Commentaries A Point-by-Point Response to Recent Arguments Against the Use of Statins in Primary Prevention
Address for correspondence: Roger S. Blumenthal, MD Ciccarone Center for the Prevention of Heart Disease Johns Hopkins School of Medicine 600 N. Wolfe Street, Blalock 524C Baltimore, MD 21287
[email protected]
This Statement is Endorsed by the American Society for Preventive Cardiology Parag H. Joshi, MD; Sameer Chaudhari, MD, MPH; Michael J. Blaha, MD, MPH; Steven R. Jones, MD; Seth S. Martin, MD; Wendy S. Post, MD; Christopher P. Cannon, MD; Gregg C. Fonarow, MD; Nathan D. Wong, PhD; Ezra Amsterdam, MD; John W. Hirshfeld Jr, MD; Roger S. Blumenthal, MD Johns Hopkins Ciccarone Center for the Prevention of Heart Disease (Joshi, Chaudhari, Blaha, Jones, Martin, Post, Blumenthal), Johns Hopkins School of Medicine, Baltimore, Maryland; Cardiovascular Division (Cannon), TIMI Study Group, Brigham and Women’s Hospital, Boston, Massachusetts; Division of Cardiology (Fonarow), University of California, Los Angeles, California; Heart Disease Prevention Program, Division of Cardiology (Wong), University of California, Irvine, California; Division of Cardiovascular Medicine (Amsterdam), University of California, Davis, California; Cardiovascular Division (Hirshfeld), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Recently, a debate over the merits of statin therapy in primary prevention was published in the Wall Street Journal. The statin opponent claimed that statins should only be used in secondary prevention and never in any primary-prevention patients at risk for cardiovascular events. In this evidence-based rebuttal to those claims, we review the evidence supporting the efficacy of statin therapy in primary prevention. Cardiovascular risk is a continuum in which those at an elevated risk of events stand to benefit from early initiation of therapy. Statins should not be reserved until after a patient suffers the catastrophic consequences of atherosclerosis. Contrary to the assertions of the statin opponent, this principle has been demonstrated through reductions in heart attacks, strokes, and mortality in numerous randomized controlled primary-prevention statin trials. Furthermore, data show that once a patient tolerates the initial treatment period, the few side effects that subsequently emerge are largely reversible. Accordingly, every major guidelines committee endorses statin use in secondary prevention and selectively in primary prevention for those with risk factors. The foundation for prevention remains increased physical activity, better dietary habits, and smoking cessation. However, prevention of heart attacks, strokes, and death from cardiovascular disease does not have to be all or none—all statin or all lifestyle. In selected at-risk individuals, the combination of pharmacotherapy and lifestyle changes is more effective than either alone. Future investigation in prevention should focus on improving our ability to identify these at-risk individuals.
Drs Amsterdam, Blumenthal, and Wong serve on the board of directors and/or are officers of the American Society for Preventive Cardiology. Dr Wong has received research support from Merck and Bristol Myers-Squibb and advisory board consultant fees from Merck in the past 12 months. Dr Cannon is a senior investigator in the TIMI Study Group; has received research support from Accumetrics, AstraZeneca, GlaxoSmithKline, Merck, Essentialis, and Takeda; has donated advisory board consultant fees to charity from Bristol-Myers
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Squibb/Sanofi, Novartis, and Alnylam; has received honoraria for development of independent educational symposia from Pfizer and AstraZeneca; and has equity in Automedics Medical Systems. Dr Jones has received research support and advisory board consultant fees from Atherotech Diagnostics Lab and has served as a consultant for Amylin Pharmaceuticals. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Received: February 27, 2012 Accepted with revision: April 27, 2012
Introduction Prevention of cardiovascular disease (CVD) is a primary focus of the American Heart Association1 and is centered upon preventing or slowing the progression of atherosclerosis through the attainment of optimal levels of established cardiovascular risk factors. Atherosclerosis is a complex, clinically ‘‘silent’’ process based on lipoprotein retention in the arterial wall and the subsequent maladaptive inflammatory response.2 Unfortunately, atherosclerosis often first manifests catastrophically as strokes, heart attacks, and sudden cardiac death. These events occur primarily in those with advanced atherosclerosis in the setting of vulnerable features, including factors contributing to plaque instability (ie, inflammation), the propensity for thrombosis, and the tendency for cardiac electrical instability. Statins primarily lower circulating lipoproteins but have multiple other antiatherogenic effects.3 Recently, a debate over the merits of statin therapy in the primary prevention of CVD was published in the Wall Street Journal.4 A statin opponent argued against the use of statins in any patients prior to the occurrence of a clinical event due to risks of potential side effects, a perceived lack of benefit in morbidity and mortality, costs, and the potential for a ‘‘moral hazard.’’ The statin opponent also wrote that physicians should inform their patients with known heart disease ‘‘that statins likely won’t extend their life.’’ Statins prevent, stabilize, and even induce the regression5 of atherosclerosis, hence making it overly simplistic always to distinguish between those who have and have not experienced cardiac events. Statins have an extensive evidence base to support their use in reducing risk of atherothrombotic events.6 Cardiovascular risk is more accurately considered as a continuum rather than an all-or-none phenomenon. Consequently, there are high-risk ‘‘healthy’’ individuals with atherosclerosis who stand to benefit from early intervention before suffering from the consequences. To accurately assess the risk/benefit of a medication, one must first appraise the existing literature and then correctly interpret the data. We believe that statin opponents are misguided in both of these respects, particularly in selectively neglecting large and important clinical trials that contribute to a scientifically sound evidence base.6 Through cherry-picking which studies to believe, personalopinion biases are introduced. Furthermore, publicized controversial statements that are in discord with the general consensus of the medical community can create mistrust and compromise the patient-doctor relationship. Ultimately, statin opponents have taken an unfounded stance against statin therapy, which could potentially be lifesaving in some patients. In this rebuttal, we show that many of the assertions made by statin opponents are directly countered by the existing evidence. Do Statins Prevent Heart Disease? The case against statin use in primary prevention begins with the assertion that ‘‘data show that statins do not prevent heart disease, nor extend life or improve quality of life.’’4 In reality, reductions in heart attacks, strokes,
and mortality are consistently demonstrated in numerous randomized controlled primary- and secondary-prevention statin trials. Meta-analyses show a statistically significant, clinically relevant mortality benefit that emerges within the first few years of statin treatment. The Cholesterol Treatment Trialists (CTT) Collaborators published a prospective meta-analysis including 169 138 individuals. Treatment with a statin vs placebo, or moreintensive vs less-intensive statin therapy, resulted in proportional reductions of 10% in all-cause mortality, 20% in coronary mortality, and 22% in heart attacks, coronary death, coronary revascularization, and fatal or nonfatal stroke per mmol/L reduction in low-density lipoprotein cholesterol.6 There was homogeneity in the relative outcome benefits of statin therapy between apparently healthy individuals and those with clinically established atherosclerotic vascular disease.6 Regarding primary-prevention patients, there are 3 major meta-analyses that have been published to date.7 – 9 The first, published in 2009, showed a significant reduction in mortality by 12% (odds ratio [OR]: 0.88, 95% confidence interval [CI]: 0.81–0.96) over 4 years. Statin opponents have previously insisted that we cannot infer mortality data in this meta-analysis because it included some patients with known heart disease. Indeed, the investigators performed a secondary analysis in which they excluded trials where participants had known heart disease and noted a similar 13% decrease in all-cause mortality (OR: 0.87, 95% CI: 0.78–0.97). Furthermore, when excluding the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which some opponents wrongly discount, the researchers noted a persistent 11% reduction in mortality (OR: 0.89, 95% CI: 0.81–0.97). Two subsequent meta-analyses by Ray et al in 2010 and by the Cochrane Research Group in 2011 showed similar reductions in mortality in primary-prevention patients (9% and 17%, respectively).8,9 Notably, the statistical uncertainty of the Ray et al trial just crossed the traditional boundary of statistical significance with a 95% CI of 0.83–1.01. Had the CI not equaled or exceeded 1, there would be no further discussion. As Mark Twain said, there are ‘‘lies, damned lies, and statistics.’’10 Statin opponents have taken a hard stance that in primaryprevention trials, statins provide no mortality benefit based on the borderline results of one of these 3 meta-analyses. When interpreting the 3 meta-analyses together, there is at least a very strong trend, if not concrete evidence, that statin therapy results in a reproducible reduction in the relative risk of all-cause mortality by 10% to 15%. Although total mortality is one standard by which interventions are measured, reduction in nonfatal myocardial infarctions (MI) and strokes, prevention of hospitalizations and need for invasive procedures, and improvement in quality of life through a reduction in morbidity is a more pragmatic expectation from statin therapy in primaryprevention patients. Statin opponents downplay the benefits in morbidity by stating that in ‘‘the most optimistic projections, for every 100 healthy people who take statins for 5 years, 1 or 2 will avoid a heart attack.’’4 Based on the JUPITER trial, however, the estimated 5-year number Clin. Cardiol. 35, 7, 404–409 (2012) P.H. Joshi et al: Response to arguments against statin use Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22016 © 2012 Wiley Periodicals, Inc.
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needed to treat (NNT) to prevent MI, stroke, revascularization, hospitalization for unstable angina, or cardiovascular death was 25, or 4 patients out of 100 who will avoid those events.11 In the meta-analyses by Brugts et al and the Cochrane group, there were reductions of nearly 30% in major coronary events, 20% in major cerebrovascular events, 44% in nonfatal MIs, and 33% in revascularizations.7 The Ray et al analysis did not address morbidity.8 For those who believe that ‘‘statins do not prevent heart disease. . .or improve quality of life,’’4 the evidence clearly shows a reduction in heart attacks, strokes, and invasive procedures, which we consider an improvement in quality of life. There is also evidence of benefit in subgroups where controversy previously existed, such as women.12 Accordingly, every major guidelines committee has endorsed the use of statins in secondary prevention and selectively in primary prevention in those with risk factors.
How Long Must We Wait? Statin opponents advocate for longer-term primaryprevention statin trials ‘‘to see if treatment really results in lower mortality’’ despite the abundance of evidence already available.4 Given the low intrinsic event rate in primary prevention, a 4-year follow-up period is very short. As most subjects in primary-prevention trials are comparatively early in the evolution of their atherosclerosis, the impact of statin therapy on atherosclerosis progression will not be fully revealed by catastrophic vascular endpoints over a short period of observation. Based on the wealth of clinical-trial evidence and the supportive meta-analyses, it is unlikely such larger or longer-term primary-prevention trials will be done (especially given that most major statins are now generic). Consistent with the biological activity of statins, preventing atherosclerosis results in fewer heart attacks, strokes, revascularizations, and cardiovascular mortality. As a whole, statins neither eliminate nor contribute to other causes of death, though there has been a suggestion of a decrease in noncardiac mortality.13 Furthermore, evidence already exists addressing outcomes over a longer timeframe.13 – 15 Statin opponents choose to selectively criticize trials such as the West of Scotland Coronary Prevention Study (WOSCOPS) for a lack of applicability to ‘‘most Americans taking statins today.’’4 WOSCOPS shows a decrease in the combined risk of death from coronary heart disease (CHD) or nonfatal MI extending 10 years after trial completion. At 10-year follow-up, the rate of death from CHD or nonfatal MI was 11.8% in the group originally assigned to statin therapy and 15.5% in the group originally assigned to placebo (OR: 0.73, 95% CI: 0.63-0.83).14 Like JUPITER, WOSCOPS is dismissed, although rather than attacking the credibility of the investigators it is claimed that there is a lack of applicability to Americans due to ‘‘high-risk’’4 characteristics such as obesity (although mean body mass index was 26.0 ± 3 mg/kg2 ) and smoking (44% current smokers).16 However, the America we treat is in the midst of an obesity epidemic, and approximately 20% of Americans remain smokers.17 Furthermore, in a subgroup analysis of WOSCOPS, the relative risk reduction
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in events with pravastatin compared with placebo was the same in nonsmokers and smokers (31% in each, P< 0.05).16 WOSCOPS enrolled only men, but the recent meta-analysis by Kostis et al found that the benefits of statins extended to women as well in both primary and secondary prevention.12 Similar long-term results were seen in follow-up of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA), in which primary-prevention patients with hypertension were randomized to atorvastatin 10 mg vs placebo in addition to randomization to antihypertensive treatments.13 An analysis 2 years after the trial noted a relative risk reduction in fatal CHD and nonfatal MIs of 36% in those randomized to atorvastatin (OR: 0.64, 95% CI: 0.53–0.78). A benefit in all-cause mortality (OR: 0.86, 95% CI: 0.76–0.98) extended out to 8 years after closure of the lipid-lowering arm despite extensive crossover. In a combined population of primary- and secondary-prevention patients, the 11-year follow-up of the Heart Protection Study (HPS) shows that the benefit of statin therapy increases every year.15 Long-term follow-up of WOSCOPS, ASCOT-LLA, and HPS strongly suggests that early exposure to statins in primary and secondary prevention has long-lasting, beneficial effects. This is particularly evident with statin treatment in patients with familial hypercholesterolemia, in whom earlier conversion of the familial hypercholesterolemia phenotype results in low lifetime risk in a previously extremely high-risk population.18,19 Statin opponents state that they are not ‘‘setting the burden of proof too high’’ and that interventions for elevated blood pressure have ‘‘strong evidence’’ compared with statins.4 In reality, evidence for mortality benefit is still lacking in treating hypertension aggressively in healthy patients without other cardiovascular risk factors and for treatment of systolic blood pressures 60 years, which is fortunate for young, otherwise ‘‘healthy,’’ at-risk individuals who could benefit from earlier initiation of statin therapy.24 A meta-analysis of 35 randomized controlled trials including 74 102 participants with follow-up times ranging from 1.5 to 65 months (mean, 17 mo) found no significant increase in the risk of myalgias, creatine kinase elevations, rhabdomyolysis, or discontinuation of statin therapy due to any adverse event.25 The National Lipid Association Statin Safety Task Force analyzed 180 000 person-years of follow-up and found myopathy in 5 patients per 100 000 person-years and rhabdomyolysis in 1.6 patients per 100 000 person-years.26 Many of the side effects mentioned by statin opponents are anecdotal or exaggerated. Although some randomized controlled trials had runin periods that may have selected against statin-intolerant patients, these data show that once a patient tolerates the initial treatment period, few side effects subsequently emerge. Most importantly, there are few irreversible side effects to statin therapy. The reversibility of potential harm from statin therapy by either switching to a different formulation or discontinuation is a crucial aspect to consider when considering the risk/benefit ratio. Responsible prescribing practice involves adequate counseling and education of the side effects as well as follow-up examinations to evaluate for any signs of toxicity upon initiation of therapy. Generalizations regarding side effects have a magnifying effect and fuel fear in patients whose physicians have prescribed statins thoughtfully and responsibly. Indeed, many patients without side effects stop taking statins after hearing these claims.
What We Can All Agree On We applaud the passion for ‘‘making fruits and vegetables and physical activity more accessible,’’ and we share the belief that the ‘‘effect on heart disease, as well as high blood pressure, diabetes, cancer and overall lifespan’’ would be tremendous if such a lifestyle were initiated early in life.4 Using the 7 targets of ideal cardiovascular health set forth by the American Heart Association,1 an analysis from the National Health and Nutrition Examination Survey (NHANES) of adults age ≥20 years demonstrated a relative risk reduction of 78% for all-cause mortality (HR: 0.22, 95% CI: 0.10–0.50) and 88% for cardiovascular mortality (HR: 0.12, 95% CI: 0.03–0.57) for those who had 5 ideal factors compared with those who had none. Equally striking, however, only 1.7% of adults met all 7 ideal targets.27 The foundation for prevention of CVD remains increased physical activity, better dietary habits, and smoking cessation. Time invested in encouraging patients toward achieving these goals is well spent. There are also some model examples demonstrating the effectiveness of intensive lifestyle regimens to reverse atherosclerosis28 or prevent DM.29 The evidence to support practical and sustainable approaches to multifactorial lifestyle modifications is limited despite the potential for a significant impact on outcomes.30,31 Healthcare providers need to take a more active role in providing patients with the necessary resources, including access to dietitians and exercise specialists, to implement these changes and improve adherence.
We need to design interventions targeted at reversing our culture of atherogenicity. Our food supply needs to be restructured so that the focus is not on meat and high-calorie, high-fat foods without nutritional value. Our quotidian activities should promote physical activity and healthy behaviors. As Fyodor Dostoevsky said, ‘‘The second half of a man’s life is made up of nothing but the habits he has acquired during the first half.’’32 The change to our culture needs to happen at a primordial level, on a broad scale, and directed toward our youth.33 Fortunately, efforts are being made, including removal of sugar-sweetened beverages from schools, elimination of trans-fats from foods in California and New York City, and calls for an overall reduction in sodium content.34 The increasing epidemic of obesity and inactivity threatens the progress made in recent years in preventing heart disease.17 These necessary primordial interventions are time-consuming and costly. In addition to changing lifestyles, we need medications to address the accumulation of years of atherogenic habits in current at-risk adults. Statin opponents claim that ‘‘statins present a moral hazard, since some people will make less effort to follow a healthy diet and get regular physical activity because they feel falsely reassured by their medications.’’4 We agree that this is a potential risk of statin therapy, just as it is with antihypertensive and DM therapies. The role of the physician is to remind patients that a medication is not a panacea, particularly in primary prevention. There is evidence to suggest that statin users are more concerned about lifestyle factors and possibly eat better diets.35 The combination of lifestyle modifications and pharmacotherapy is more effective than either alone in selected at-risk patients.31
What Can We Focus Resources On? There is much room for improvement in the current application of statins in primary prevention. Current practice begins with risk assessment to identify those who stand to benefit the most from statins. Subsequently, we treat groups of at-risk individuals to benefit as many as possible; however, this approach results in unnecessary treatment in some. Improvement in risk assessment will lead to reductions in NNT by better identifying those who will truly benefit from therapy. Atherosclerosis, like any complex process, results from a combination of environmental factors and intermediate phenotypes (ie, hyperlipidemia, DM) acting upon genetic predispositions. In efforts to optimize the NNT, we use statins in those at intermediate or high risk over the next decade to achieve more aggressive cholesterol targets while tolerating less-than-ideal metrics in those at low overall risk.36 Given the tremendous variability in the interactions of environmental risk factors with genetic predispositions and the relative contribution of intermediate phenotypes, our current methods of risk assessment are imprecise. Many young, ‘‘healthy’’ individuals with risk factors who have a low 10-year risk in fact have a much higher lifetime risk and may benefit from earlier initiation of statin therapy.37 With wide availability of low-cost generic statins, primary prevention has become far less expensive. A recent analysis of statin cost-effectiveness demonstrated that low-cost statins were cost-saving for most apparently healthy men Clin. Cardiol. 35, 7, 404–409 (2012) P.H. Joshi et al: Response to arguments against statin use Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22016 © 2012 Wiley Periodicals, Inc.
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and women with only modestly elevated cholesterol or any CHD risk factors.38 Additionally, this study showed adverse effects of statins were unlikely to outweigh benefits in any subgroup in which statins are found to be efficacious. Efforts to improve risk assessment have generated interest in directly imaging atherosclerosis noninvasively in certain patients, thereby eliminating some of the guesswork involved, particularly in those at ‘‘intermediate’’ risk for cardiovascular events. One such approach involves the identification of coronary artery calcium (CAC), a specific finding for atherosclerosis that correlates strongly with the burden of atherosclerosis and events.39 In an analysis from the Multi-Ethnic Study of Atherosclerosis (MESA) in primary-prevention patients who met qualifications for the JUPITER trial, we found that the NNT estimates improved remarkably when stratified by burden of atherosclerosis as measured by CAC. For CHD events, applying the observed relative risk reduction seen in JUPITER, the predicted 5-year NNT improved from 549 for CAC score 0, to 94 for scores 1 to 100, and to 24 for scores >100. For CVD events, the NNT was 124, 54, and 19, respectively.40 Based on this analysis, CAC scanning can help better identify who will and will not benefit from statin therapy and serves as an example of why current resources in primary prevention should be allocated toward efforts to improve risk assessment and better understand who benefits from therapies such as statins. Future studies will need to demonstrate whether such imaging-guided risk assessment ultimately improves clinical outcomes in those persons identified for the initiation of statin or other preventive therapy who otherwise would not have been treated.
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Conclusion Statins represent one of the most important pharmacologic advances in the primary prevention of CVD. It is unfortunate that claims against statin use in primary prevention were published in a public periodical with enormous readership.4 Although the press may be driven by a pressure to sell articles, and accordingly seek individuals who can generate controversy, the general medical community should guard against dissemination of an extreme position to the general public. All cardiologists (but one) would agree that the biological, mechanistic, and clinical-trial evidence supports statin use in those at high risk of heart disease. Prevention of heart attacks, strokes, and death from CVD does not have to be all or none—all statin or all lifestyle. Rather, the combination of the 2 in appropriately selected patients should be the focus of clinical practice. We should not focus on reinventing the wheel through expensive long-term trials when the data are already clear. Instead, we should dedicate limited resources toward implementing guideline-recommended, evidence-based therapies and efforts to improve and better personalize risk assessment to more accurately identify patients who stand to benefit from therapies in primary prevention. References 1.
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