The Effect of Statins on Skeletal Muscle Function - Circulationcirc.ahajournals.org/content/circulationaha/early/2012/11/26/... · PhD2; Stephanie M. Cole, PhD2; Justin Keadle, BS2;

DOI: 10.1161/CIRCULATIONAHA.112.136101

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The Effect of Statins on Skeletal Muscle Function

Running title: Parker et al.; Statins and Skeletal Muscle

Beth A. Parker, PhD1; Jeffrey A. Capizzi, MS1; Adam S. Grimaldi, BS1; Priscilla M. Clarkson,

PhD2; Stephanie M. Cole, PhD2; Justin Keadle, BS2; Stuart Chipkin, MD2; Linda S. Pescatello,

PhD3; Kathleen Simpson, MS3; C. Michael White, PharmD3; Paul D. Thompson, MD1

1Division of Cardiology, Henry Low Heart Center, Hartford Hospital, Hartford, CT; 2University

of Massachusetts, Amherst, MA; 3University of Connecticut, Storrs, CT

Address for Correspondence:

Paul D. Thompson, MD

Director of Cardiology, Henry Low Heart Center

Hartford Hospital

Hartford, CT06102

Tel: 860-545-1793

Fax: 860-545-2882

E-mail: [email protected]

Journal Subject Codes: [112] Lipids; [118] Cardiovascular Pharmacology

PhD2; Stephanie M. Cole, PhD2; Justin Keadle, BS2; Stuart Chipkin, MD2; Lindda a a S.S.S. PPPesesescacacatetetellllllo,

PhD3; Kathleen Simpson, MS3; C. Michael White, PharmD3; Paul D. Thompson, MMD111

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Abstract:

Background—Many clinicians believe that statins cause muscle pain, but this has not been

observed in clinical trials and the effect of statins on muscle performance has not been carefully

studied.

Methods and Results—The Effect of STatins On Skeletal Muscle Function and Performance

(STOMP) study assessed symptoms and measured creatine kinase (CK), exercise capacity, and

muscle strength before and after atorvastatin 80 mg or placebo were administered for 6 months

to 420 healthy, statin-naive subjects. No individual CK value exceeded 10 times normal, but

average CK increased 20.8 ± 141.1 U/L (p<0.0001) with atorvastatin. There were no significant

changes in several measures of muscle strength or exercise capacity with atorvastatin, but more

atorvastatin than placebo subjects developed myalgia (19 vs 10; p = 0.05). Myalgic subjects on

atorvastatin or placebo decreased muscle strength in 5 of 14 and 4 of 14 variables respectively (p

= 0.69).

Conclusions—These results indicate that high-dose atorvastatin for 6 months does not decrease

average muscle strength or exercise performance in healthy, previously untreated subjects.

Nevertheless, this blinded, controlled trial confirms the undocumented impression that statins

increase muscle complaints. Atorvastatin also increased average CK suggesting that statins

produce mild muscle injury even among asymptomatic subjects. This increase in CK should

prompt studies examining the effects of more prolonged, high-dose statin treatment on muscular

performance.

Clinical Trial Registration Information—www.clinicaltrials.gov; Identifier: NCT00609063.

Key words: atorvastatin; statins; muscle strength; aerobic capacity; myalgia

average CK increased 20.8 ± 141.1 U/L (p<0.0001) with atorvastatin. There weree nnnoo o sisigngng ifificicanant

changes in several measures of muscle strength or exercise capacity withr atorvasstataatititinnn, bbbuttut mmmorroreee

atorvastatin than plp acebo subjects developed myayalggia (19 vs 10; p = 0.05)5 . Myalgic subjects on

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Introduction

Hydroxy-methyl-glutaryl (HMG) CoA reductase inhibitors or statins are the most effective

medications for reducing elevated concentrations of low-density lipoprotein cholesterol (LDL-C)

and produce remarkable reductions in cardiovascular events.1Statins can produce life-threatening

rhabdomyolysis, but this is rare.2 Statins are more frequently associated with mild muscle

complaints including myalgia, cramps and weakness which may compromise medication

compliance and quality of life. The reported incidence of myalgia during statin therapy ranges

from 1% in controlled studies 3 to 25% 4 in clinical reports. Muscle weakness has also been

reported with statin therapy, but muscle and exercise performance have not been carefully

studied. 5

The Effect of STatins On Muscle Performance study (STOMP; NHLBI 5R01HL081893,

NCT00609063) determined the incidence of statin-associated muscle complaints and examined

the effect of statins on muscle performance and exercise capacity by administering atorvastatin

80 mg daily or placebo to healthy subjects for 6 months or until subjects developed myalgia.

Methods

Study overview

STOMP was a double-blind, random-assignment clinical trial whose methods have been

described.6 Equal numbers of men and women across three age ranges (20-39, 40-54, and 55+

yrs) were recruited over 4 years. Baseline lipid, liver, kidney, thyroid, and CK measurements

were obtained. Subjects completed a baseline muscle symptom questionnaire and exercise testing

including a maximal exercise test with gas analysis; handgrip, elbow flexor, and knee extensor

strength testing; and a knee extensor endurance exercise test. Subjects were then randomly

tudied. 5

The Effect of STatins On Muscle Performance study (STOMP; NHLBI 5R01HL081893,

NCNCCT0T0T00606060909090606063) dddeeteteermined the incidence of staatititin-n-aassociated mususscle cccomomomplaints and examined

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assigned in a double-blind fashion to identical placebo or atorvastatin 80mg daily (Lipitor;

Pfizer, Inc., New York, NY). Atorvastatin tablets were crushed for compounding, but this does

not influence relative bioavailability of the statin (Medical Information Letter 337882; Pfizer,

Inc.) Subjects were called twice monthly to ascertain symptoms. Subjects performed repeat

testing after 6 months or after they developed muscle symptoms meeting the study definition of

statin-induced myalgia. The study was approved by the Institutional Review Boards at Hartford

Hospital, University of Massachusetts, and University of Connecticut and monitored by a Data

Safety and Monitoring Board.

Subject Inclusion / Exclusion Criteria

1,415 possible subjects were evaluated. Subjects were not included if they had cancer within 5

years, a baseline alanine aminotransferase (ALT) value > 2 times upper normal limits (UNL), a

creatinine> 2 mg/L, an abnormal thyroid stimulating hormone level, a history of cardiovascular

disease or an ischemic appearing electrocardiographic response to exercise testing, diabetes

mellitus, subjective muscle complaints or weakness, or physical disabilities that would prohibit

exercise testing. LDL-C was not an inclusion/exclusion criterion because many patients with

cardiovascular disease or other cardiovascular risk factors presently receive statin therapy

regardless of their baseline LDL values. Women who were pregnant or planned to become

pregnant were not recruited and all women in the study of child-bearing age agreed to use an

established method of birth control for the duration of the trial. Subjects presently or previously

treated with lipid-lowering medications were excluded, as were individuals treated with

medications known to affect skeletal muscle or to alter statin metabolism 7. Subjects with

hypertension were recruited if their blood pressure was controlled and <140/90 at baseline. A

total of 468 subjects were randomized to atorvastatin or placebo of whom 203 in the atorvastatin

1,415 possible subjects were evaluated. Subjects were not included if they had cacaancecec r wiwiwithththininin 55

years, a baseline alanine aminotransferase (ALT) value > 2 times upper normal limits (UNL), a

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and 214 in the placbo group provided complete data for analysis. Subjects were removed from

the study if their CK exceeded 10 times UNL on any occasion or if their ALT exceeded 3 times

UNL on two measurements performed within one week of the first elevated value. No subject

was excluded for elevated CK values, but 9 atorvastatin and 1 placebo subjects were excluded

for elevated ALT levels (Figure 1).

Serologic markers

Total, LDL and HDL cholesterol, triglycerides, ALT, creatinine, 25-hydroxy Vitamin D

(25(OH)D (which measures both vitamin D2 andD3)), and CK levels were obtained at baseline

and 6 months. Participants, their physicians and investigators were unaware of subjects’ lipid

values during the study.

Study Measurements

Body anthropometrics, handgrip isometric strength of the dominant hand, elbow and knee

extension/flexion isometric and isokinetic strength as well as knee endurance fatigue index 8 of

the dominant limb, maximal oxygen uptake (VO2max), resting and peak respiratory gas exchange

ratio (RER) and ventilatory threshold, as well as habitual self-reported and directly-measured

physical activity were measured at baseline and after 6 months of drug treatment as described.6

Compliance with study medications was assessed by pill counts of unused medication at 3

months and again at 6 months.

Myalgia/Muscle Symptoms

Muscle complaints were assessed at the baseline, 3 and 6 month visits and by phone twice

monthly using the Short-Form Brief Pain Inventory as described.6Subjects met the study

definition for “myalgia” if all of the following occurred: 1) They reported new or increased

muscle pain, cramps, or aching, unassociated with exercise; 2) Symptoms persisted for at least 2

values during the study.

Study Measurements

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weeks; 3) Symptoms resolved within 2 weeks of stopping the study drug; and 4) Symptoms

reoccurred within 4 weeks of restarting the study medication. Subjects who tested positive for

myalgia using these criteria subsequently performed repeat serological, muscle and aerobic

testing immediately after reoccurrence of muscle symptoms.

Sample Size

The primary outcome was the incidence of statin-associated myalgia, and thus sample size

estimates were based on the projection that 10% of the statin group would develop myalgia. 9

Assuming a nonspecific muscle complaint rate of 2% with placebo, 162 subjects per group were

needed to detect a significant difference between groups ( =0.05, power = 0.80). In addition,

groups of 200 subjects each provided power to detect a 5-10% change with statin therapy in all

exercise outcomes.

Statistical Analyses

Outcomes were assessed for normality using normal probability plots, histograms, and

Kolmogorov test statistics. Transformations were used as necessary. All tests were two-sided

with statistical significance set at alpha=0.05. Analyses were performed using SAS9.1 (SAS

Institute Inc., Cary, NC).

Primary analyses were carried out on an intent-to-treat basis. We also compared

outcomes excluding 23 subjects who did not reduce LDL-C by 20% or more on atorvastatin (to

exclude noncompliant subjects as denoted in the original published analysis plan) but this did not

alter main study findings and thus the following data include all completed subjects. To

determine the incidence of statin muscle complaints, the proportion of subjects developing

complaints was compared between the statin and placebo groups using a Pearson chi-square. The

effect of atorvastatin on serologic markers, muscle strength, and aerobic performance was

groups of 200 subjects each provided power to detect a 5-10% change with statininn ttheheh rraapypypy iiin n n alall

exercise outcomes.

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assessed with t-tests (or a Mann-Whitney U test for CK) comparing the change scores observed

in the statin and placebo treated subjects pre-to-post treatment. Models were also run controlling

for sex and age as categorical covariates and random site effects, which did not alter findings.

Further models examined two-way and three-way interactions with ANOVA by modeling

change scores in study outcomes with age, gender and drug treatment, again controlling for

random site effects with non-significant interactions dropped for parsimony. Change scores

according to myalgia status were also examined between treatment groups given the small

number of myalgic subjects.

Results

Baseline Characteristics and Lipid Changes

Subjects randomized to the atorvastatin and placebo groups were similar at baseline, although

more women on atorvastatin used oral contraceptives or hormone therapy and more placebo

subjects used prescription pain medication (Table 1). Compliance with treatment medication was

similiar in the atorvastatin and placebo groups (94.5 ± 7.0 vs. 93.9±8.2 %). Atorvastatin subjects

showed the expected reductions in LDL-cholesterol (Table 2).

Changes in Serological Markers

Atorvastatin produced a 20.8 ± 141.1 U/L (p<0.0001) increase in CK, although no subject

demonstrated a CK value > 10 X the upper normal limit (UNL) (Figure 2). In addition, forty

subjects on atorvastatin vs. 29 subjects on placebo demonstrated CK > UNL (X2 = 3.2; p = 0.08).

Atorvastatin also increased average ALT values 15.7 ± 27.4 U/L (p< 0.0001) (Figure 2). There

was no effect of 6 months atorvastatin treatment on Vitamin D (atorvastatin: 35.1 ± 12.4 to 34.2

± 12.5 vs. placebo: 36.8 ± 14.6 to 35.1 ± 14.3 ng/mL; p = 0.94).

Results

Baseline Characteristics and Lipid Changes

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Muscle Complaints

Twenty three atorvastatin and 14 placebo subjects reported new, unexplained muscle pain.

Nineteen atorvastatin and 10 placebo subjects ultimately met the study definition for myalgia (X2

= 3.74; p = 0.05). Myalgic subjects on atorvastatin reported predominantly leg symptoms: hip

flexor, quadriceps, hamstring and/or calf aches (n=10), quadriceps or calf cramps (n=5), and/or

quadriceps, hamstring and/or calf fatigue (n=6). whereas myalgic subjects on placebo reported

more diverse symptoms such as whole-body fatigue (n=3), worsening of pain in previous injuries

(n=3), groin pain (n=3) and foot cramping (n=1), but were otherwise similar (Table 1). Time to

symptom onset was shorter in atorvastatin myalgic subjects than in myalgic subjects on placebo

(35 ± 31 vs: 61 ± 33 days; p = 0.045). Myalgic vs. nonmyalgic subjects on atorvastatin or

placebo did not exhibit differences in CK, ALT, lipid (Table 2) or Vitamin D changes with

treatment (p > 0.19).

Pain severity and pain interference with daily life in all subjects with myalgia averaged

0.7 ± 1.2 and 0.3 ± 0.6 at baseline out of a possible 10 and increased to 2.4 ± 1.8 and to 2.0 ± 2.3

with treatment (p = 0.001) and did not differ between the atorvastatin and placebo subjects

(p=0.37). Baseline pain severity and pain interference with daily life were similar in non-

myalgic subjects for the atorvastatin and placebo groups(0.4 ± 0.9 and 0.2 ± 0.7, respectively)

and did not change with treatment (p =0.14).

Effects of Atorvastatin on Muscle and Exercise Performance

There were no baseline differences in measured strength and aerobic outcomes (all p >

0.06).There were no differential effects of atorvastatin on skeletal muscle strength and

endurance, aerobic performance, or physical activity levels compared to placebo (all p values >

0.17)(Table 3). Physical activity decreased (p = 0.007) regardless of drug treatment,but the

35 ± 31 vs: 61 ± 33 days; p = 0.045). Myalgic vs. nonmyalgic subjects on atorvvaaastataatit nn n ororor

placebo did not exhibit differences in CK, ALT, lipid (Table 2) or Vitamin D changes with

rreaeaatmtmtmeenenttt (p(p(p >>> 00.1.1199)9).

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decrease in the atorvastatin group was due to a decrease in activity among the oldest tertile of

study participants (p = 0.03; Figure 3).

Outcomes in Individuals with Myalgia

One atorvastatin subject with myalgia refused final testing and was not included in analyses.

Compared to the asymptomatic subjects on atorvastatin, myalgic subjects had lower muscle

strength in 5 of 14 measured variables (Table 4). Compared to the asymptomatic subjects on

placebo, placebo myalgic subjects had significantly lower muscle strength in 4 measured

variables (X2 = 0.16; p = 0.68).

Discussion

STOMP is, to our knowledge, the first randomized double-blind, clinical trial to confirm the

common clinical impression that statins increase the incidence of myalgia. The definition of

myalgia in STOMP was predefined and required resolution of muscle symptoms promptly after

stopping study medication and reappearance of symptoms on restarting the medication. STOMP

also documented that statin-associated mild muscle complaints do not appear to have measurable

physiologic consequences in that muscle strength was not reduced to a greater extent in myalgic

participants on atorvastatin compared to placebo subjects also satisfying the study definition of

myalgia. The observation that some placebo patients satisfied the myalgia definition documents

the importance of using a double-blind trial to examine the incidence and characteristics of

statin-associated myalgia and not relying solely on clinical characteristics. STOMP also

demonstrated, we believe again for the first time, that. high-dose statin treatment increases

average CK levels, suggesting that statins produce low level muscle injury in healthy subjects

that occurs independent of muscle symptoms.

Discussion

STOMP is, to our knowledge, the first randomized double-blind, clinical trial to confirm the

coommmmmmoonon ccclililininin caal ll imimimpression that statins increaseee ththee incidence off mmyaalglglgiiaia. The definition of

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The reported incidence of myalgia during statin therapy has varied from 1% to 25%. 3, 10,

11 Determining the true incidence of mild muscle complaints from prior studies is difficult

because these complaints are typically not solicited and because most large trials typically define

myopathy as either myositis or rhabdomyolysis and require CK levels > 10 ULN. We used a

standardized study protocol and definition and observed that high-dose atorvastatin doubled the

incidence of reproducible muscle complaints, from 4.6 to 9.4% of subjects. STOMP enrolled

equal numbers of young, middle-aged and older men and women, but the incidence of myalgia

was similar to the 10.5% rate reported among 7,924 French patients.9 Observational reports

suggest that statin-associated muscle complaints are more frequent in older adults and/or

women.12-14 Subjects with statin myalgia in STOMP did tend to be older and almost 60% were

women, but the STOMP sample size was too small to detect gender differences in incidence.

Interestingly, the French study cited above 9 observed that muscle symptoms generally appeared

within a month of drug initiation. This was also true in STOMP, and the time to symptom onset

was significantly shorter in myalgic subjects on atorvastatin than on placebo, 1 vs. 2 months.

Clinical trials define statin-associated myopathy as CK levels > 10 ULN.4, 14 No subject

in STOMP recorded a CK > 10 ULN, but 6 months of treatment with atorvastatin resulted in a

small (~20 U/L) but significant (p<0.01) increase in CK. This suggests that low level muscle

injury occurs with high-dose statins, although there are other possible explanations for the CK

increase. Inflammatory conditions including rheumatoid arthritis and systemic lupus are

associated with reduced CK levels.15Statins reduce systemic inflammation 1 and could increase

average CK by decreasing inflammation. We did not measure inflammatory markers in STOMP

so cannot evaluate this possible relationship. Alternatively, hepatic macrophages participate in

the clearance of CK.16 Decreasing hepatic macrophages in animal models increases CK

women.12-14 Subjects with statin myalgia in STOMP did tend to be older and almmmosostt t 60600% % % wewewerere

women, but the STOMP sample size was too small to detect gender differences in incidence.

nnteteerererestststiininglglgly,y,y theee FFFrer nch study cited above 9 obssserere vved that muscle e e sympmpmpttotoms generally appeared

wwithhhini a monthth ooof drruugg iiinininitititiaatatioioion.n. TThThiiss wwwas alllso ttruruue innn SSTTOOMPMPM , aanand d ththt eee titimememe tto o sysys mpmpm toommm onoonsses t

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concentrations suggesting that statins, if they decrease hepatic macrophage content, could reduce

CK clearance and increase CK levels. There was no correlation between changes in CK and

ALT in STOMP, but we cannot further evaluate this possibility. Both explanations seem less

likely than the hypothesis that statins produce low-level muscle injury given the plethora of data

linking statins with skeletal muscle damage, 17-19even in the absence of muscle symptoms. 20

The long-term clinical consequences of this mild CK elevation are unclear, since the CK

elevation was not accompanied by changes in muscle strength. Anecdotally, some patients with

weakness attributed to statin therapy develop such complaints only after years of treatment.12

Therefore, it is possible that low-level muscle injury, indicated by mild elevations in CK, will

produce subsequent weakness in some statin-treated subjects. Testing this hypothesis will be

difficult since it requires a long-term placebo-controlled trial, an ethically difficult proposition

given the documented therapeutic value of statins. Also, such a study would require

sophisticated strength testing since we detected decreased strength among our myalgic subjects

even though few complained of muscle weakness.

There were no significant changes in muscle strength and endurance as well as aerobic

performance in the total atorvastatin STOMP population. Previous investigations have been

equivocal, with some studies suggesting that statins reduce muscle strength in older individuals

and that statins may shift exercise substrate utilization from fat to carbohydrate. 21-24Most studies

were small, used crude measures of strength and exercise performance and were not blinded or

placebo-controlled. 5 STOMP provides reassurance that healthy adults who tolerate high-dose

atorvastatin without muscle complaints experience no deleterious effects on muscle strength or

performance over 6 months of treatment. We did observe that average physical activity,

measured by accelerometer, decreased significantly in the oldest STOMP age group with

produce subsequent weakness in some statin-treated subjects. Testing this hypotothehhesisis ss wiwiwillllll bbbe e

difficult since it requires a long-term placebo-controlled trial, an ethically difficult proposition

gigiveveenn n thththee dododocccumememenntnted therapeutic value of statinnns.ss Also, such a sstutut dyy wwwooould require

oophphhisticated ststrereennngththh tesesestititingngng sssinincecee wwwee ddetecccteeed decececrreaasaseeded ssstrrenengggthhh amamononong g oouourr r mymyyalallgigigicc suuubbjbjeececttts

evvenenen ttthohoh ugugughh h ffefewww ccoompmpmplaaainineddd oofff mumumuscsclelee wwweaeaeaknnnesese sss.

Theree wwwererreee nonon ssigigi nininififiicacac ntntnt cchhhanana gegegess s ininn mmmusususclclle e e sts rereengngngththth aaandndnd enenndududurararancncnceee asass wwwelelelll l asasa aerobic



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atorvastatin therapy, but this could simply represent measurement variability since physical

activity increased in the youngest atorvastatin-treated subjects.

In contrast to the total study sample, statin-treated subjects meeting the study definition

of myalgia did demonstrate reductions in muscle strength in 5 of 14 measured muscle strength

variables (Table 4). Several observational studies have suggested that patients with myalgia

experience a decrease in strength.4, 25However, placebo group subjects also meeting the study

definition of myalgia also demonstrated muscle strength declines in 4 measured variables,

suggesting that the majority of muscle strength changes with myalgia in STOMP may have been

non-specific. Caution should be warranted in interpreting these data though as the analyses were

secondary to major study outcomes in a very small sample of patients. Therefore, larger studies

of patients with true statin myalgia—rigorously tested with a double-blind, randomized cross-

over period to confirm myalgia in the initial study population—are needed to determine the

effects of statin on muscle outcomes in myopathic patients.

STOMP has significant advantages over prior observational studies, but also limitations.

STOMP only examined the effect of atorvastatin on muscle complaints and function so cannot

evaluate if other statins at comparable doses would produce similar results. STOMP only

enrolled healthy individuals so cannot address the frequency or severity of muscular complaints

in patients with concomitant diseases and medications. The inclusion of younger subjects and

both genders may have reduced the number of subjects with myalgia during atorvastatin

treatment since subjects with statin myalgia in STOMP tended to be older and more were

woman. STOMP only lasted 6 months so may underestimate the incidence of myopathic

complaints during longer term statin therapy, although onset of myalgia with atorvastatin

occurred an average of one month after initiation of therapy. Longer placebo-controlled trials to

econdary to major study outcomes in a very small sample of patients. Therefore,e,, llarara gegeger r stststudududieies

of patients with true statin myalgia—rigorously tested with a double-blind, randomized cross-

ovvererer pppeererioioiod d d tototo conononfifif rm myalgia in the initial studddyyy pppopulation—aarerer neeeeedededed to determine the

efffeeectc s of statiin n ononon mmuuusclclcleee ouououtctctcomommesess innn mmmyooopaaathiccc pppatiiienenntsts..

STSTOMOMOMP P hahaas s sisiigngnnififici ananant t adadadvavavantntagagageseses oooveveer r r pppriioor obobobseseserrvrvatatatioioonanaalll ststs uududiiieses, bububut t alallsosoo limimmiititatatiioionnsns.

STOMP onlylyy eeexaxax mimiminenened d d thhe e e efefeffeeectctct ooof f f atttororo vavavastststatata inini ooon n mumuuscscs lelele cccomomomplplaiaiaintntnts s snnn ananand d d fufuuncncnctititiononon sso cannot



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examine the frequency of myopathic complaints in sicker subjects will be difficult, however,

given the general reluctance to assign statin-eligible subjects to placebo treatment. On the other

hand, given that statins have been clinically available and widely used in the US since 1987 and

the paucity of documented decreases in muscle strength among statin-treated patients, STOMP

may overestimate the frequency and strength changes of statin-associated myalgia. This seems

unlikely, however, given the rigor of the STOMP design.

Summary

STOMP is, to our knowledge, the first randomly assigned, double-blind study designed to

examine the effects of statins on muscular complaints, muscle strength and exercise

performance. The results are reassuring since there was no effect of atorvastatin 80 mg daily on

muscle strength or exercise performance over 6 months of treatment in healthy subjects. On the

other hand, STOMP did document that atorvastatin significantly increased the frequency of

myalgia. STOMP also demonstrated an increase in average CK in the atorvastatin-treated cohort

suggesting that statins could produce low level muscle injury. These results should prompt

additional studies examining muscular performance with long term statin treatment in both

healthy patients as well as those with confirmed statin-associated myalgia.

Acknowledgments: The authors wish to acknowledge the following individuals for their

participation on the Data Safety Monitoring Board: JoAnne Foody, M.D., Pamela Hartigan,

Ph.D., and Ira Ockene, M.D. (chair). In addition, Gualberto Ruano, M.D., Ph.D. provided

statistical and scientific assistance with data interpretation.

Funding Sources: The STOMP study is funded by NHLBI/NIH grant RO1 HL081893 (P.

Thompson).

examine the effects of statins on muscular complaints, muscle strength and exercrcisiise ee

performance. The results are reassuring since there was no effect of atorvastatin 80 mg daily on

mumuscscsclelele sstrtrtrenene gggth ororor eexercise performance over 6 mmmoonnths of treatmemeent iin n n hhehealthy subjects. On the

otheeer r hand, STTOMOMOMP P didid d d dododocucuummementntnt ttthahatt aaatorvvavastatinin sigggnninifificccanntntlylyy inncncrereaaaseeded ttthehehe ffrereequququenencycyy oofff

mymyyalalalgigigia.a. SSTOTOTOMPMPP aaalslsooo ddedemomonnsn trtrtratatatededed aannn ininincrcrcreaaaseses iiinn aavveeraraagegege CCCK K K inini tttheheh aaatooorvrvaasastatatatitinn-n-ttrtreaaateted d d cocoohohoortr

uggesting thahaat t t ststatatatininins s s cococ ululld d d prpp odododucucuceee looow w w lelelevevevel l mumumuscscclele iiinjnjn ururury.y.y ThThThessse ee rereresususultltltsss shshhouououldldld pppror mpt



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Conflict of Interest Disclosures: Paul D. Thompson reports receiving research grants from the

National Institutes of Health, GlaxoSmithKline, Anthera, B. Braun, Genomas, Roche, Aventis,

Novartis, and Furiex; serving as a consultant for Astra Zenica, Furiex, Regeneron, Merck,

Roche, Genomas, Abbott, Lupin, Runners World, Genzyme, Sanolfi, Pfizer, and

GlaxoSmithKline; receiving speaker honoraria from Merck, Pfizer, Abbott, Astra Zenica,

GlaxoSmithKline, and Kowa: owing stock in General Electric, JA Wiley Publishing, J&J,

Sanolfi-Aventis and Abbott; and serving as a medical legal consultant on cardiac complications

of exercise, statin myopathy, tobacco, ezetimibe and non-steroidals.

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6. Thompson PD, Parker BA, Clarkson PM, Pescatello LS, White CM, Grimaldi AS, Levine BD, Haller RG, Hoffman EP. A randomized clinical trial to assess the effect of statins on skeletal muscle function and performance: rationale and study design. Prev Cardiol. 2010;13:104-111. 7. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003;289:1681-1690. 8. Katsiaras A, Newman AB, Kriska A, Brach J, Krishnaswami S, Feingold E, Kritchevsky SB, Li R, Harris TB, Schwartz A, Goodpaster BH.Skeletal muscle fatigue, strength, and quality in the elderly: the Health ABC Study. J Appl Physiol. 2005;99:210-216. 9. Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients--the PRIMO study. Cardiovasc Drugs Ther. 2005;19:403-414.

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3.3. PPhhyhysicianns's's' DDesessk kk ReReefefef rererencncn e.e. 2220000002.2. MMonontvtvalale,e, NNNJJ, MMededdicicicalala EEcococonnonomimicscscs.. p556.6.

4.4.. PPhhillips PSPS, ,, HHaaaaas RRH,H, Baannnnynykhk SSS, , HaHaHathawwwaaay SS, GrGrayayay NNNL,LL Kimmmuuura BBBJ,,, VVllaaddutu iuu GGGD,D, EEEnglllannnd JDDD. StStStatata inin-a-aasssssocociiiatteted d mymymyopopatatthyhyhy wwwititithhh nnnororrmamamall crcrcreaeae tttinnene kkkininnasasasee leleleveveelsss.. AnAnAnnn IInInteteernrnrn MMMededed. 200202;1;13737:5:5818 -5-5855.

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15. Lee YH, Choi SJ, Ji JD, Song GG. Serum creatine kinase in patients with rheumatic diseases. Clin Rheumatol.2000;19:296-300. 16. Radi ZA, Koza-Taylor PH, Bell RR, Obert LA, Runnels HA, Beebe JS, Lawton MP, Sadis S. Increased serum enzyme levels associated with kupffer cell reduction with no signs of hepatic or skeletal muscle injury. Am J Pathol. 2011;179:240-247. 17. Hanai J, Cao P, Tanksale P, Imamura S, Koshimizu E, Zhao J, Kishi S, Yamashita M, Phillips PS, Sukhatme VP, Lecker SH. The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. J Clin Invest. 2007;117:3940-3951. 18. Urso ML, Clarkson PM, Hittel D, Hoffman EP, Thompson PD. Changes in ubiquitin proteasome pathway gene expression in skeletal muscle with exercise and statins. ArteriosclerThromb Vasc Biol. 2005; 25:2560-2566. 19. Parker BA, Augeri AL, Capizzi JA, Ballard KD, Troyanos C, Baggish AL, D'Hemecourt PA, Thompson PD.Effect of statins on creatine kinase levels before and after a marathon run. Am J Cardiol. 2012;109:282-287. 20. Mohaupt MG, Karas RH, Babiychuk EB, Sanchez-Freire V, Monastyrskaya K, Iyer L,Hoppeler H, Breil F, Draeger A. Association between statin-associated myopathy and skeletal muscle damage. CMAJ.2009;18:E11-E18. 21. Paolisso G, Barbagallo M, Petrella G, Ragno E, Barbieri M, Giordano M, Varricchio M. Effects of simvastatin and atorvastatin administration on insulin resistance and respiratory quotient in aged dyslipidemic non-insulin dependent diabetic patients. Atherosclerosis. 2000;150:121-127. 22. Phillips PS, Phillips CT, Sullivan MJ, Naviaux RK, Haas RH. Statin myotoxicity is

15. Lee YH, Choi SJ, Ji JD, Song GG. Serum creatine kinase in patients with rheuumamamatiticc didiseseasasesClin Rheumatol.2000;19:296-300.

16. Radi ZA, Koza-Taylor PH, Bell RR, Obert LA, Runnels HA, Beebe JS, Lawton MP, Sadis Sncreased serum enzyme levels associated with kupfp fer cell reduction with no signs of hepatic orkkelelletetetalalal mmmususu cccle inininjjujury. Am J Pathol. 2011;179:22244040---247.

1177. HHanai J, CCaoao PPP, TaTaTanknkksasaalelele PPP,, ImImmaamamururaa S,, KKKoshhhimmmizuzuu EE,, ZhZhZhaoao J,, KiKiishshshii S,S, YYYamamasasashihihitata MMM,PhPhPhillllil ps PS, SSukhahahatmeee VVVP, LeLeLeckc ere SSSH.H. TTThe mmmuscllele-s-spepeecicicififificcc uuubiqqquuiitin llliggagasesee aaatrtrogiinin--1-1//MMAAFbxbxbx memeedididiatatateses sstatatatititin-n-iinndduduceceed d mumuscscclele tttoxoxoxiicicititty.y.y JJ J CCClininn IInnnveesestt.. 202020070707;11117171 :3:39494940-0--399951511..

18. Urso ML,L, CCClalarkrkrksososon n n PMPMM,,, HiHiH ttttttelele DDD, HoHoHofffff mamamannn EEEP,P,P, TTThohoompmpmpsososon n n PDPDP .. . ChChChananangegegess ininn uuubibibiquququiti in prprototeaeasosomeme ppatathwhwayay ggenenee exexprpresessisionon iinn skskeleletetalal mmususclclee wiwithth eexexercrcisisee anandd ststatatininss ArArteteririososclclerer



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Table 1. Subject Baseline Characteristics And Medication Use By Drug Assignment For All Subjects and Those Who Developed Myalgia

Entire Sample Myalgic Sample ATOR (n=203) PL (n=217) ATOR (n=19) PL (n=10)

Women (n) 103 113 11 5 Caucasian (n) 92 201 18 10 Age (years) 43.6(41.4,45.8) 44.6(42.4,46.8) 52.5(47.1,50.9)* 56.9±8.0

(51.9,61.9)* BMI (kg/m2) 26.3(25.6,27.0) 26.5(25.8,27.2) 24.7(22.8,26.6) 25.0±3.0(23.1,26.9)VO2max (mL/kg/min)

34.6(33.3,35.9) 33.2(31.9,34.5) 31.0(26.7,35.3) 30.7(26.0,35.4)

Resting SBP (mmHg)

119.5(117.7,121.3) 118.3(116.5,120.1) 122.3(117.4,127.2) 119.0(112.7,125.3)

Resting DBP (mmHg)

75.5(74.2,76.8) 75.1(73.8,76.4) 76.4(73.2,79.6) 72.6(68.9,76.3)

Total-C (mg/dL) 198.7(193.3,204.1) 194.8(189.9,199.7) 215.3(195.9,234.7) 212.0(195.6,228.4)LDL-C (mg/dL) 119.0(114.1,123.9) 116.0(111.8,120.2) 128.9(110.8,147.0) 130.2(116.1,144.3)HDL-C (mg/dL) 57.6(55.2,60.0) 58.6(56.3,60.9) 68.7(61.5,75.9)* 61.0(53.2,68.8) TRIG (mg/dL) 110.5(102.9,118.1) 103.1(95.7,110.5) 88.1(72.4,103.8) 114.2(73.5,154.9) Medication OTC Pain (n) 21 21 3 2 Prescription Pain (n)

5 16* 2 2

Blood Pressure (n) 9 15 2 0 Thyroid (n) 12 13 4 2 Hormone Therapy (n)

31 18* 2 0

Data are presented as point estimates and 95% confidence intervals for atorvastatin (ATOR) vs. placebo (PL) subjects in the entire sample and only in subjects classified as myalgic. BMI = body mass index; VO2max = maximal oxygen uptake; SBP = systolic blood pressure; DBP = diastolic blood pressure; C = cholesterol; LDL = low density lipoprotein; HDL = high density lipoprotein; TRIG = triglycerides. OTC Pain = regular use of over-the-counter pain medications such as nonsteroidal anti-inflammatory drugs and acetaminophen; Prescription Pain = regular use of prescription pain medications; Blood Pressure = used a blood-pressure lowering drug; Thyroid = used a synthetic thyroid drug; hormone therapy = if female, used oral contraceptives or hormone replacement therapy. * indicates significant difference between myalgic and nonmyalgic subjects within a treatment group at p < 0.05.

Entire Sample Myalgic Saampmpmplele ATOR (n=203) PL (n=217) ATOR (n=19) PLPLL (((n=n=n=101010) )

Women (n) 103 113 11 555Caucasian (n) 92 201 18 10 Age (years) 43.6(41.4,45.8) 44.6(42.4,46.8) 52.5(47.1,50.9)* 56.9±8.0

(51.9,61.9)* BMBMMI I (k(kgg/mm22) ) 2626.33(2(25.6,6,2727.0. ) ) 262 .5.5(2(2555.88,27.22)) 24244.7.7(2( 2.2.8,8,2626.6) ) 2525.0.0±33.00(2(23.1,,2626.9VVOVO22m2maxmmmLL/L/kgk /min)

33434.6.6.6(3(3(33.3..3,3,3,353535.9.99)) ) 33333 .22.2(3311.99,344 5.5.5))) 313131.00(2(2(26.6.6 77,7,335.33)) ) 303030.7.77(2(2(26.6.0,0,0,353535.4.4.4)

ReReesttinini g g SBP mmmHmHmHg)g)g)

1119..5(5(11177.77,7,121...3)3)3 11888.333(1( 1666.55,11202020.1.1) ) 11222.3((117..4,4,1212777.2)2)2) 11999.0.00(111222.7,1,12555.3)

ReReststiningg g DBDBPP mmHg)

7575.5.5(7(7( 4.4.2,2,,7676.8.8)) ) 7575.1.1(7(7( 3.3.8,8,,7676.4.4))) 7676.4.4(7(7( 3.3.2,2,,7979.6.6)) ) 7272.6.6(6(6( 8.8.9,9,,7676.3.3)) )

TTottall CC ((m /g/dLdL)) 191988 7(7(191933 33 202044 1)1) 119494 88(1(18989 99 119999 77)) 212155 3(3(191955 99 232344 7)7) 221212 00(1(19595 66 222828 44)



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Table 2. Lipid Changes By Drug Assignment and Myalgia Status

Total Sample Myalgic Sample ATOR (n=203) PL (n=217) ATOR (n=19) PL (n=10)

Total-C (mg/dL) -65.3(-70.1,-60.5)* 2.7(-0.2,5.6) -73.9(-88.0,-59.8)* 12.2(0.0,24.4) LDL-C (mg/dL) -59.0(-63.4,-54.6)* 0.9 (-1.8,3.6) -70.6(-83.5,-57.7)* 10.1(-1.4,21.6) HDL-C (mg/dL) -0.8(-2.0,0.4) 0.4(-0.7,1.5) 0.2(-4.3,4.7) -3.4(-9.1,2.3) TRIG (mg/dL) -28.3(-34.4,-22.3)* 3.5(-3.1,10.1) -18.2(-28.0,-8.4)* 16.5(-12.3,45.3)

Data are presented as point estimates and 95% confidence intervals for atorvastatin (ATOR) vs. placebo (PL) subjects in the entire sample and only in subjects classified as myalgic. = absolute change from pre-to-post study; C = cholesterol; LDL = low-density lipoprotein; HDL = high-density lipoprotein; TRIG = triglycerides. * indicates significant change from baseline at p < 0.01; there were no differences between myalgic and nonmyalgic subjects within a treatment group.

Table 3. Absolute (Post-Baseline) Aerobic and Strength Data by Drug Assignment

ATOR (n=202*) PL (n=217) Resting RER 0.0 (-0.01,0.01) 0.0(-0.03,0.03) VO2max(mL/kg/min) -0.8(-1.3,-0.3) -0.8(-1.4,-0.2) VT (mL/kg/min) -0.9(-1.6,-0.2) -0.6(-1.6,0.4) Handgrip (kg) 0.1(-0.5,0.7) -0.6(-1.3,0.1)

Arm Strength (APT; N-M)

Isom Ext 0.8(-0.2,1.8) 0.3(-0.6,1.2) Isom Flex -0.5(-2.1,1.1) -0.2(-1.1,0.7) Isok Ext @ 60° /sec 0.5(-0.2,1.2) -0.2(-0.9,0.5) Isok Flex @ 60° /sec 0.0 (-0.6,0.6) 0.0(-0.6,0.6) Isok Ext @ 180° /sec 0.5(-0.2,1.2) 0.6(0.2,1.2) Isok Flex @ 180° /sec 0.2(-0.6,1.0) 0.1(-0.5,0.7)

Leg Strength (APT; N-M)

Isom Ext -2.1(-5.1,0.9) -0.4(-3.4,2.6) Isom Flex -1.8(-3.2,-0.4) -1.3(-2.6,0.0) Isok Ext @ 60° /sec 1.2(-0.8,3.2) 0.9(-1.1,2.9) Isok Flex @ 60° /sec 0.9 (-0.5,2.3) -0.5(-2.7,1.7) Isok Ext @ 180° /sec 3.9(2.0,5.8) 3.8(2.3,5.3) Isok Flex @ 180° /sec 2.7 (1.5,3.9) 2.1(1.0,3.2) Knee Endurance Fatigue Index -0.1(-1.6,1.4) 0.2(-0.8,1.2) Data are presented as point estimates and 95% confidence intervals for atorvastatin (ATOR) vs. placebo (PL) subjects.. RER = Respiratory exchange ratio; VO2max = maximal oxygen uptake; VT = ventilatory threshold; APT = average peak torque; Isom = Isometric; Ext = Extension; Flex = Flexion. There were no significant differences in change scores between ATOR and PL treatment groups.*One ATOR subject with myalgia did not complete muscle and aerobic post-testing and thus was not included in analyses.

VO2max(mL/kg/min) -0.8(-1.3,-0.3) -0.8(-1.1..44,4,-0-00.2.2.2)) ) VT (mL/kg/min) -0.9(-1.6,-0.2) -0.6(-11-1.6.6.6,0,0,0.4.4.4) ) )Handgrip (kg) 0.1(-0.5,0.7) -0.6(-1.3,0.1)

Arm m StStrerengngthth (APAPAPT;T N-M)

ssomomom EExt 00.8.8(-(-000.222,1.8)8)) 00.3.3(-(-( 0.0.6,6,1.1.2)2)) ssommm Flex ---0..5(-222.11,1...11)1) --0.0.0.22(2(-1-11.1.1.1,0,0,0.7.7.7) sssokokk Ext @ 660°00 ///seeec 0.0.55(-000.222,1,1.2.22))) --0-0.22. (-( 0.9,9,0.0.555) ssokokok FFFlelelexxx @ @ @ 60600°° /s/ssececec 000.0.00 ((-0-0-0.6.66,0,0,0.6.6.6) ) ) 0.0.0 0(0(0(-0-0-0.6.6.6,0,0.6.6.6) ))sssokokok EEExtxtxt @@@ 111808080° /s/s/sececec 000 55.5(-(-( 000.222,111.2)2)2) 000 66.6(0(0(0 22.2 11,1 22.2))) sok Flex @ @ 1818180°00° ///seseec cc 000.2(2(2(-00-0.666,11,1.00))) 000.1(1(1(-0-00 55.5 0,0,0.7) )



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Table 4. Absolute (Post-Baseline) Aerobic and Strength Data by Drug Assignment in Myalgic Patients. ATOR (n=18*) PL (n=10) Resting RER 0.0(-0.05,0.05) 0.1(-0.1,0.3) VO2max(mL/kg/min) -0.5(-1.3,0.3) -1.3(-2.8,0.2) VT (mL/kg/min) -2.1(-3.9,0.3) -2.3(-5.9,1.3) Handgrip (kg) -1.4(-3.4,0.6) -1.0(-3.7,1.7)

Arm Strength (APT; N-M)

Isom Ext -0.4(-4.2,3.4) 1.1(-2.4,4.6) Isom Flex -3.2(-7.5,1.1) 0.7(-3.6,5.0) Isok Ext @ 60° /sec -2.6 (-6.2,1.0) 0.3(-1.9,2.5) Isok Flex @ 60° /sec -3.8(-7.8,0.2)* 0.8(-1.2,2.8) Isok Ext @ 180° /sec -1.3(-4.4,1.8) -0.4(-2.2,1.4)* Isok Flex @ 180° /sec -0.5(-4.1,3.1) 0.2(-2.2,3.6)


Isom Ext -17.3 ± (-25.1,-9.5)* -21.5(-30.6,-12.4)* Isom Flex -5.3(-10.4,-0.2) -4.3(-10.2,1.6) Isok Ext @ 60° /sec -10.4(-20.2,-0.6)* -6.6(-14.5,1.3) Isok Flex @ 60° /sec -3.6(-8.6,1.4)* -4.6(-8.7,-0.5) Isok Ext @ 180° /sec -3.0(-8.9,2.9)* -4.1(-10.1,1.9)* Isok Flex @ 180° /sec -1.0(-4.6,2.6) -3.9(-6.8,-1.0)* Knee Endurance Fatigue Index -2.1(-4.4,0.2) -3.6(-5.7,-1.5) Data are presented as point estimates and 95% confidence intervals for atorvastatin (ATOR) vs. placebo (PL) subjects in subjects classified as myalgic. RER = Respiratory exchange ratio; VO2max = maximal oxygen uptake; VT = ventilatory threshold; APT = average peak torque; Isom = Isometric; Ext = Extension; Flex = Flexion.* indicates significant difference in change scores between myalgic and nonmyalgicgroups (from Table 3) within a treatment group at p < 0.05. 1One ATOR subject with myalgia did not complete muscle and aerobic post-testing and thus was not included in analyses.

Figure Legends:

Figure 1.Study flow diagram detailing numbers (n) of participants who were screened,

randomized, completed and analyzed in the study.

@ ( , ) ( , ))


som Ext -17.3 ± (-25.1,-9.5)* -21.5(-30.6,-12.4)* somm FFlelelex xx -5.3(-100.4.44,-, 0.2) -4.3(-10.2,1.6)ssokokok EEExxt @@@ 66600° //sesec c -10.4((-20.0.2,-0.6)*) -6.6(-( 14.5,1.3))sssokkk Flex @ @ 60600°°° s/s/seccc -333.6.6. (-(-( 8.8 666,11.4)))*** -444.6.6.6(-((-8.8.8 7,7,7,-0-00.5.5.5))sssokkk Ext @ 180°° /sssec -3..0(((-8.999,222.9))** -444.11(-10...1,,11.999)** ssokoko FFFlelex @ @ @ 1811800°° ///sesecc -1-11.00(-(-( 4.4.6,6,22.666) -3-33.9.9(-(-( 6.6.8,8,8,--1-1.000)***

Kneeee EEE dndndururanncece FFatatigiguee IIndndexex --2.2.1(1(-4-4 4.4 0,0 2.2)) -3-3.66(-((-555.7,-1-1 5.5))Data are presentntededed aass popopoininntt t esee timamam tetetes ananandd d 959595% % cococonfnfn idididenenencecec iiintntntererervav lslss fffororor aaatotoorvrvrvasasa taaatititin n n (A(A(ATOTOTOR)R)R vvvs.s. ppplalalacececebob (PL) uubjbjecectsts iinn susubjbjecectsts cclalassssififieiedd asas mmyayalglgicic. RERERR == ReRespspiriratatororyy exexchchanangege rratatioio;; VOVO2m2maxax == mmaxaximimalal ooxyxygegenn upuptatakeke;;



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19

Figure 2.Group mean ± SD of creatine kinase (CK; top) and alanine aminotransferase (ALT;

bottom) before (Pre) and after (Post) 6 months of atorvastatin (ATOR) or placebo (PL) treatment

with brackets indicating the p value for group-by-time interaction. *Significant difference

between groups within a timepoint at p <0.05.

Figure 3.Group mean ± SD of changes in physical activity (average counts/day) by age group

after 6 months of atorvastatin (ATOR) or placebo (PL) treatment with brackets indicating the p

value for treatment-by-age interaction.



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ThompsonJustin Keadle, Stuart Chipkin, Linda S. Pescatello, Kathleen Simpson, C. Michael White and Paul D.

Beth A. Parker, Jeffrey A. Capizzi, Adam S. Grimaldi, Priscilla M. Clarkson, Stephanie M. Cole,The Effect of Statins on Skeletal Muscle Function

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2012 American Heart Association, Inc. All rights reserved.

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