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Circulation. 2006;114:2788-2797
Published online before print December 11, 2006, doi: 10.1161/CIRCULATIONAHA.106.624890
CLINICAL PERSPECTIVE
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 Circulation: December 19/26, 2006, Volume 114, Number 25
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(Circulation. 2006;114:2788-2797.)
© 2006 American Heart Association, Inc.

Epidemiology

Risks Associated With Statin Therapy

A Systematic Overview of Randomized Clinical Trials

Amir Kashani, MS, MD; Christopher O. Phillips, MD, MPH; JoAnne M. Foody, MD; Yongfei Wang, MS; Sandeep Mangalmurti, MD; Dennis T. Ko, MD; Harlan M. Krumholz, MD, SM

From the Section of Cardiovascular Medicine, Department of Medicine, Yale University School of Medicine, New Haven, Conn (A.K., J.M.F., Y.W., H.M.K.); Department of General Internal Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio (C.O.P.); VA Connecticut Healthcare System, West Haven, Conn (J.M.F.); Ambulatory Health Clinic, United States Navy, Groton, Conn (S.M.); Sunnybrook and Women’s College Health Sciences Centre, Toronto, Ontario, Canada (D.T.K.); and Section of Health Policy and Administration, Department of Epidemiology and Public Health, and the Robert Wood Johnson Clinical Scholars Program, Department of Medicine, Yale University School of Medicine, and Center for Outcomes Research and Evaluation, Yale–New Haven Hospital, New Haven, Conn (H.M.K.).

Correspondence to Harlan M. Krumholz, MD, SM, 333 Cedar St, Room I-456 SHM, PO Box 208088, New Haven, CT 06520-8088. E-mail harlan.krumholz{at}yale.edu

Received March 9, 2006; revision received October 20, 2006; accepted October 25, 2006.


*    Abstract
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 *Abstract
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Background— Although statins reduce the risk of cardiovascular events, concerns about adverse effects may deter physicians from prescribing these agents. We performed a systematic overview of randomized statin trials to quantify the risks of musculoskeletal, renal, and hepatic complications associated with therapy.

Methods and Results— Major statin trials were identified by electronic search of the MEDLINE database from 1966 to December 2005. We included English language reports of adults with documented hyperlipidemia; double-blind, random allocation of ≥100 patients to statin monotherapy versus placebo; and reports of myalgia, creatine kinase elevations, rhabdomyolysis, transaminase elevations, and discontinuation due to adverse events. Among 74 102 subjects enrolled in 35 trials (follow-up range, 1 to 65 months), statin therapy (excluding cerivastatin) did not result in significant absolute increases in risks of myalgias (risk difference/1000 patients [RD], 2.7; 95% CI, –3.2 to 8.7), creatine kinase elevations (RD, 0.2; 95% CI, –0.6 to 0.9), rhabdomyolysis (RD, 0.4; 95% CI, –0.1 to 0.9), or discontinuation due to any adverse event (RD, –0.5; 95% CI, –4.3 to 3.3). The absolute risk of transaminase elevations was significantly higher with statin therapy (RD, 4.2; 95% CI, 1.5 to 6.9).

Conclusions— On the basis of data available from published clinical trials, statin therapy is associated with a small excess risk of transaminase elevations, but not of myalgias, creatine kinase elevations, rhabdomyolysis, or withdrawal of therapy compared with placebo. Further study is necessary to determine whether the results from these published clinical trials are similar to what occurs in routine practice, particularly among patients who are older, have more severe comorbid conditions, or receive higher statin doses than most patients in these clinical trials.


Key Words: coronary disease • creatine kinase • lipids


*    Introduction
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 *Introduction
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Statin therapy is underutilized,1,2 and concerns about potential adverse effects may deter physicians from prescribing these agents in appropriate patients. The recent withdrawal of cerivastatin by the US Food and Drug Administration (FDA) in 2001 because of reports of rhabdomyolysis3 led to heightened concerns about the safety of statins.4 After the withdrawal of cerivastatin, it is estimated that >200 000 patients with dyslipidemia discontinued statin therapy.5

Clinical Perspective p 2797

Although the effect of statins in reducing the risk of cardiovascular disease is well established, less is known about the risks. Previous studies of statin adverse effects have focused only on a few adverse reactions rather than the entire spectrum.6,7 For instance, previous meta-analyses have evaluated only transaminase elevations6 or cancer incidence and rhabdomyolysis.7 The pooling of data from clinical trials assessing adverse effects is an emerging approach to determine the risks associated with statin therapy.8–10 Accordingly, we sought to quantify the risk of adverse events among patients taking statins through a systematic review of the published clinical trials.


*    Methods
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 *Methods
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Selection of Trials
We performed the present review in accordance with the Quality of Reporting of Meta-analyses Statement and recommendations for assessing harm in randomized clinical trials.11 Eligible studies were identified by searching MEDLINE (1966 to December 2005), EMBASE (1980 to December 2005), the Cochrane Library (Controlled Trials Register and Database of Systematic Reviews, all years), the National Institutes of Health Clinical Trials Web site (www.clinicaltrials.gov), the FDA Web site (http://www.FDA.gov), and relevant bibliographies. A combination of medical subject headings and text terms was used: hydroxymethylglutaryl-CoA reductase inhibitors, statins, atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin.

Inclusion Criteria
We included English language reports of trials targeting adults (age ≥18 years) with hyperlipidemia (defined uniquely within each study) and random allocation of ≥100 patients to statin monotherapy versus placebo; double blinding of study subjects and study investigators; and reporting of adverse effects. We chose a sample size of ≥100 to maintain a normal distribution of baseline patient characteristics in each study, to reduce uncertainty in the estimates of adverse effects on account of underpowered studies, and to reduce confounding because of publication bias. Studies limited to specific patient populations were excluded from this systematic review (Figure 1).


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  		Figure 1. Search strategy and results. HMG-CoA indicates 3-hydroxy-3-methylglutaryl coenzyme A.

Data Collection
We extracted adverse events data from published reports of the trials. Paired reviewers independently reviewed each eligible report without the use of masking. Results reflect adverse event counts reported in the primary studies or, when studies reported event counts as a percentage, the calculated number of adverse events, rounded to the nearest integer. Discrepancies in data abstraction were resolved by consensus. In addition, the methodological quality of each study was scored by extracting the following information based on the Jadad score: randomization, allocation generation, double blinding, description of withdrawals, and dropouts.12

Outcome Measures and End Point Definitions
We extracted data for the following end points from each study: myalgias, creatine kinase (CK) elevations, rhabdomyolysis, transaminase elevations, and discontinuation due to any adverse events when available. For each study, there were variations in the frequency of evaluating patients for adverse events.

Myalgias
We defined myalgias as any musculoskeletal pain/symptoms without documented CK elevations. Myalgias were defined in the studies as myalgias,13–19 myopathy,20–22 arthralgias,23 musculoskeletal pain24,25 or symptoms/disorders,26–30 muscle pain,31–34 severe or unusual muscle aches or pains,35 and musculoskeletal/connective tissue symptoms.36

CK Elevations
Varying laboratory parameters were used by different studies to define CK elevations: CK >upper limit of normal (ULN),23 CK >3 times ULN,17,31,35,37,38 CK >4 times ULN or pretreatment value,15,24,25,32,33,39 CK >ULN on 2 consecutive visits,40 CK >5 times ULN,13,20 increased CK,41 CK elevations on ≥2 occasions,36 elevated CK with muscle pain,30,42 and significant CK elevations.19

Rhabdomyolysis
We defined rhabdomyolysis as CK elevations ≥10 times ULN. This definition has been used in numerous studies.*

Transaminase Elevations
We recorded hepatotoxicity as any combination of serum alanine aminotransferase or aspartate aminotransferase elevations. The definitions used by different studies include the following: >ULN,40,47 >2 times ULN,17,32,48 >3 times ULN,{dagger} ≥3 times ULN,41 >3 or ≥3 times ULN on 2 consecutive occasions,26,28,29,43 consecutive elevations of transaminases ≥3 times ULN,22 "no clinically significant elevations" in alanine aminotransferase or aspartate aminotransferase,18,19 and ≥2 elevations in alanine aminotransferase or aspartate aminotransferase.36

Discontinuations Due to Any Adverse Event
In addition, we evaluated discontinuations of study drug due to any adverse event.{ddagger}

Statistical Analysis
We combined information from the trials using the general variance-based methods of DerSimonian and Laird, which incorporate weighting based on inverse variance.52 However, the assumption of homogeneity was rejected when tested with the {chi}2 statistic, implying the presence of significant variation between studies. To estimate and control for this heterogeneity, we applied a random-effects model to estimate the variance component associated with between-study variation. With the use of this method, the variance for each individual study in the review is the sum of within- and between-study components of the variance. The use of the random-effects method has 2 major implications: (1) the meta-estimate of the relative risk (RR) now represents the mean of observed effect sizes rather than the true effect size in the population, and (2) this method will generally lead to wider CIs because of the additional source of variation being considered in the presence of heterogeneity. We checked the publication bias using funnel plots and repeated our analysis limiting it to those trials with ≥1 year of follow-up.

For each end point, we calculated a meta-estimate of the risk difference per 1000 patients (RD) as well as the RR between statin-treated subjects and placebo controls using the general random-effects model. RD is reported as incidence per 1000 patients. CIs were obtained by calculating the exponential of the upper and lower confidence limits for the log RRs and RDs. To account for the wide variation in the duration of follow-up in our trials (1 month to 65 months), we calculated pooled incidence RD and numbers needed to treat per 1000 patients to estimate the absolute risks of statin therapy on adverse effects. We used SAS version 9.1 (SAS Institute, Inc, Cary, NC) and SAS Macros for meta-analysis53 for all calculations.

The authors had full access to the data and take responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.


*    Results
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 *Results
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We identified a total of 1976 potentially relevant trials. Of these, 1937 publications failed to meet all inclusion criteria. We identified 35 randomized controlled trials including 74 102 participants, assessing 6 currently approved statins (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin). Additionally, we analyzed 4 studies of cerivastatin separately. There was no significant evidence of publication bias in pooled analyses or any of the individual listed end points. Tests for heterogeneity (probability value range, 0.13 to 0.49) did not reveal any significant interstudy differences in random-effects models. All studies were double blind and placebo controlled, and 27 of the 35 studies were primary prevention trials. The methodological quality of the studies included was high, with an average Jadad score of 4.1 points.12 The statins assessed were as follows: atorvastatin, 5 studies (14%; n=12 148 patients); fluvastatin, 4 studies (11%; 2295 patients); lovastatin, 9 studies (26%; 17 178 patients); pravastatin, 8 studies (23%; 15 262 patients); rosuvastatin, 4 studies (11%; 835 patients); and simvastatin, 7 studies (20%; 26 649 patients). Cerivastatin was analyzed separately (4 studies; 2282 patients). The total numbers of patients randomized to treatment and placebo, respectively, for each statin are as follows: atorvastatin (6572 versus 5576); cerivastatin (1898 versus 384); fluvastatin (1304 versus 991); lovastatin (11 294 versus 5884); pravastatin (7918 versus 7344); rosuvastatin (631 versus 204); and simvastatin (13 728 versus 12 921).

Follow-up times ranged from 1.5 to 64.8 months (mean, 17 months). The mean age of patients across all treatment groups ranged from 49 to 81 years. The majority of patients studied were male; the proportion of men ranged from 25% to 100%. Patients enrolled in clinical trials were predominantly white (ranging from 79% to 100% of the study cohort). Baseline characteristics by study are shown in Table 1. Follow-up times and doses of statins used are listed in Table 2.


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  		TABLE 1. Baseline Characteristics


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  		TABLE 2. Study Characteristics

Myalgias, reported in 21 studies (60%) including 48 138 patients, were not significantly more common among those treated with currently available statins (Table 3).§ The RR of myalgia in patients on a statin compared with placebo was 0.99 (95% CI, 0.96 to 1.03). When myalgia was evaluated among individual statins, only atorvastatin had a significantly higher incidence RD compared with placebo (5.1% versus 1.6%; P=0.04; RD, 31.9; 95% CI, 2.1 to 61.6).


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  		TABLE 3. Risk Difference of Various End Points Associated With Currently FDA-Approved Statins

CK elevation, reported in 16 studies (46%) including 41 457 patients, was no more frequent in patients treated with statins (Table 3).|| The RR of CK elevations with statin therapy did not reach statistical significance (RR, 1.18; 95% CI, 0.89 to 1.56). None of the atorvastatin trials reported CK elevations as an end point.

Rhabdomyolysis, reported in 20 studies (57%) including 68 110 patients, was not more common in the statin group, with an RR of 1.09 (95% CI, 0.65 to 1.83) (Table 3).

Transaminase elevations, reported in 28 studies (80%) including 62 184 patients, were more common in patients allocated to statins (Table 3).# The RR was significantly higher in patients receiving statins in comparison with placebo (RR, 1.30; 95% CI, 1.06 to 1.59). The higher incidence of liver toxicity with statin therapy reached statistical significance in the fluvastatin and lovastatin trials (Table 3). Two studies reported transaminase elevations as any elevations higher than the ULN.40,47 This unusually low threshold definition of transaminase elevations may include patients without a clinically important elevation. After these 2 studies were excluded, the RR of transaminase elevations remained similar (RR, 1.32; 95% CI, 1.07 to 1.64).

When individual statins were compared with placebo, rosuvastatin had a higher incidence of myalgias, CK elevations, and rhabdomyolysis (Table 3). Although these did not reach statistical significance, the number of patients randomized in rosuvastatin trials was low, decreasing the power to detect a statistically significant change.

Discontinuations due to any adverse events, reported by 26 studies (74%) including 45 268 patients, did not occur more frequently in the statin group (Table 3).** The rate of discontinuations was 5.6% in the statin group and 6.1% in the placebo group (P=0.80).

Long-term follow-up (≥1 year) was available in 19 studies (54%) evaluating atorvastatin,44,45,49 fluvastatin,20,43 lovastatin,21,30,35,42,45,48 pravastatin,16,25,34 and simvastatin.31,32,46 Limiting the analysis to only these long-term follow-up trials did not result in any significant changes with regard to myalgias (RD, –0.1; 95% CI, –5.2 to 5.0]), CK elevations (RD, 0.2; 95% CI, –0.6 to 0.9), rhabdomyolysis (RD, 0.3; 95% CI, 0.0 to 0.6), transaminase elevations (RD, 2.5; 95% CI, 0.4 to 4.6), or discontinuation due to any adverse events (RD, –1.5; 95% CI –5.8 to 2.8).

To account for the varying follow-up times in each study, we also evaluated our end points on the basis of RD per 1000 patient-years of therapy: myalgias (RD, –0.03; 95% CI, –2.3 to 2.2), CK elevations (RD, –0.02; 95% CI, –0.2 to 0.1), rhabdomyolysis (RD, –0.01; 95% CI, –0.03 to 0.02), transaminase elevations (RD, –0.2; 95% CI, –0.7 to 0.2), and discontinuations due to any adverse events (RD, 0.4; 95% CI, –0.5 to 1.4). Again, there was no statistically significant increased risk with any of the end points.

Cerivastatin
When cerivastatin was compared with placebo, the risk of myalgias (RR, 0.67; 95% CI, 0.33 to 1.35)13,17,23 or discontinuation due to any adverse event (RR, 2.46; 95% CI, 0.01 to 957.21)13,23 was not significantly increased. There was a nonsignificant trend toward higher rates of CK elevations (RR, 1.25; 95% CI, 0.68 to 2.31).13,17,23,40 There was a significant increase, however, in the incidence of rhabdomyolysis13,40 and transaminase elevations13,17,23,40 with cerivastatin use compared with placebo (Table 4). Cerivastatin was the only statin demonstrating significantly higher rates of rhabdomyolysis with drug therapy (Figure 2).


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  		TABLE 4. Cerivastatin Trials


Figure 2180097
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  		Figure 2. Risk difference of FDA-approved statins vs cerivastatin. The significant increased risk of CK elevation and rhabdomyolysis with cerivastatin compared with currently FDA-approved statins is shown. However, cerivastatin was not associated with an increased risk of myalgias. This may result in the elimination of warning signs (ie, musculoskeletal symptoms) before the development of more serious adverse events. IRD indicates incidence risk difference. Probability value is for statin vs placebo.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
On the basis of this systematic overview, the incidence of adverse events associated with currently available, FDA-approved statins is low. Although statin therapy (after exclusion of cerivastatin trials) was associated with a significant absolute increase in risk of transaminase elevations, this risk was small, with an absolute increase per 1000 patients treated of 4.3.

One of the most frequently discussed side effects of statins is myalgia. According to package inserts, the incidence of myalgia with currently prescribed statins ranges from 1.1% to 5.0%.54 In this analysis of 35 randomized, placebo-controlled trials of FDA-approved statins, there was a nonsignificant trend toward lower reports of myalgia in statin-treated patients compared with placebo-treated patients. This is consistent with recent reports suggesting relatively low rates of myalgia in patients enrolled in clinical trials.55,56 Furthermore, CK elevations (defined as elevations <10 times ULN) occurred in only 0.9% of patients treated with any of the 6 FDA-approved statins, and this number did not reach statistical significance compared with the incidence of CK elevations in patients receiving placebo therapy. This finding is difficult to reconcile with the observation in clinical practice of the association with myalgias but suggests that the risk was not substantial in patients enrolled in these trials.

Despite its low incidence, but due to its high case fatality rate, rhabdomyolysis has been the focus of many previous studies of adverse effects of statins.57,58 Analyses conducted by the FDA have reported the rate of fatal rhabdomyolysis as 0.15 per 1 million statin prescriptions dispensed (ranging from 0 with fluvastatin to 3.16 with cerivastatin).58,59 The present study is consistent with previous studies58,59 and supports the rare incidence of rhabdomyolysis with currently available statins and a 12-fold increased risk with the withdrawn statin (cerivastatin). In {approx}60% of the total number of cases, statin-related rhabdomyolysis was found to be related to drug-drug interactions. In a review of all cases of fatal rhabdomyolysis associated with statin use, reporting rates were <1 death per million prescriptions in the case of all statins except cerivastatin.57 It should be noted that in the present study, however, long-term follow-up analyses demonstrated a trend toward higher rates of rhabdomyolysis, and future studies are required to define this issue further. The present study expands currently available literature by showing that although there is a trend toward higher rates of rhabdomyolysis with statin therapy compared with placebo, this difference does not reach statistical significance, and the absolute rate remains small. Thus, in this population of patients enrolled in clinical trials, with rare use of concomitant fibrate therapy, the clinical trials were not able to detect an increase in the rate of rhabdomyolysis with statin therapy.

Elevations in hepatic transaminases occurred significantly more frequently with statins than with placebo. However, progression to liver failure is exceedingly rare, if present,4,60 and transaminase elevations are usually reversible with reduction of dose or termination of therapy. This finding is consistent with previous reports.61,62 In an evaluation of cases of severe statin-related transaminitis within a large health maintenance organization, 0.1% of 23 000 patients had severe transaminitis deemed directly attributable to statin use.63

In practice, clinicians frequently follow muscular and hepatic serum markers in asymptomatic patients on statin therapy. In a previous report, however, Smith et al64 failed to find any efficacy in routine screening of serum CK and transaminases in this patient population. The low incidence of adverse events seen in the present study supports current American College of Cardiology/American Heart Association/National Heart, Lung, and Blood Institute guidelines recommending screening only after symptoms are reported by patients.4

Although the present study is the largest, most comprehensive assessment of adverse effects associated with statins, several issues warrant consideration. Event rates reported in this systematic review are reasonable estimates of event rates in patients with characteristics similar to those enrolled in clinical trials and with close physician monitoring (Table 1). Nevertheless, the external validity is an issue because clinical trials typically enroll patients who are younger and healthier than those seen in routine practice. In addition, in some cases data were limited because of the design of the studies. For example, patients receiving atorvastatin had a significantly higher incidence of myalgias, but none of the atorvastatin trials reported CK levels or elevations. Additionally, >95% of patients treated with atorvastatin received doses <40 mg, and the majority of patients treated with simvastatin received doses <80 mg. There are only limited data on the newest statin available in the United States, rosuvastatin, which hampers efforts to fully characterize risks associated with this particular statin. We had insufficient data to perform subgroup analyses based on dosages, and thus no inferences can be made with respect to very high doses of individual statins not assessed in clinical trials. Thus, our findings must be interpreted from the perspective of the limitations of the clinical trial data available for the present analysis. Finally, for truly rare adverse events, the clinical trial populations may not, even in the aggregate, be large enough to detect an increased risk.

In addition, concerns have been raised regarding the risk of concomitant treatment with statins and fibrates, but the trials examined in this study cannot determine the risk associated with combination therapy. Another concern is the possible relationship between statins and memory loss,65 which we were unable to evaluate because of limited available data. It should also be noted that 5.9% of patients included in this study had <3 months of follow-up. This may underestimate the incidence of adverse events in these patients.

Appropriate use of statins in carefully selected patients can markedly reduce vascular and coronary events in high-risk patients.4,66 Our findings confirm that the use of statins in selected patients is associated with low adverse event rates in the clinical trials. Population surveillance may provide information that would complement the trial data. Nevertheless, the trial data provide support for the safety of these medications.


*    Acknowledgments
 
Sources of Funding

Dr Phillips is supported by grant 3 R01 HL 080228-01S1 from the National Heart, Lung, and Blood Institute. Dr Ko is supported by the Heart and Stroke Foundation of Ontario Clinician Scientist Award.

Disclosures

Dr Foody is on the advisory boards for Merck, Pfizer, and BMS/Sanofi and has received speaker honoraria from the same. The remaining authors report no conflicts.


*    References
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 up arrowAbstract
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 up arrowResults
 up arrowDiscussion
 *References
 

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CLINICAL PERSPECTIVE

Statin therapy is underutilized, and concerns about potential adverse effects may deter physicians from prescribing these agents in appropriate patients. Although the effect of statins in reducing the risk of cardiovascular disease is well established, less is known about the magnitude of risks. Postmarketing surveillance reports and other retrospective analyses have focused primarily on rhabdomyolysis rather than the spectrum of muscle and liver adverse effects associated with statins. Moreover, previous studies have reported varying rates of statin-related adverse events. A more complete evaluation of adverse effects seen with statin therapy is currently missing from the literature. Accordingly, we sought to quantify the risk of adverse events among patients taking statins on the basis of the published randomized trials. The pooling of data from clinical trials assessing adverse effects is an emerging approach to determine the risks associated with statin therapy.


*    Footnotes
 
Guest Editor for this article was John Z. Ayanian, MD, MPP.

*References 13, 14, 16, 18, 19, 22, 24, 26, 28–30, 32, 34, 38–46. Back

{dagger}References 13–16, 20, 21, 23, 25, 30, 31, 33–35, 37, 39, 42, 45, 46. Back

{ddagger}References 13–16, 18–29, 31, 32, 36, 37, 39, 41, 42, 46, 47, 49–51. Back

§References 14–16, 18–22, 24–36. Back

||References 15, 19, 20, 24, 25, 30–33, 35–39, 41, 42. Back

¶References 14, 16, 18, 19, 22, 24, 26, 28–30, 32, 34, 38, 39, 41–46. Back

#References 14–16, 18–22, 25, 26, 28–37, 39, 41–43, 45–48. Back

**References 14–16, 18–22, 24–29, 31, 32, 36, 37, 39, 41, 42, 46, 47, 49–51. Back


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