Statins and Safety: Applying the Resultsof Randomized Trials to Clinical Practice

David Waters, MD

In this issue of The American Journal of Cardiology,Newman et al1 review the safety profile of atorva-

statin in nearly 10,000 patients involved in 44 clinicaltrials. Most of these studies included placebo groupsor groups treated with another statin, allowing forcomparisons. The studies cover the dose range from10 to 80 mg, with large numbers of patients treated atthe higher doses. Atorvastatin is the most widely usedstatin in the United States and worldwide. This reportis thus a welcome addition to the literature. By defin-ing the risk of treatment more accurately, the investi-gators allow us to calculate more accurately the risk/benefit ratio of treatment.

BENEFITS OF STATIN THERAPYIt is easy to forget that until a decade ago, the

utility of cholesterol lowering was controversial. Ameta-analysis published in 1992 concluded: “loweringserum cholesterol concentrations does not reduce mor-tality and is unlikely to prevent coronary heart dis-ease.”2 The failure of earlier clinical trials to convinc-ingly demonstrate that cholesterol lowering wasbeneficial can be blamed on the cholesterol-loweringagents available at the time. Their potency was limitedand they frequently induced adverse events, such thatit was difficult to maintain a large difference in low-density lipoprotein (LDL) cholesterol levels betweendrug and placebo treatment groups over several years.

Statins changed this. In the Scandinavian Simva-statin Survival Study (4S),3 published in 1994, 20 to40 mg/day of simvastatin reduced LDL cholesterol by35% over 5 years, producing a 30% reduction in totalmortality and comparable reductions in all of the usualcoronary end points. Patients in 4S had clinical evi-dence of coronary disease and high cholesterol levels.Subsequent studies showed that the benefits of statinsextended to coronary patients with average cholesterollevels,4,5 to hypercholesterolemic men without knowncoronary disease,6 and to subjects with average LDLcholesterol, low high-density lipoprotein (HDL) cho-lesterol levels, and no known coronary disease.7

More recent trials have demonstrated that statinsare beneficial for patients at high risk for coronaryevents, irrespective of their serum cholesterol levels.In the Heart Protection Study,8 20,536 patients atincreased risk for a coronary event, who had a meantotal cholesterol of �135 mg/dl, were randomized to

simvastatin 40 mg/day or placebo and followed for 5years. Coronary events, strokes, and revascularizationprocedures were each reduced by approximately 25%in the statin group. Event reduction was just as greatfor patients whose baseline LDL cholesterol was�100 mg/dl as it was for those with higher baselinelevels. These high-risk patients benefited from treat-ment irrespective of their baseline cholesterol levels.

The Anglo-Scandinavian Cardiac Outcomes Trial(ASCOT)9 also confirms that statins benefit high-riskpatients, irrespective of their cholesterol levels. Thistrial randomized 10,305 hypertensive patients with�3 other risk factors (but no known coronary disease)to atorvastatin 10 mg/day or to placebo if their totalcholesterol was �250 mg/dl. This part of ASCOT wasdiscontinued by the Data and Safety MonitoringBoard after 3.3 years of patient follow-up, because ofa 36% reduction in the primary end point, nonfatalmyocardial infarction plus fatal coronary heart disease(p � 0.005), and a 27% reduction in fatal and nonfatalstroke (p � 0.0235). Benefit was similar at all levelsof baseline total or LDL cholesterol. The primary riskfactor in patients in ASCOT was hypertension, butcholesterol lowering reduced their risk of events.

Statins appear to reduce risk irrespective of the riskfactor, be it diabetes,8 low HDL cholesterol,7 hyper-tension,9 smoking,10 or even advanced age.8,11 Doesthis mean that the benefits of statins are due to mech-anisms other than cholesterol lowering? A simplerexplanation is that by historical standards, almost ev-eryone in modern societies is hypercholesterolemic(as well as hypertensive and overweight). Law andWald12 have shown that when physiologic variablessuch as systolic blood pressure or cholesterol levelsare plotted against risk across the “normal” physio-logic range, using epidemiologic data, the relation islinear when risk is on a logarithmic scale. As a con-sequence, for a given change in a risk factor from anystarting level, the change in risk is a constant propor-tion. Thus, the absolute reduction in risk from reduc-ing a risk factor will be large in patients who are athigh risk for any reason. This concept explains whycholesterol lowering and control of other risk factorsis beneficial in high-risk patients even when choles-terol levels are “normal.”

RISK OF STATINSIn epidemiologic studies, very low blood choles-

terol levels are associated with increases in noncardiacmortality and in a variety of noncardiac diseases.13

When statins first became available for research stud-ies in the 1980s, the list of potential adverse effectsincluded sleep disturbances, violent death, decreasedmental acuity, depression, hemorrhagic stroke, cata-

From the Division of Cardiology, San Francisco General Hospital, andthe School of Medicine, University of California, San Francisco,California. Manuscript received and accepted June 3, 2003.

Address for reprints: David Waters, MD, Division of Cardiology,Room 5G1, San Francisco General Hospital, 1001 Potrero Avenue,San Francisco, California 94110. E-mail: d.waters@sfgh.ucsf.edu.

692 ©2003 by Excerpta Medica, Inc. All rights reserved. 0002-9149/03/$–see front matterThe American Journal of Cardiology Vol. 92 September 15, 2003 doi:10.1016/S0002-9149(03)00825-7

racts, cancer, hepatic dysfunction, and myopathy.Well-designed studies have demonstrated that statinsdo not disturb sleep,14–16 impair cognitive func-tion,16,17 or cause cataracts.18,19 Violent death andhemorrhagic stroke rates are not increased in statin-treated groups in randomized trials. The risks of sta-tins that still remain are elevations of hepatic en-zymes, myopathy, and possibly cancer.

STATINS AND THE LIVERHigh-dose lovastatin causes hepatic necrosis in

rabbits, and early clinical studies with lovastatin re-vealed frequent minor elevations of hepatic en-zymes.20 The FDA therefore approved this first statinwith the recommendation that “liver function tests beperformed before initiation of treatment, at 6 and 12weeks after initiation of treatment or elevation in dose,and periodically thereafter (e.g., semi-annually).” If anincrease in serum alanine aminotransferase (ALT) oraspartate aminotransferase (AST) to �3 � the upperlimit of normal (ULN) persisted, discontinuation oftherapy was recommended.20 The “Warnings” sectionof package inserts have been similar for other statins.

Monitoring of hepatic enzymes in large random-ized clinical trials has provided a wealth of data that isrelevant to clinical practice. In Air Force/Texas Cor-onary Atherosclerosis Prevention Study (AFCAPS/TexCAPS),21 ALT and AST were measured every 6weeks for the first year and then semi-annually for theremaining 4 years of the trial. Among the 3,242 lova-statin-assigned patients, 36% had an elevated enzymelevel on �1 occasion, but so did 30% of the 3,248patients assigned to placebo (p �0.001). However,consecutive elevations of �3 � ULN occurred in only0.6% of lovastatin and 0.3% of placebo patients,which is a nonsignificant difference.21 Of the 18 pa-tients who received lovastatin with confirmed ALT orAST elevations �3 � ULN, the abnormalities re-solved with continued treatment, or did not recur witha rechallenge in 14 patients; 3 patients had an alternatediagnosis and only 1 had a positive rechallenge. Thesefindings indicate that isolated minor elevations in ALTor AST are not a cause for alarm or a reason todiscontinue treatment in most cases.

In the Heart Protection Study, in which 20,536subjects took simvastatin 40 mg/day or placebo for 5years, there was no significant excess of ALT or ASTelevation in patients who received simvastatin com-pared with controls; only 9 simvastatin and 4 placebopatients had persistent elevations �4 � ULN.8 Simi-larly, no significant differences in the rates of hepaticenzyme elevations were reported in the pravastatintrials, Cholesterol and Recurrent Events (CARE),4Long-term Intervention with Pravastatin in IschemicDisease (LIPID),5 and West of Scotland CoronaryPrevention Study (WOSCOPS).6 In the Anglo-Scan-dinavian Cardiac Outcomes Trial (ASCOT),9 in which10,305 patients took atorvastatin 10 mg/day or pla-cebo for 3.3 years, no significant differences werenoted in ALT or AST elevations between the 2 treat-ment groups.

The results reported by Newman et al1 thus are no

surprise: 0.5% of 9,416 atorvastatin-treated patientshad persistent ALT or AST elevations �3 � ULN,compared with 0.3% of placebo-treated patients. Therate of these enzyme elevations at the 10 and 20mg/day doses was actually lower than the placeborate.

The cause of minor hepatic enzyme abnormalitiesin patients receiving statins is unknown.20 Minor en-zyme elevations do not presage liver failure, and inmost cases they resolve spontaneously with continuedtreatment.20 Acute liver failure did not occur in any ofthe statin-treated patients in the previously mentionedrandomized trials3–9; isolated cases have occurred, butwhether they are more frequent than the expected rateof idiopathic acute liver failure in the general popula-tion is unclear.20 In any case, periodic monitoring ofAST and ALT is unlikely to prevent exceedingly rarecases of acute liver failure.

STATINS AND MYOPATHYThe most serious risk associated with statins is

myositis with rhabdomyolysis. This risk was high-lighted by the withdrawal of cerivastatin from themarket worldwide in August 2001, because of approx-imately 100 deaths due to this complication. Accord-ing to data reported to the FDA, the risk of fatalrhabdomyolysis was 3.16/million prescriptions of cer-ivastatin.22 This is much higher than the rates for otherstatins: 0.19/million prescriptions for lovastatin, 0.12for simvastatin, 0.04 for pravastatin and atorvastatin,and zero for fluvastatin.22

The risk of rhabdomyolysis is increased by factorsthat increase the serum concentration of statins. Theseinclude small body size, advanced age, renal or he-patic dysfunction, diabetes, and hypothyroidism.23

Drugs that interfere with the metabolism of statins arethe most important risk factor for rhabdomyolysis.These include fibric acid derivatives, niacin, cyclo-sporine, azole antifungals, macrolide antibiotics, pro-tease inhibitors, nefazodone, verapamil, diltiazem,amiodarone, and large quantities of grapefruit juice.23

The mechanism by which statins induce muscleinjury is unknown, but recent studies have focused onthe small guanosine triphosphate binding proteins,Ras, Rac, and Rho.23 These proteins promote cellmaintenance and growth and attenuate apoptosis.23 Byblocking the hydroxymethylglutaryl co-enzyme A re-ductase enzyme, statins reduce the levels of the me-valonate metabolites farnesyl pyrophosphate and gera-nylgeranyl pyrophosphate, thus reducing theprenylation of Ras, Rac, and Rho.23

Serious muscle problems have been uncommon inthe statin trials. In the report by Newman et al,1 noneof the atorvastatin-treated patients had rhabdomyoly-sis and only 1 had a creatine kinase elevation �10 �ULN; 0.4% of patients discontinued the drug due tomyalgias. In ASCOT,9 1 of 5,168 atorvastatin-treatedpatients had rhabdomyolysis. As calculated byThompson et al,23 of 83,858 patients randomly as-signed to a statin or placebo in previous large statintrials, 49 cases of myositis and 7 cases of rhabdomy-olysis were reported in the statin groups compared

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with 44 and 5 cases, respectively, in the placebogroups. In the Heart Protection Study, persistent cre-atine kinase elevations �4 � ULN occurred in only 7simvastatin-treated and 1 placebo patient.8 Only 49 of10,269 statin patients, compared with 50 of 10,267control patients discontinued treatment because ofmuscle symptoms.8 However, muscle complaintswere common: 1/3 of patients in both the simvastatinand placebo groups reported unexplained muscle painor weakness during �1 of the 3 first year or subse-quent semi-annual visits.8

Muscle complaints also appear to be very commonin patients treated with statins in clinical practice.Some of these patients have elevated blood levels ofcreatine kinase, but most will not. Creatine kinasemeasurements may not be helpful in the assessment ofmuscle symptoms because creatine kinase levels areoften elevated in the absence of a statin. For example,in 1 study, 29% of patients receiving placebo had �1creatine kinase elevation over a 48-week treatmentperiod.24 In contrast, muscle biopsies have docu-mented statin-associated myopathy in a few patientswith normal creatine kinase levels.25

STATINS AND CANCERA lingering concern with statins is the possibility

that they might increase the long-term risk of cancer.Statins cause cancer in rodents, but extrapolation fromrodents to humans is an uncertain process.26 A meta-analysis of the first 5 large statin trials revealed nodifference in cancer rates between statin-treated andplacebo patients.27 The Heart Protection Study subse-quently reported equal numbers of new primary can-cers, excluding nonmelanoma skin cancers, in patientsrandomized to simvastatin or placebo who were fol-lowed for 5 years (relative risk 1.0, 95% confidenceinterval 0.91 to 1.11).8 The large number of patients inthis trial and the 5-year follow-up yielded enough newcancers to produce reassuringly narrow confidenceintervals.

However, in the PROspective Study of Pravastatinin the Elderly at Risk (PROSPER) Trial,11 the risk ofnew cancers was increased in the pravastatin groupcompared with controls (hazard ratio 1.25, 95% con-fidence interval 1.04 to 1.51, p � 0.02). The relativelyshort follow-up period of PROSPER, 3.2 years, andthe fact that almost 1/3 of the cancers appeared in thefirst year, led the investigators to conclude that achance imbalance of occult disease at randomizationbetween the groups was the most likely explanationfor this finding. In the CARE Trial,4 breast canceroccurred more commonly in the pravastatin groupthan in the placebo group (p � 0.002), but a meta-analysis of all pravastatin trials, including PROSPERand CARE, revealed no significant effect of the drugon cancer rates.11

A case-control study reported a borderline increasein breast cancer among statin users compared withcontrols (odds ratio 1.5, 95% confidence interval 1.0to 2.3),28 but 2 other cohort studies found no associ-ation.29,30 Observational studies such as these are con-founded by the fact that hypercholesterolemia itself is

a risk factor for breast cancer.29 The effect of mostcarcinogens, such as tobacco smoke, becomes appar-ent only after many years of exposure. The duration ofexposure to statins has been less than a decade in mostusers, and not �5 years in most of the clinical trials.

In contrast, the effect of statins on the mevalonatepathway and thus the prenylation of the smallguanosine triphosphate binding proteins can induceapoptosis in some types of tumor cells.31 Statins arebeing investigated as potential chemotherapeuticagents for the treatment of breast cancer32 and mela-noma.33

STATINS IN PRACTICEThe foregoing considerations support the aggres-

sive use of statins in patients at high risk for coronaryor cerebrovascular events, particularly patients withestablished disease, irrespective of their baseline cho-lesterol levels. The small risk of a serious adverseevent in such patients is dwarfed by the large benefitin preventing death, myocardial infarction, stroke, andthe need for revascularization. In contrast, statinsshould be used more conservatively in younger pa-tients at very low risk, even when hyperlipidemia ispresent, because the very long-term effects of thesedrugs are not yet known. Diet and exercise are moreappropriate approaches under these circumstances.

The main limitation of statins in clinical practice ispoor adherence to treatment. Although 80% to 90% ofpatients remain on a statin for up to 5 years in clinicaltrials, more than half of patients in clinical practicediscontinue treatment within 2 years, even if they donot pay for the drug.34,35

Although frequent monitoring of hepatic enzymesis mentioned in package inserts, this recommendationis now archaic. Minor enzyme elevations are of noclinical significance, and the very rare cases of acuteliver failure that occur during statin use are not pre-ventable by monitoring. Measuring liver enzymesonce, together with lipids, 4 to 6 weeks after startingtherapy is probably sufficient for the usual patient.Patients taking any of the previously mentioned drugsthat interfere with statin metabolism, and those withhepatic or advanced renal dysfunction should bestarted on a low statin dose and monitored moreclosely.

Patients who develop minor myalgias should beencouraged to continue treatment if they are at highrisk for a vascular event. Serious myalgias or muscleweakness necessitate a discontinuation of the drug.Measuring creatine kinase levels is rarely useful inclinical practice because minor elevations are com-mon in statin users and nonusers alike.

Accumulating evidence suggests that the reductionin risk with statins is proportional to the amount ofcholesterol lowering, so that large decrements in LDLcholesterol are preferable to smaller ones. Random-ized clinical trials have shown that atorvastatin signif-icantly reduces events in patients without documentedcoronary disease,9 in stable patients with coronarydisease,36 and in subsets of patients with acute coro-nary syndromes.37 The safety data reported by New-

694 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 92 SEPTEMBER 15, 2003

man et al1 confirm that this potent statin is remarkablysafe, making it an excellent therapeutic choice.

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