Accumulating Evidence for Statins in Primary Prevention

Abstract

Many voices in the public and themedical community argue strongly against thewidespreaduse of statins for the primary prevention of atherosclerotic cardiovascular disease. Critics give several reasons to avoid statin therapy, including concerns about adverse effects, lack of a total mortality benefit, cost, and a philosophical aversion to drug therapy. However, the passage of time has allowed sufficient evidence to accumulate to refute each of these concerns. Meta-analyses now provide extensive evidence that statins reduce cardiovascular events and totalmortality in individuals at lower risk of cardiovascular events than has previously been appreciated, and do sowith an excellentmargin of safety.1-3 In this issue of JAMA, Taylorandcolleagues4 provide a summary of the 2013Cochrane2meta-analysis (anupdatedversionof the2011Cochranemeta-analysison this topic3) of 18 primary prevention statin trials including 56 934 participants. The authors report that statins significantly reduce all-causemortality (−14%), fatal andnonfatal cardiovascular disease (−22%), coronary heart disease (−27%), stroke (−22%), and coronary revascularization (−38%). These risk reduction benefits occurred in the absence of an increased risk of cancer, myalgia, rhabdomyolysis, liver enzyme elevation, renal dysfunction, or arthritis. Importantly,participants treatedwithstatinswerenomore likely to discontinue treatment than the placebo group (12%). This means that the adverse event rates were similar in both statin and placebo/control groups, and not just an artifact of thosewith adverse effectswho stopped the statin. Only newonset diabetes was observed to occur frequently in the statin group, consistentwith anothermeta-analysis of statin trials.5 The 2013 Cochrane meta-analysis was reviewed as part of theevidence-base for the recently released2013AmericanCollegeofCardiologyandAmericanHeartAssociationguidelineon thetreatmentofbloodcholesterol topreventatheroscleroticcardiovascular disease in adults.6 The 2013 cholesterol guideline was the result of a rigorous systematic review of higherquality randomized trials, and systematic reviews and metaanalysesof randomized trialsofdrug therapy to reduceatherosclerotic cardiovascular disease events. The 2010 and 2012 Cholesterol Treatment Trialists (CTT) individual-level metaanalyses of statin trials and the individual primary prevention trialswerealso included in theguidelineevidence review.7The guideline recommends moderateor high-intensity statin therapy for the primary prevention of atherosclerotic cardiovasculardisease in individualswith7.5%orgreater 10-yearatherosclerotic cardiovascular disease risk based on strong evidence that the reduction in atherosclerotic cardiovascular disease events outweighs the potential for adverse effects (includingnew-onsetdiabetes).6Moderate-intensitystatintherapy canbeconsidered in individualswith5%to lower than7.5%10yearatheroscleroticcardiovasculardiseaserisk.Thesecutpoints are indeed lower than were recommended in the Adult Treatment Panel III update8 and are consistent with the findings in the 2013 Cochranemeta-analysis. Notably, the2013cholesterolguidelinecutpointswerederived fromtheplacebo rates formyocardial infarction, stroke, and cardiovascular disease death observed in the 3 exclusively primary prevention statin trials, Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study, and the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER).9-11 Subsequent to the initial development of the 2013 cholesterol guidelineprimarypreventionrecommendations, the2012CTT individual-levelmeta-analysisconfirmedthereduction incardiovascular disease events, as well as in total mortality, from statin therapy used in low-risk individuals.1 Indeed, the 2012 CTTmeta-analysis foundagreater reduction intherelativerisk ofmajor cardiovascular disease events (including revascularizations) inthosewithalowerthan10%5-yearriskthaninthose with 10% or higher 5-year risk. To guide the decision to initiate a statin for primary prevention, the 2013 cholesterol guideline used estimated 10year atherosclerotic cardiovasculardisease risk (definedas the first of “hard” events of nonfatalmyocardial infarction, coronaryheart diseasedeath, and fatal andnonfatal stroke, not including revascularization).6 Rates of revascularization are roughly equivalent to the rates of myocardial infarction and stroke,7 so theguideline cutpoints of 7.5%and5%10-year atherosclerotic cardiovascular disease risk roughly correspond to 15% and 10% 10-year combined event rates (including revascularizations), respectively, in the 2013 Cochrane evidence synopsis.4 In contrast to the 2013 Cochrane trial-level meta-analysis of 18 primaryprevention trials, theCTT individual-levelmetaanalysisof28primaryandsecondarypreventionstatin trialsdid findavery slightly increased riskof seriousmyopathy, rhabdomyolysis, andhemorrhagicstroke instatin-treated individuals.1 These findings do not alter the atherosclerotic cardiovascular diseasebenefit-adverseeffect considerationsused for the2013 cholesterol guideline primary prevention recommendations.5 The guideline further notesmuscle complaints are common in patientswhoaretreated,aswellas thosewhoareuntreated,and it is difficult to determine whether those symptoms are related to statin treatment without a rechallenge. Thus, a manRelated article page 2451 Opinion