HEARTBEATA Publication of South Jersey Heart Group

September 2017

Statin-associated muscle symptoms (SAMS) are a

commonly reported problem in patients who use or

start to use statins. This Heartbeat will provide a guide

for clinicians by detailing a structured approach that is

based on published data as well as expert opinion.

Statin Benefits: The cardiovascular (CV) benefits

of statins are backed by a vast database, and statins

have a favorable benefit/risk profile. Treatment with

moderate- and high-intensity statins reduces the

risk of CVD in the setting of high-risk primary and

secondary prevention.1,2 For every 18mg/dl reduction

in low-density lipoprotein-cholesterol (LDL-C), CVD

events are reduced by 21% after one year of treatment

with moderate- or high-intensity statins.3 The reduction

in ASCVD increases with long-term statin use.4

Problem: However, many patients taking statins

report SAMS that prevent the use of guideline-

recommended doses, even though randomized clinical

trials (RCTs) indicate that statins have a side-effect

profile almost indistinguishable from placebo or

comparative drugs, particularly when used in low

dosages.5 But “real world” data obtained from

surveys, registries and insurance claims suggest

that side effects of statins are common, especially

at higher doses.6 Many patients are unwilling to

continue with guideline-recommended statin doses

after experiencing side effects.7

Consequences: Patients who stop statins have a higher risk for recurrent myocardial infarction andstroke.8 This in turn leads to higher healthcare costs.9

The Challenge of SAMS: What makes this amore difficult problem is the overriding “nocebo

effect.” Muscle symptoms are common in the middle-aged population taking statins. The difference between the muscle symptom data from observationalstudies and data from RCTs is due to the nocebo effect. The nocebo effect—opposite of placebo—(Latin for “I do harm”) explains why some patients misattribute symptoms to their exposure to statins. Inthe context of SAMS (without significantly elevatedcreatine phosphokinase [CK] muscle enzyme) or otheradverse events, the nocebo effect is strengthened by exaggerated reports readily available online about thedangers of taking statins and by warnings appropriatelycommunicated by physicians and patient informationleaflets about myopathy/rhabdomyolysis.

Managing Statin Intolerance

In some cases, the patient becomes more conscious of background aches and pains when learning aboutthe adverse effects of statins; in other cases, newmuscle symptoms arise. Because a placebo-controlledrechallenge is not possible in the clinic, the return of symptoms upon rechallenge with the same or a different statin may well also be a nocebo effect.

Plan: Techniques to minimize the nocebo effect inpatients starting statins may help prevent statin intolerance. We should:

• Avoid communications that create negative expectations about statins.

• Emphasize the benefits of statins in reducing CV disease and indicate that serious muscle side effects are very unlikely and are easily detected with a blood test (CK).

• Remind patients that muscle aches and pains are common in middle age and older, and usually are due to other causes.

Management of SAMS

Whatever the etiology, these muscle symptoms are real to the

patient and must be carefully addressed by the physician in

order to keep the patient on a statin.

An excellent expert opinion piece from this month’s

JACC presenting a clinical approach is summarized

in the illustration below.10

How can we diagnose SAMS? Statin discontinuation

and rechallenge is the primary strategy for confirming

the presence of statin intolerance secondary to SAMS.

SAMS Unlikely:1. Symptoms start immediately after initiation

and/or resolve within minutes to hours upon cessation

2. Symptoms that do not improve or disappear within 12 weeks after statin discontinuation (four weeks often enough)

3. Symptom onset that is present after protracted use (>12 weeks) without changes in any other apparent patient status

4. Symptoms that occur with other classes of lipid-lowering agents

Asymmetric, intermittent or non-specific symptoms

to a particular area also make SAMS less likely.

Treatment of SAMSWe need to:

(a) Be convinced of the benefits of statins to convince

the patient to take one

(b) Listen to the patient when he/she reports symptoms,

assess severity of muscle symptoms and individualize

treatment accordingly. If the patient’s symptoms do

not interfere with activities of daily living and/or

post-exercise symptoms generally abate with rest and

occasional acetaminophen, I encourage the patient to

hang in there, and emphasize how important the statin

is to preventing heart attacks and strokes. When a

patient tells me his/her symptoms are unbearable, I’m

concerned about rhabdomyolysis and immediately stop

the statin if the patient hasn’t already done so, and use

the laboratory to further evaluate the patient.

(c) Educate the patient regarding benefits of a statin

(d) Let the patient decide (buy in) among several

recommended approaches:

1. Lower the dose.

2. Change the dose to every other day with high-

dose atorvastatin or rosuvastatin in our highest-

risk patients (both have long half-lives and are as

efficacious as daily dosing in reducing LDL-C,

though efficacy on ASCVD outcomes has not been

established).

CENTRAL ILLUSTRATION Clinical Approach to Patient With SAMS

After symptom resolution, initiate:Same dose of same statin

(low likelihood that SAMS will reoccur)or

Alternative high-intensity statin

Promote a healthy lifestyle If still high SAMS-CI score, initiate:

Consider non-statin LDL-C lowering therapy

Promote a healthy lifestyle

Clinical assessment: Statin-Associated Muscle Symptom Clinical Index (SAMS-CI)

Patient with suspected statin-associated muscle symptoms (SAMS)

High SAMS-CI scoreLow SAMS-CI score

Before establishing a diagnosis of statin intolerance:Review drug-drug interactions and co-morbidities

Check for hypothyroidism and vitamin D

Statin discontinuation

Readminister SAMS-CI

After symptom resolution, initiate:Lower dose of same statin

orAlternative high-intensity statin

Statin discontinuation

Evaluate for:

HDepression and anxiety

Rosenson, R.S. et al. J Am Coll Cardiol. 2017;70(10):1290–301.

3. Try pitavastatin or pravastatin, which have

less toxic effects because of different pharmokinetic

properties.

4. Discontinue and rechallenge.

All of these have been shown to improve patient adherence to

treatment in medical practice. Our favorite among those most

refractory is rosuvastatin one to three times per week.

Lifestyle Therapeutic lifestyle changes (TLC) should be considered

first-line therapy for lowering LDL-C and reducing CVD

risk. Several non-pharmacological approaches are

effective in lowering LDL-C and CVD risk, including

consumption of a heart-healthy diet, maintaining a

normal weight, avoidance of tobacco products and

regular exercise. TLC is particularly important for

patients with SAMS who cannot tolerate statin therapy.

Beyond statin rechallenge, working with patients to

help them achieve a healthy lifestyle is an essential

component of treating those with SAMS.

Non-Statin TherapiesConsideration should be given to adding non-statin

agents to prevent ASCVD events among patients

unable to tolerate statin therapy or able to tolerate

only low doses or intermittent dosing. Our first choice

is ezetimibe, usually well tolerated and generally

lowering LDL-C by 15% to 25%, as an add-on to

attempt to get your patient to acceptable LDL-C levels.

A PCSK9 inhibitor should be considered to lower LDL-C

in high-risk patients who cannot tolerate any statin.

Bile acid sequestrants, fenofibrates and niacin may

also be considered, but efficacy on ASCVD outcomes

is not convincing.

ConclusionsSAMS are the most common cause for statin

discontinuation or dose reduction. Most of the muscle

symptoms reported in patients taking statins are not

due to a statin-induced myopathy and can be overcome

with an individualized approach to management. We

should avoid statin discontinuation, which results in

increased ASCVD risk, especially in high-risk patients.

Mario L Maiese, DO, FACC, FACOI

Clinical Associate Professor of Medicine, Rowan SOM

Email: maiese1@comcast.net

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Heartbeat is a South Jersey Heart Group publication.

When a patient presents with SAMS, we should verify

that the patient truly cannot tolerate statin therapy.

These efforts involve evaluation of symptoms after

drug withdrawal and assessment of symptoms upon

re-initiation with an alternative statin or lower doses

of the same or a different statin.

CorrectionLast month’s Heartbeat, “Heart of a Woman,” was based

on a study from JACC called “Knowledge, Attitudes

and Beliefs Regarding CVD.” In the study, the authors

reported that heart disease in women was a top

concern for only 39% of primary care doctors. After

publication, the study authors issued a correction. In

fact, 76% of doctors gave heart disease a concern score

of 4 or 5 on a scale of 1 to 5, with 5 being

“extremely concerned.”

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References

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7 Colantonio LD, Huang L, Monda KL, et al. Adherence to high intensity statins following a myocardial infarction hospitalization among Medicare beneficiaries. JAMA Cardiol, [E-pub ahead of print]. 2017 Apr 19.

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10 Rosenson RS, et al. Optimizing cholesterol treatment in patients with muscle complaints. J Am Coll Cardiol September 5 2017; 70: 1290-1301.