AOPXXX10.1177/1060028014540609Annals of PharmacotherapyDietrich and Davis

Therapeutic Controversies

A Statin a Day to Keep the Doctor Away? Comparing Aspirin and Statins for Primary Prevention of Cardiovascular Disease

Annals of Pharmacotherapy 1­–4 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014540609 aop.sagepub.com

Eric Dietrich, PharmD, BCPS1, and Kyle Davis, PharmD, BCPS2

Abstract For the primary prevention of cardiovascular (CV) disease, aspirin reduces the risk for major vascular events by approximately 15% to 20% with an absolute reduction of approximately 0.1%. Major bleeding occurs at an excess of approximately 2 cases per 1000 patient-years with aspirin therapy. For primary prevention, statin therapy has been shown to reduce the risk of CV events by approximately 30% to 40% with an absolute reduction of 1% to 2%. Rhabdomyolysis is rare, with an incidence of 3.4 cases per 100 000 patient-years. Compared with aspirin, statins have a more favorable riskto-benefit profile for primary prevention. Keywords statins, aspirin, cardiovascular disease, primary prevention, rhabdomyolysis, bleeding In recent years, the use of aspirin to reduce the risk of cardiovascular (CV) disease has become well accepted among physicians and patients alike. In 2005, approximately 43 million American adults reported taking aspirin daily or every other day. Furthermore, aspirin’s over-the counter availability may also contribute to its high rate of use. Although the majority of these patients reported having indicators of CV disease (as informed by their physician), nearly 15% reported no indicators of heart disease.1 The high rate of aspirin use may in part be attributed to the 2002 US Preventative Services Task Force (USPSTF) recommendation that clinicians discuss aspirin chemoprevention with adults who are at increased risk of coronary heart disease (CHD).2 Based on the widespread use of aspirin, it appears that many patients and providers feel that the efficacy of aspirin therapy in the setting of primary prevention of CV disease outweighs the risk of adverse events (AEs). And so goes the saying “an aspirin a day keeps the doctor away.” In 2013, the American Heart Association (AHA) in conjunction with the American College of Cardiology (ACC) released guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease (ASCVD) risk in adults.3 This guideline updated the previous cholesterol guideline as produced by the National Heart, Lung, and Blood Institute in 2002. The 2013 AHA/ ACC guidelines recommend initiating statin therapy in 3 distinct patient populations for primary prevention of CV

disease: patients aged 40 to 75 years old with diabetes (type 1 or 2), patients with a low-density lipoprotein cholesterol (LDL-C) level of ≥190 mg/dL who were older than 21 years of age, and patients 40 to 74 years old with an estimated ASCVD risk ≥7.5% and a baseline LDL of 70 to 189 mg/dL.3 Therapy recommendations for the latter group have received widespread criticism from the medical and nonmedical communities. Opponents of initiating statin therapy in patients for primary prevention with a low estimated ASCVD risk (ie, less than 7.5%) state that this population is unlikely to benefit from such therapy and will be subject to unnecessary harm.4 Opponents cite an arbitrary cutoff of 7.5% as well problems with the risk calculator, including a potential overestimation of risk and lack of validation, as major concerns when deciding treatment for this patient population. Although this recommendation does warrant investigation, it is important to examine it within the appropriate arena with specific attention paid to widespread belief of aspirin’s benefits in the setting of primary prevention of CV disease.


University of Florida College of Medicine, Gainesville, FL, USA Jackson Memorial Hospital, Miami, FL, USA


Corresponding Author: Eric Dietrich, University of Florida College of Medicine, 1707 North Main Street, Gainesville, FL 32609, USA. Email: [email protected]

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Annals of Pharmacotherapy 

The efficacy of aspirin in the primary prevention of CV disease has been substantiated through several large metaanalyses. One of the earliest of these analyses evaluated 6 primary prevention trials, which included more than 90 000 participants selected to receive aspirin therapy or placebo. Results of this analysis demonstrated a significant reduction in CHD-related events (CV death, myocardial infarction [MI], or stroke; odds ratio [OR] = 0.772; 95% CI = 0.70.86; P = 0.001), driven by a significant reduction in nonfatal MI (OR = 0.755; 95% CI = 0.67-0.85; P = 0.001). However, aspirin therapy had no significant effect on fatal CHD, stroke, or mortality.5 In an effort to evaluate the benefits of aspirin therapy in specific patient groups, the Antithrombotic Trialists’ (ATT) Collaboration6 performed a second meta-analyses of the same studies using individual participant data. Aspirin therapy achieved a small but significant absolute risk reduction (ARR) in serious vascular events (MI, stroke, or vascular death; ARR = 0.07% per year; P = 0.0001). This reduction was primarily a result of a significant reduction in nonfatal MI (ARR = 0.05% per year; P < 0.0001). There was no significant reduction in CHD-related mortality, stroke, or vascular mortality.6 In 2011, an updated meta-analyses was performed, which included 3 additional trials pertaining to aspirin in primary prevention.7 Aspirin was associated with a small reduction in overall mortality (relative risk [RR] = 0.94; 95% CI = 0.88-1.0; ARR = 0.09%) but had no effect on CV mortality. Similar to previous meta-analyses, aspirin significantly reduced the risk of MI (RR = 0.83; 95% CI = 0.69-1.00; ARR = 0.23%); aspirin therapy also resulted in a significant reduction in ischemic stroke (RR = 0.86; 95% CI = 0.75-0.98; ARR = 0.13%).7 The efficacy of aspirin therapy has not been shown to be uniform across all patient subgroups. Whereas aspirin therapy in the primary prevention setting has been shown to reduce the risk of MI in men, these results have not translated to the female patient population. Conversely, aspirin therapy has been shown to reduce the risk of stroke in women, an outcome that was not reduced in male populations.8 Furthermore, in diabetic populations, aspirin therapy has not been shown to consistently reduce CV events.9 In March of 2009, the USPSTF reevaluated the 2002 recommendation supporting the use of aspirin therapy for primary prevention of CV disease. Based on the available data, the USPSTF recommended aspirin for the prevention of MI in men 45 to 79 years of age when the benefit outweighs the risk of gastrointestinal hemorrhage. Additionally, the Task Force recommended aspirin for the prevention of stroke in women 55 to 79 years of age when the benefit outweighs the risk of gastrointestinal hemorrhage.8 Multiple studies have demonstrated the efficacy of statins in the primary prevention of CV disease. The AFCAPS/TexCAPS10 study evaluated lovastatin 20 to 40 mg daily versus placebo in those without ASCVD and

below-average LDL levels; participants enrolled had an estimated average 5-year risk for first major vascular event of 5.2%.11 After a mean follow-up of 5.2 years, treatment with lovastatin reduced the risk for the primary outcome (composite of nonfatal MI, unstable angina, or sudden cardiac death) by 37% compared with placebo (RR = 0.63; 95% CI = 0.5-0.79; P < 0.001; ARR = 2%). Additionally, treatment reduced the risk for coronary revascularization procedures by 33% (P = 0.001; ARR = 1.55%).10 The JUPITER12 study evaluated the efficacy of rosuvastatin 20 mg daily versus placebo in 17 802 otherwise healthy patients with a baseline LDL 2 mg/L. Participants had an estimated average 5-year risk for a first major vascular event of 4.4%.11 The trial was stopped early after a median followup of 1.9 years as a result of the significant reduction in events afforded by treatment with rosuvastatin because the primary outcome (composite of MI, stroke, arterial revascularization, hospitalization for unstable angina, or death from CV causes) was reduced by 44% (HR = 0.56; 95% CI = 0.46-0.69; P < 0.00001; ARR = 1.23%) compared with placebo. Rosuvastatin also reduced the combined end point of MI, stroke, or death from CV causes by 47% (95% CI = 0.40 to 0.69; P < 0.00001; ARR = 0.83%).12 The Cholesterol Treatment Trialists meta-analysis confirmed the efficacy of statin therapy across a wide range of baseline risk categories.11 It is important to note that in those with a baseline 5-year risk of 50%, respectively, in all patients who can tolerate such doses. However, routine monitoring and assessment of on-treatment LDL values is no longer recommended by the guidelines.3 An important consideration for statin and aspirin efficacy is the reduction in absolute risk resulting from treatment. In the setting of primary prevention, the absolute risk is low, and although the relative risk reduction may be significant, the reduction in absolute risk will be considerably smaller; those at higher baseline risk are more likely to receive a larger benefit. Therefore, a comparison of the risks and benefits of statin or aspirin therapy must be made

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Dietrich and Davis to ensure that the benefits outweigh the risks before initiating treatment. The major AEs associated with aspirin mainly involve bleeding, either gastrointestinal (GI) bleeding or intracranial hemorrhage (ICH). The ATT meta-analysis found an increased risk for major GI and extracranial bleeding associated with aspirin use (RR = 1.54; 95% CI = 1.3-1.82; P < 0.0001), although the absolute difference was small (0.1% for aspirin users vs 0.07% for nonusers; absolute risk difference [ARD] = 0.03%).6 An Italian population-based observational study conducted over a median follow-up of 5.7 years evaluated the risk for major GI bleeding or ICH in 186 425 patients receiving aspirin compared with matched controls.13 The rate of major hemorrhagic events among aspirin users was found to be 5.58 (95% CI = 5.39-5.77) per 1000 person-years compared with 3.60 (95% CI = 3.48-3.72) per 1000 person-years for those not using aspirin (incidence rate ratio = 1.55; 95% CI = 1.48-1.63)—approximately 5 times higher than the bleeding incidence found in the ATT meta-analysis. A meta-analysis of 9 randomized trials evaluating aspirin in the setting of primary prevention also identified an increased risk in the rate of major bleeding (RR = 1.66; 95% CI = 1.41-1.65; ARD = 0.33%), ICH (RR = 1.36; 95% CI = 1.01–1.82; ARD = 0.08%), and GI bleeding (RR = 1.37; 95% CI = 1.15-1.62; ARD = 0.82%).7 Authors of a separate meta-analysis evaluating aspirin in the setting of primary prevention found an increased risk of nontrivial bleeding events (OR = 1.31; 95% CI = 1.14-1.50; ARD = 0.92%).13 Recently, the FDA has issued a warning that the potential for bleeding may outweigh potential benefits with aspirin in certain patients without a history of CV disease.14 Furthermore, the USPSTF is in the process of updating their recommendation for the use of aspirin in the prevention of CV disease, which may further affect the role of aspirin in primary prevention of CV disease. The most serious statin-related AEs include hemorrhagic stroke and rhabdomyolysis. Although the overall incidence of statin AEs is rare, the risks are dependent on both the specific statin and the dose. Although myopathy represents an important statin-related AE, myopathy alone is rarely life threatening; liver dysfunction is such a rare event that the FDA no longer mandates routine monitoring of liver enzymes once treatment is initiated.15 A systematic review of cohort studies, randomized trials, case reports, and reports to national regulatory authorities noted an incidence of rhabdomyolysis of 3.4 (95% CI = 1.6-6.5) per 100 000 person-years; this estimate was corroborated by clinical trial data of 20 randomized statin trials.16 Furthermore, the authors found an uncertain risk of hemorrhagic stroke that was primarily identified in cohort studies but not in randomized trials; they concluded that the risks for hemorrhagic stroke are generally outweighed by the benefits in reducing the risk for CV disease and ischemic stroke.16 The 2013 ACC/AHA Cholesterol Guidelines echo these

conclusions, noting that the risk of “myopathy (0.01 excess cases per 100) and hemorrhagic stroke (0.01 excess cases per 100) make minimal contributions to the excess risk from statin therapy (p 32).”3 Statin therapy has also been associated with adverse cognitive effects, and although this risk for this AE is not clearly defined, it is unclear how it contributes to the overall risk-to-benefit profile of statin therapy. The risk of diabetes has also been proposed as a significant contributing factor to the overall risks of statin therapy. The JUPITER trial demonstrated a 25% increased risk for physician-reported diabetes with rosuvastatin compared with placebo.12 However, a post hoc analysis of JUPITER identified 4 major risk factors associated with an increased risk for diabetes: impaired fasting glucose, body mass index >30 kg/m2, baseline hemoglobin A1c greater than 6%, and presence of metabolic syndrome.17 The presence of one or more risk factors was associated with a 28% increased risk for the development of diabetes, whereas there was no increased risk of diabetes if no risk factors were present. Because each of the 4 identified risk factors represents an independent risk factor for the development of diabetes, it appears as if statin therapy simply increased the risk for diabetes in those already likely to develop the disease in the near future. Indeed, the authors noted an accelerated time to diagnosis of diabetes in those receiving statin therapy by 5.4 weeks (average = 84.3 weeks with rosuvastatin compared with 89.7 weeks with placebo).18 The 2013 ACC/ AHA3 also note an increased risk of diabetes with statin therapy that is dose dependent (0.1 and 0.3 excess cases per 100 statin-treated patients per year for moderate- and highintensity regimens, respectively), but both the 2013 ACC/ AHA Guidelines3 and authors of the JUPITER re-analysis17 clearly state that the benefits of statin therapy significantly outweigh the potential risk associated with development of diabetes. Furthermore, statin therapy is recommended for most individuals with a diagnosis of diabetes by the 2014 ADA Guidelines.18 Compared with aspirin in the setting of primary prevention, statin therapy appears to be safer because the risk for major AEs (rhabdomyolysis and hemorrhagic stroke) are of the order of 100 000 patient years compared with 1000 patient-years for aspirin (GI bleeding and ICH). Furthermore, the benefits of statin therapy are more pronounced than those of aspirin because the risk for major vascular events is reduced by approximately 20% for every 39 mg/dL reduction in LDL compared with an approximately 15% reduction with aspirin; because moderate- and high-intensity statin regimens are often able to lower LDL by more than 39 mg/dL, statin therapy is likely to offer further benefit. ARRs with statins (of the order of 1%) also appear to be significantly greater than aspirin (of the order of 0.1%). Furthermore, the benefits of aspirin therapy appear to be variable, whereas the benefits of

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Annals of Pharmacotherapy 

statin therapy appear to be more consistent across various patient subgroups and ages. While there are no direct head-to-head comparisons evaluating aspirin versus statins for the primary prevention of ASCVD, given the more favorable safety and efficacy profile of statin therapy compared with aspirin therapy, the time may have come to change the saying to “a statin a day keeps the doctor away.” Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849-1860. 7. Raju N, Sobieraj-Teague M, Hirsh J, O’Donnell M, Eikelboom J. Effect of aspirin on mortality in the primary prevention of cardiovascular disease. Am J Med. 2011;124:621-629. 8. US Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150:396-404. 9. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA. 1998;279:1615-1622. 10. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380:581-590. 11. Soejima H, Morimoto T, Saito Y, Ogawa H. Aspirin for the primary prevention of cardiovascular events in patients with peripheral artery disease or diabetes mellitus: analyses from the JPAD, POPADAD and AAA trials. Thromb Haemost. 2010;104:1085-1088. 12. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207. 13. De Berardis G, Lucisano G, D’Ettorre A, et al. Association of aspirin use with major bleeding in patients with and without diabetes. JAMA. 2012;307:2286-2294. 14. Food and Drug Administration. FDA safety communication: use of aspirin for the primary prevention of heart attack and stroke. Accessed June 1, 2014. http://www.fda.gov/Drugs/ ResourcesForYou/Consumers/ucm390574.htm. Accessed June 9, 2014. 15. Brewer HB. Benefit-risk assessment of rosuvastatin 10 to 40 milligrams. Am J Cardiol. 2003;92(suppl):23K-29K. 16. Food and Drug Administration. FDA drug safety com munication: important safety label changes to cholesterollowering statin drugs. http://www.fda.gov/drugs/drugsafety/ ucm293101.htm. Accessed February 26, 2014. 17. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97(suppl 8A):52C-60C. 18. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380:565-571.

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A Statin a Day to Keep the Doctor Away? Comparing Aspirin and Statins for Primary Prevention of Cardiovascular Disease.

For the primary prevention of cardiovascular (CV) disease, aspirin reduces the risk for major vascular events by approximately 15% to 20% with an abso...
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