

initiation or dosage

increase, per Canadian

labelling), and when

clinically indicated.4



to be involved in drug interactions. Do

not exceed 20 mg once daily with

cyclosporine. Do not exceed 40 mg once

daily with clarithromycin. Caution with

fibrates (avoid gemfibrozil). Consider

dose reduction with niacin

>1000 mg/day.

40 mg:

$18.82

(generic)/

$18.65

(generic)

Rosuvastatin

(Crestor, generics

[Canada])

5 mg: 45%

10 mg: 46-49%

20 mg: 50-55%

40 mg: 55-63%

If CrCl <30

mL/min/1.73 m2

(but not on

hemodialysis),

starting dose is

5 mg daily,

maximum

10 mg daily.

Rosuvastatin

levels in

hemodialysis

patients are

about 50%

higher than

levels in normal

renal function.



12 weeks after

initiation, and before

and 12 weeks after

titration to 40 mg, per

Canadian labelling),

and when clinically

indicated.4



to be involved in drug interactions.

Substrate of transporter proteins

OATP1B1 and BCRP. Drugs that may

increase rosuvastatin levels include

dronedarone and itraconazole. Caution

with niacin. Limit to 10 mg with

lopinavir/ritonavir or

atazanavir/ritonavir. Use caution with

other protease inhibitor/ritonavir

combos. Protease inhibitor use

discouraged in Canadian labelling.

Canada: cyclosporine contraindicated.

Rosuvastatin 40 mg contraindicated with

fibrate or niacin.

U.S.: max rosuvastatin dose 5 mg with

cyclosporine, and 10 mg with

gemfibrozil (avoid gemfibrozil

preferred); caution with fenofibrate.

5 mg:

$171.33/

$10.45

(generic)







decrease in

LDL)1,2,8

Renal

Considerations

Liver Function

Monitoringc


Cost/month

(U.S./

Canada)b

Simvastatin

(Zocor, generics)

5 mg: 26%

10 mg: 29%

20 mg: 38%

40 mg: 30-41%

80 mg: 36-47%

In severe renal

impairment,

starting dose is

5 mg daily with

close

monitoring.

(Per Canadian

labelling,

caution with

doses >10 mg

daily with

severe renal

impairment

[CrCl

<30 mL/min].)



when clinically

indicated.4

(Per Canadian

labelling, for patients to

be titrated to 80 mg,

check prior to dosage

increase, three months

later, then periodically

[e.g., semiannually] for

the first year.)

Metabolized by CYP3A4.

Contraindicated with strong CYP3A4

inhibitors including erythromycin,


itraconazole, ketoconazole,

posaconazole, voriconazole, protease

inhibitors, and nefazodone.

Cyclosporine and danazol

contraindicated. Avoid grapefruit. Do

not exceed 20 mg daily with amiodarone,

amlodipine, ranolazine, or lomitapide.


diltiazem, verapamil, or dronedarone.


extended-release niacin (Niaspan), in

Chinese patients taking >1 g/day niacin,

or with lomitapide in patients who have

previously tolerated simvastatin 80 mg.

Contraindicated with gemfibrozil.

Caution with fibrates (do not exceed

10 mg with fenofibrate [Canada]).

20 mg:

$<4

(generic)/

$20.26

(generic)

a. The following product labeling was used for the above chart: Lipitor (October 2012), Lescol/Lescol XL (October 2012), Mevacor (October 2012),

Livalo (October 2013), Pravachol (October 2012), Crestor (August 2013), Zocor (October 2013), Niaspan (March 2013), Lipitor Canada (May

2013), Lescol/Lescol XL Canada (September 2013), Mevacor Canada (April 2013), Pravachol Canada (January 2013), Crestor Canada (May 2013),

Zocor Canada (March 2013).

b. U.S. cost is wholesale average cost (WAC). Canadian cost is wholesale cost. Cost is for generic if available.

c. Tell statin users to stop the statin and report symptoms of liver injury (e.g., jaundice, abdominal pain, etc) right away. Stop the statin in the event

of evidence of liver injury (e.g., elevated direct bilirubin level, hepatomegaly, jaundice, increased prothrombin time).5,6

If the statin cannot be

excluded as a cause of liver injury, do not restart a statin.5 But if elevated transaminase levels are the only problem, experts recommend continuing

the statin.5 There’s no proof that dose reduction is necessary.

5 If transaminases exceed three times the upper limit of normal, repeat the test.

6 In

asymptomatic patients with transaminases less than five times normal and no evidence of liver injury, the repeat test can be deferred for six months.






In the meantime, stop alcohol and hepatotoxic medications, encourage weight loss, and control diabetes.7 If still elevated, rule out other causes and

consider decreasing the dose or stopping the statin.6

Abbreviations: ACS = acute coronary syndrome; CHD = coronary heart disease; HDL = high-density lipoprotein cholesterol; LDL = low-density

lipoprotein cholesterol; MACE = major adverse cardiac event (cardiac death, non-fatal MI, or revascularization); MI = myocardial infarction; OATP

= organic anion transporting polypeptide; PCI = percutaneous coronary intervention; TIA = transient ischemic attack. Evidence is Level A for all

studies except CARDS, FLORIDA, TREADMILL [Level A/B] and GREACE and L-CAD [Level B].

Clinical Benefit of Statins (Study acronym in parentheses; FDA-labeled indications are underlined. Full update April 2012.)

Atorvastatin (Lipitor)

▪ Primary prevention of CHD: Reduces non-fatal MI and fatal CHD, and stroke in patients with hypertension and total cholesterol <250 mg/dL

(ASCOT).

▪ Primary prevention of CHD in diabetes: Reduces stroke and MI in patients with type 2 diabetes, an additional CHD risk factor, and LDL

<160 mg/dL (CARDS).

▪ Secondary prevention of CHD: 80 mg/day reduced risk of major cardiovascular events in patients with CHD and LDL<130 mg/dL vs 10 mg. No

overall mortality difference (TNT).

Secondary prevention of CHD: 80 mg/day reduced risk of non-fatal cardiovascular events vs simvastatin 40-80 mg/day in patients with CHD and

previous MI (mean LDL 121.5 mg/dL) (IDEAL).

▪ Secondary prevention of CHD:* Reduced risk of coronary morbidity and mortality, and stroke in open-label comparison with usual care of patients

with LDL >100 mg/dL (GREACE). (*Note: GREACE not used to support this indication.)

▪ 80 mg/day begun within 1 to 4 days after ACS reduced recurrent ischemic events and stroke over 4 months (MIRACL).

▪ In ACS, intense lipid lowering (median LDL 62 mg/dL) lowers risk of death/major cardio events more than moderate lipid lowering (median LDL

95 mg/dL) (PROVE-IT).

▪ Regresses/slows progression of atherosclerosis (ASAP, ARBITER, REVERSAL).

▪ Unclear benefit in peripheral arterial disease (TREADMILL).






Fluvastatin (Lescol)

▪ Slows progression of atherosclerosis in patients with CHD and mild to moderate hypercholesterolemia (LCAS).

▪ Secondary prevention of CHD: Reduces need for revascularization. Dose of 40 mg twice daily reduced risk of MACE when begun within days

after PCI in patients with average cholesterol levels (LIPS).

▪ Did not reduce MACE in renal transplant recipients, but secondary endpoints of cardiac death and MI were reduced (ALERT).

▪ No benefit for early treatment of ACS with 80 mg/day (FLORIDA).

Lovastatin (Mevacor)

▪ Primary prevention of CHD: Reduces first acute coronary event, MI, unstable angina, and revascularization in patients with average LDL

(AFCAPS/ TexCAPS).

▪ Slows progression of coronary atherosclerosis in CHD (CCAIT, FATS, MARS). Improvement also in carotid arteries (ACAPS).

Pitavastatin (Livalo)

▪ Pitavastatin 4 mg and atorvastatin 20 mg similarly reduce nonculprit coronary plaque volume post-ACS (JAPAN-ACS).

Pravastatin (Pravachol)

▪ Primary prevention of CHD: Reduces cardiovascular death, MI, and revascularization in patients with high LDL and multiple risk factors

(WOSCOPS).

▪ Secondary prevention of CHD: Reduces recurrent MI, coronary death, revascularization, and stroke/TIA across range of cholesterol levels (CARE,

LIPID).

▪ Slows progression of coronary atherosclerosis in CHD; improvement also in carotid arteries (REGRESS, PLAC I, PLAC II, KAPS).

▪ Failed to show benefit in hypertensive patients (ALLHAT-LLT), but result probably due to high non-study statin use in usual care group.

▪ Preliminary study found lower risk of MACE with early therapy of ACS (L-CAD).

▪ Reduced composite of coronary death, non-fatal MI, and stroke in high-risk patients >70 years old, but no benefit for stroke alone; result attributed

to short study duration (PROSPER).






Rosuvastatin (Crestor)

▪ Regression of atherosclerosis with intensive statin therapy in patients with angiographic coronary disease.

▪ 40 mg/day reduced LDL (mean 60.8 mg/dL), raised HDL (mean 49.0 mg/dL), and reduced percent mean atheroma volume by 0.98% (ASTEROID).

▪ Slows progression of atherosclerosis (METEOR).

▪ Primary prevention of CAD: Reduces MI, stroke, and cardiovascular death in patients with LDL <130 mg/dL and hs-CRP >2 mg/L (JUPITER).

Simvastatin (Zocor)

▪ Primary and secondary prevention of CHD: Reduces risk of total mortality, non-fatal MI, stroke, and revascularization in patients at high risk of

coronary eventsc, but with normal cholesterol (including LDL <100 mg/dL, women, diabetes, and peripheral arterial disease) (HPS).

▪ Secondary prevention of CHD: Reduces recurrent MI, coronary and total mortality, revascularization, and stroke in patients with high LDL (4S).

▪ Slows progression of atherosclerosis in patients with CHD and normal to high cholesterol (MAAS, SCAT).

▪ Combined with niacin reduces major coronary events in patients with CHD and HDL <35 mg/dL (HATS).

▪ Reduces vascular events (HPS) and development/progression of intermittent claudication (4S) in peripheral arterial disease.

c. In patients with CHD or CHD risk-equivalent (diabetes, peripheral arterial disease, history of stroke or other cerebrovascular disease).

Statin Clinical Trials 4S - Scandinavian Simvastatin Survival Study: Lancet 1994;344:1383-9. Am J Cardiol 1998;81:333-5.

ACAPS - Asymptomatic Carotid Artery Progression Study: Circulation 1994;90:1679-87.

AFCAPS/TEXCAPS - Air Force/Texas Coronary Atherosclerosis Prevention Study: JAMA 1998;279:1615-22.

ALERT - Assessment of Lescol in Renal Transplantation Study: Lancet 2003;361:2024-31.

ALLHAT-LLT - Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: JAMA 2002;288:2998-3007.

ARBITER - Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: Circulation 2002;106:2055-60.

ASAP - Atorvastatin versus Simvastatin on Atherosclerosis Prevention: Lancet 2001;357:577-81.

ASCOT - Anglo-Scandinavian Cardiac Outcomes Trial: Lancet 2003;361:1149-58.

ASTEROID - A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden: JAMA

2006;295:1556-65.

CARDS - Collaborative Atorvastatin Diabetes Study. Lancet 2004;364:685-96.

CARE - Cholesterol and Recurrent Events Trial: N Engl J Med 1996;335:1001-9.

CCAIT - Canadian Coronary Atherosclerosis Intervention Trial: Circulation 1994;89:959-68. Circulation 1995;92:2404-10.






FATS - Familial Atherosclerosis Treatment Study: N Engl J Med 1990;323:1289-98.

FLORIDA - Fluvastatin on Risk Diminishing after Acute Myocardial Infarction: [Abstract] Circulation 2000;102:2672d.

GREACE - GREek Atorvastatin and Coronary-heart-disease Evaluation study: Curr Med Res Opin 2002;18:220-8.

HATS - HDL Atherosclerosis Treatment Study: N Engl J Med 2001;345:1583-92.

HPS - Heart Protection Study: Lancet 2002;360:7-22. Lancet 2003;361:2005-16.

IDEAL - Incremental Decrease in End points through Aggressive Lipid lowering. JAMA 2005;294:2437-45.

JAPAN-ACS - Effect of intensive statin therapy on regression of coronary atherosclerosis in patients with acute coronary syndrome: a multicenter

randomized trial evaluated by volumetric intravascular ultrasound using pitavastatin versus atorvastatin (JAPAN-ACS [Japan assessment of

pitavastatin and atorvastatin in acute coronary syndrome] study. J Am Coll Cardiol 2009;54:293-302.

JUPITER - Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin. N Engl J Med 2008;359:2195-207.

KAPS - Kuopio Atherosclerosis Prevention Study: Circulation 1995;92:1758-64.

LCAS - Lipoprotein and Coronary Atherosclerosis Study: Am J Cardiol 1997;80:278-86.

L-CAD - Lipid-Coronary Artery Disease Study: Am J Cardiol 2000;86:1293-8.

LIPID - Long-term Intervention with Pravastatin in Ischaemic Disease: N Engl J Med 1998;339:1349-57.

LIPS - Lescol Intervention Prevention Study: JAMA 2002;3215-22.

MAAS - Multicentre Anti-Atheroma Study: Lancet 1994;344:633-8.

MARS - Monitored Atherosclerosis Regression Study: Ann Intern Med 1993;119:969-76.

METEOR - Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin: JAMA 2007;297:1344-53.

MIRACL - Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering: JAMA 2001;285:1711-8.

PLAC-I - Pravastatin Limitation of Atherosclerosis in the Coronary arteries (PLAC-I): J Am Coll Cardiol 1995;26:1133-9.

PLAC-II - Pravastatin Limitation of Atherosclerosis in the Carotid arteries. Am J Cardiol 1995;75:455-9.

PROSPER - Prevention of First Stroke: Lancet 2002;360:1623-30.

PROVE-IT - Pravastatin or Atorvastatin Evaluation and Infection Therapy: New Engl J Med 2004;350 (early release).

REGRESS - Regression Growth Evaluation Study: Circulation 1995;91:2528-40.

REVERSAL - Reversal of Atherosclerosis with Aggressive Lipid Lowering. JAMA 2004;291:1071-80.

SCAT - Simvastatin/Enalapril Coronary Atherosclerosis Trial: Circulation 2000;102:1748-54.

TNT - Treating to New Targets. N Engl J Med 2005;352:1425-35.

TREADMILL - Treatment of Peripheral Atherosclerotic Disease with Moderate or Intensive Lipid Lowering: Creager MA, et al [Abstract].

Presented at the 14th International Symposium on Drugs Affecting Lipid Metabolism, New York, September 9-13, 2001. Mohler E, et al. [Abstract].

Presented at the 75th Scientific Sessions of the American Heart Association, Chicago, November 17-20, 2002.

WOSCOPS - West of Scotland Coronary Prevention Study: N Engl J Med 1995;333:1301-7.


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.



(Detail-Document #280502: Page 9 of 9)

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. PL Detail-Document, Statin Dose Comparison (U.S.).

Pharmacist’s Letter/Prescriber’s Letter. August 2009 (Full update June 2013).

2. PL Detail-Document, Statin Dose Comparison (Canada). Pharmacist’s Letter/Prescriber’s Letter.

August 2009 (Last modified November 2011). 3. Shitara Y, Sugiyama Y. Pharmacokinetic and

pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual

differences in transporter and metabolic enzyme functions. Pharmacol Ther 2006;112:71-105.

4. FDA. FDA drug safety communication: important safety label changes to cholesterol-lowering statin drugs. February 28, 2012. http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm. (Accessed March 16, 2012).

5. Cohen DE, Anania FA, Chalasani N. An assessment of statin safety by hepatologists. Am J Cardiol

2006;97:77C-81C. 6. McKenney JM, Davidson MH, Jacobson TA, Guyton

JR. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006;97:89C-94C.

7. American Gastroenterological Association. American Gastroenterological Association medical position statement: evaluation of liver chemistry tests. Gastroenterology 2002;123:1364-6.

8. Stone NJ, Robinson J, Lichtenstein C, 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 2013. (Published ahead of print Nov 12). DOI: 10.1161/01.cir.0000437738.63853.7a.

Cite this document as follows: PL Detail-Document, Characteristics of the Various Statins. Pharmacist’s

Letter/Prescriber’s Letter. May 2012.


3120 West March Lane, P.O. Box 8190, Stockton, CA 95208 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Copyright 2012 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


P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 www.pharmacistsletter.com ~ www.prescribersletter.com ~ www.pharmacytechniciansletter.com

PL Detail-Document #280606 −This PL Detail-Document gives subscribers

additional insight related to the Recommendations published in− PHARMACIST’S LETTER / PRESCRIBER’S LETTER

June 2012

Statin-Associated Muscle Symptoms

Background As many as 30% of patients taking a statin

report muscle aches or weakness.1 A thorough understanding of this side effect by health care professionals may minimize unnecessary statin dose reduction or discontinuation of these life-saving medications, while reducing the risk of life-threatening outcomes. This article discusses proposed mechanisms, risk factors, prevention, monitoring, and management of statin myopathy.

Mechanism and Risk Factors

According to the American College of Cardiology/American Heart Association/National Heart, Lung, and Blood Institute Clinical Advisory on the Use and Safety of Statins, myopathy is a general term for any muscle disease. Myalgia refers to muscle pain or weakness without increased creatine kinase, whereas myositis includes elevated creatine kinase. Rhabdomyolysis is defined as muscle symptoms, very high creatine kinase (10 times the upper limit of normal), and increased serum creatinine, often with dark urine and myoglobinuria.2 Other groups use different terminology.3,4 Patients may use terms like weakness, cramping, tenderness, soreness, stiffness, or heaviness to describe their symptoms. Symptoms are usually symmetrical and often involve proximal muscles.5 In the PRIMO study, the thighs or calves are the predominant site of complaints in over a quarter of sufferers.4

Risk factors for statin myopathy include being elderly, small size, high statin dose, liver or renal disease, diabetes, uncontrolled hypothyroidism, and interacting medications.3

The mechanism of statin myopathy is unclear. It may involve statins’ inhibition of the production of substances needed for muscle cells to function normally. These substances include dolichols, isoprenylated proteins, and coenzyme Q10, which participate in cellular respiration. Another theory involves altered muscle cell membrane function as

the result of decreased cell membrane cholesterol content. However, myopathy risk is not related to cholesterol levels. There is evidence that increased LDL receptor sensitivity caused by statins could cause increased intake of fat or plant sterols into the muscle.3

Evidence from the PRIMO study suggests that fluvastatin carries the lowest risk of myopathy followed by pravastatin. Myalgia occurred in 10.9% of patients receiving pravastatin (Pravachol) 40 mg daily and in 5.1% of patients receiving fluvastatin (Lescol XL) 80 mg daily (p<0.001). Muscle symptoms were reported in 14.9% of patients receiving atorvastatin 40 mg or 80 mg daily (p=0.04, compared to pravastatin), and in 18.2% of patients receiving simvastatin at a dose of 40 mg or 80 mg daily (p<0.001, compared to pravastatin). The apparently lower risk of myalgia with fluvastatin and pravastatin may be explained by their low propensity for drug interactions (see below) and/or, in theory, their relatively low distribution into muscle due to their hydrophilic nature. In addition, fluvastatin has low systemic bioavailability (i.e., it has high first-pass hepatic elimination) and is highly bound to serum proteins. Rosuvastatin is also hydrophilic and has a relatively low propensity for drug interactions, but it has a long half-life.4

Drug Interactions

The risk of myopathy is increased when statins are coadministered with medications that inhibit their metabolism. Interactions vary among the statins due to differences in their metabolic pathways. Atorvastatin (Lipitor), lovastatin (Mevacor), and simvastatin (Zocor) are CYP3A4 substrates and when coadministered with potent CYP3A4 inhibitors the incidence of myopathy is increased by about five-fold.6 The extent of interaction between atorvastatin and CYP3A4 inhibitors is less than that with lovastatin and simvastatin.7 Lovastatin and simvastatin are termed “sensitive substrates” because their levels




may be increased five-fold or higher by CYP3A4 inhibitors.7 Fluvastatin is primarily metabolized by CYP2C9 and to a lesser extent by CYP3A4 and CYP2D6.8 Pravastatin is not significantly metabolized by the cytochrome P450 system and does not interact with other CYP substrates.5 Rosuvastatin (Crestor) and pitavastatin (Livalo) also aren’t extensively metabolized by the cytochrome P450 system.9-11 Statins are substrates for P-glycoprotein; therefore, drugs that inhibit P-glycoprotein (e.g., cyclosporine, diltiazem, etc) may increase statin levels.7

Other medications increase risk because they themselves have been associated with myopathy (e.g., cyclosporine, danazol, niacin, fibrates). The increased risk of myopathy is well recognized when statins and fibric acid derivatives are coadministered since both classes of drugs have the potential for inducing myopathy. However, the risk is less with fenofibrate than gemfibrozil. This may be because gemfibrozil inhibits hepatic glucuronidation of statins, thereby interfering with statin elimination.12-14

In managing statin interactions, choosing a noninteracting medication or switching to a noninteracting statin (i.e., for chronic therapy) may be the safest or easiest option. For certain statin interactions, reducing the statin dose may be an acceptable management technique. In patients with stable cardiovascular disease, interactions between lovastatin or simvastatin and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole) are managed by stopping the statin as soon as the interacting drug is started. Recommendations vary, but some experts suggest restarting the statin three days or so after the interacting drug has been discontinued. See our chart for more detailed information about clinically significant statin drug interactions, including mechanisms and management. Management

When statin therapy is initiated, clinicians can consider checking a baseline creatine kinase level as a point of reference, especially in those at high risk of myopathy.2,15 Routine monitoring is not necessary in most patients. Increases are common, particularly with physical exertion. Surveillance may be helpful in patients with liver or renal insufficiency or in patients taking interacting medications.1

Symptomatic patients should have creatine kinase level checked.2,15 Some experts recommend checking a thyroid-stimulating hormone level to rule out hypothyroidism as a cause of myalgia.2 It has also been suggested that vitamin D deficiency should be ruled out as a cause of muscle symptoms.16 In one report, statin users with muscle symptoms had lower vitamin D levels than statin users without muscle symptoms. Elevated creatine kinase levels were not more common among the patients with myalgia. Vitamin D supplementation was given to patients with myalgia plus 25-hydroxyvitamin D levels less than 32 ng/mL. Myalgia resolved in over 90% of these patients despite statin continuation.17

Symptoms, creatine kinase level, and development of risk factors determine the necessity of statin discontinuation. Statins (and niacin or fibrate, if applicable) should be discontinued if creatine kinase becomes markedly increased (i.e., 10 or more times the upper limit of normal), especially in symptomatic patients.2 Others recommend stopping statins in patients with severe muscle symptoms regardless of creatine kinase results.1,15 Statins should also be held in the event of rhabdomyolysis; sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled seizure disorders.9-11,18-

27 Canadian labeling for lovastatin and simvastatin recommends holding these statins beginning a few days before major elective surgery.18,19

Asymptomatic patients with a creatine kinase <5 times the upper limit of normal in whom other causes (e.g., physical exertion) have been excluded should simply be educated to report symptoms. If the creatine kinase is >5 to <10 times the upper limit of normal, asymptomatic patients should be educated about symptoms and retested monthly or bimonthly.3

Symptomatic patients with a creatine kinase <10 times the upper limit of normal should have symptoms and creatine kinase checked weekly until resolution. If creatine kinase worsens, consider statin discontinuation or dose reduction.2 Others recommend using symptoms to guide treatment decisions and as long as symptoms are tolerable they don’t recommend serial creatine kinase monitoring in these patients.15

Assuming benefits of continuing the statin outweigh the risk of myopathy, patients with




tolerable symptoms can try coenzyme Q10. Efficacy studies have found conflicting results.3,28 However, some patients and cardiologists feel it is beneficial. It is likely safe when dosed appropriately.28 A dose of 100 mg once daily or 200 mg divided two or three times daily (to minimize gastrointestinal side effects) has been recommended.28

If statin discontinuation is indicated, the risks and benefits of restarting the statin can be reviewed once the patient’s signs and symptoms have resolved.2 This can take two months or more.1,29 For patients who suffered acute renal failure or a creatine kinase over 10,000 units/L, a nonstatin alternative should be considered.3 Patients with less serious sequelae can be rechallenged with the same statin, preferably at a lower dose, or an alternate regimen can be tried.2,3 Some patients may tolerate fluvastatin, alone or with ezetimibe (Zetia), a low-dose statin plus ezetimibe, or extended interval dosing using a more potent, longer-acting statin (rosuvastatin, atorvastatin).3,5,30 Studied or suggested regimens include rosuvastatin 5 mg to 20 mg once weekly; rosuvastatin 5 mg twice weekly; rosuvastatin at a dose of 2.5 mg to 10 mg three times weekly; rosuvastatin 5 mg or 10 mg daily; atorvastatin or rosuvastatin every other day; or 10 mg atorvastatin twice weekly plus 10 mg ezetimibe daily.3,31 Sometimes, patients can tolerate statins for several weeks before symptoms occur. These patients can be given “pulse” therapy (e.g., four weeks on, one or two weeks off), depending on their individual tolerance [Evidence level D; anecdotal evidence].3

Commentary

Alternate statin dosing regimens reportedly can provide good LDL reduction with improved tolerability.3 When deciding on an alternative lipid-lowering regimen in a patient with statin myopathy, consider the evidence of benefit. For example, the effect of reduced frequency regimens (e.g., every other day) on cardiovascular morbidity and mortality has not been studied. Statin doses used in secondary prevention studies showing a mortality benefit were moderate (e.g., pravastatin 40 mg, simvastatin 20 mg).32 Patients taking a low statin dose may need additional LDL lowering. The addition of ezetimibe (Zetia) or a bile acid sequestrant (e.g., cholestyramine [Questran, others], colestipol [Colestid],

colesevelam [Welchol-U.S.; Lodalis-Canada]) to a statin may reduce LDL by up to an additional 20% to 25% in some cases. Of the nonstatins, bile acid sequestrants have the best evidence for cardiovascular event prevention.33 If patients cannot tolerate a statin, a bile acid sequestrant, niacin, or ezetimibe can be considered either as monotherapy or in combination. For example, the combination of ezetimibe plus a bile acid sequestrant can reduce LDL by about 40%.33,34

Also consider the risk/benefit ratio. For example, rechallenge with a statin in a patient with a history of statin-associated rhabdomyolysis should be avoided, especially if the indication for the statin is primary prevention [Evidence level C; expert opinion].35 Diet and lifestyle changes to improve cardiovascular risk are especially important interventions in this situation.35

Another consideration is the cardiovascular risk of stopping a statin. Stopping a statin for up to six weeks in a stable patient appears safe.36 For example, simvastatin could be held to allow treatment of an infection with clarithromycin. (Alternately, a noninteracting antibiotic [e.g., moxifloxacin (Avelox)] or statin [e.g., rosuvastatin (Crestor)] could be substituted). The cardiovascular risk of stopping a statin is higher in unstable patients. Morbidity and mortality is increased in acute myocardial infarction (MI) and ischemic stroke patients whose statins are discontinued.37-39 This association may be seen quickly. In one study there was increased risk of in-hospital death in patients with non-ST segment elevation MI whose statin was discontinued.37 In addition, stopping statin therapy in acute ischemic stroke patients resulted in early neurologic deterioration and poorer outcomes.39 Therefore, statins should only be discontinued in acute MI or stroke when clearly indicated.37-40

As the population ages, more patients will be at risk of statin myopathy. Advanced age is a risk factor, and the elderly tend to take more medications that could potentially interact. To provide the best margin of safety, heed drug interaction warnings and dosing recommendations, weighing cardiovascular benefit against myopathy risk.2





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. Heart Protection Study Collaborative Group.

MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.

2. Pasternak RC, Smith SC, Bairey-Merz CN, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation 2002;106:1024-8.

3. Venero CV, Thompson PD. Managing statin myopathy. Endocrinol Metab Clin North Am 2009;38:121-36.

4. Jacobson TA. Toward “pain-free” statin prescribing: clinical algorithm for diagnosis and management of myalgia. Mayo Clin Proc 2008;83:687-700.

5. Eckel RH. Approach to the patient who is intolerant of statin therapy. J Clin Endocrinol Metab 2010;95:2015-22.

6. Jacobson TA. Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol 2004;94:1140-6.

7. Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet 2002;41:343-70.

8. FDA Center for Drug Evaluation and Research. Guidance for industry. Drug interaction studies-study design, data analysis, implications for dosing, and labeling recommendations. Draft guidance. February 2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf. (Accessed May 10, 2012).

9. Product information for Crestor. AstraZeneca Pharmaceuticals LP. Wilmington, DE 19850. February 2012.

10. Product monograph for Crestor. AstraZeneca Canada Inc. Mississauga, ON L4Y 1M4. April 2012.

11. Product information for Livalo. Kowa Pharmaceuticals America, Inc. Montgomery, AL 36117. February 2012.

12. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin. Am J Cardiol 2005;95:120-2.

13. Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with fibrates. Am J Cardiol 2004;94:935-8.

14. Corsini A, Bellosta S, Davidson MH. Pharmacokinetic interactions between statins and fibrates. Am J Cardiol 2005;96:44K-49K.

15. McKenney JM, Davidson MH, Jacobson TA, Guyton JR. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006;97(8A):89C-94C.

16. Goldstein MR. Myopathy, statins, and vitamin D deficiency. Am J Cardiol 2007;100:1328.

17. Ahmed W, Khan N, Glueck CJ, et al. Low serum 25(OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients. Transl Res 2009;153:11-6.

18. Product monograph for Mevacor. Merck Frosst Canada Ltd. Kirkland, QC H9H 3L1. March 2011.

19. Product monograph for Zocor. Merck Frosst Canada Ltd. Kirkland, QC H9H 3L1. October 2011.

20. Product information for Mevacor. Merck & Co., Inc. Whitehouse Station, NJ 08889. February 2012.

21. Product information for Zocor. Merck & Co., Inc. Whitehouse Station, NJ 08889. February 2012.

22. Product information for Lipitor. Pfizer Inc. NY, NY 10017. February 2012.

23. Product monograph for Lipitor. Pfizer Canada Inc. Kirkland, QC H9J 2M5. March 2011.

24. Product information for Lescol and Lescol XL. Novartis Pharmaceuticals Corporation. East Hanover, NJ 07936. February 2012.

25. Product monograph for Lescol and Lescol XL. Novartis Pharmaceuticals Canada, Inc. Dorval, QC H9S 1A9. March 2012.

26. Product information for Pravachol. Bristol-Myers Squibb Company. Princeton, NJ 08543. February 2012.

27. Product monograph for Pravachol. Bristol-Myers Squibb Canada. Montreal, QC H4S 0A4. October 2010.


28. Jellin JM, Gregory PJ, et al. Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. (Accessed May 10, 2012).

29. Vladutiu GD. Genetic predisposition to statin myopathy. Curr Opin Rheumatol 2008;20:648-55.

30. Arca M, Pigna G. Treating statin-intolerant patients. Diabetes Metab Syndr Obes 2011;4:155-66.

31. Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med 2009;150:858-68.

32. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-421.

33. PL Detail-Document, Non-statin Lipid-lowering Agents. Pharmacist’s Letter/Prescriber’s Letter. December 2009.

34. Xydakis AM, Guyton JR, Chiou P, et al. Effectiveness and tolerability of ezetimibe add-on therapy to a bile acid resin-based regimen for hypercholesterolemia. Am J Cardiol 2004;94:795-7.

35. Antons KA, Williams CD, Baker SK, Phillips PS. Clinical perspectives of statin-induced rhabdomyolysis. Am J Med 2006;119:400-9.

36. McGowan MP, Treating to New Target (TNT) Study Group. There is no evidence for an increase in acute coronary syndromes after short-term abrupt discontinuation of statins in stable cardiac patients. Circulation 2004;110:2333-5.

37. Daskalopoulou SS, Delaney JA, Filion KB, et al. Discontinuation of statin therapy following an acute myocardial infarction: a population-based study. Eur Heart J 2008;29:2083-91.

38. Spencer FA, Fonarow GC, Frederick PD, et al. Early withdrawal of statin therapy in patients with non-ST-segment elevation myocardial infarction: National Registry of Myocardial Infarction. Arch Intern Med 2004;164:2162-8.

39. Blanco M, Nombela F, Castellanos M, et al. Statin treatment withdrawal in ischemic stroke: a controlled randomized study. Neurology 2007;69:904-10.

40. Liao JK. Is statin discontinuation an option in patients who have had a stroke? Nat Clin Pract Neurol 2008;4:18-9.

Cite this document as follows: PL Detail-Document, Statin-Associated Muscle Symptoms. Pharmacist’s Letter/Prescriber’s Letter. June 2012.


3120 West March Lane, P.O. Box 8190, Stockton, CA 95208 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Copyright © 2012 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