Almost Everyone Over 50 Should be Put on a Statin to Reduce the Risk of Cardiovascular Disease: A Contrarian View

Abstract

3-Hydroxy-3-methyl-glutaryl-CoA reductase inhibitors, or statins, are a mainstay in the treatment of patients with established coronary artery disease (CAD) because of their proven efficacy in reducing cardiovascular death, myocardial infarction, and coronary revascularization procedures in this patient population. Statin therapy has also proven successful in the primary prevention of CAD. However, the absolute reduction in cardiovascular events is lower in primary prevention than in secondary prevention trials, and many of the primary prevention trials enrolled a significant number of patients with established cardiovascular disease and/or other high-risk features, such as diabetes mellitus. For these reasons we do not recommend widespread treatment of the general adult population with a statin. Rather, we advocate a strategy which involves collection of standard clinical data and the use of validated risk-prediction tools to stratify patient risk and limit initiation of a statin to those who are more likely to benefit from such therapy.

Introduction

Coronary artery disease (CAD) is a leading cause of morbidity and mortality in the United States and worldwide. 3-Hydroxy-3-methyl-glutaryl-CoA reductase inhibitors, or statins, are a mainstay in the treatment of patients with established CAD because of their proven efficacy in reducing cardiovascular death, myocardial infarction, and coronary revascularization procedures in this patient population. Several studies have examined the efficacy of statins in the primary prevention of cardiovascular events and death in individuals without established CAD. As a whole, these studies revealed that statins also provide a beneficial effect in this population. These results beg the question “should most individuals >50-years old be treated with a statin to reduce the risk of developing CAD later in life, even if they are in good health and do not have hyperlipidemia?” Our reply to this intriguing and complex question is “no”.

First, let’s briefly review the data. Several studies examined the role of statins in the primary prevention of CAD. The drugs studied included pravastatin,^1–4 lovastatin,⁵ atorvastatin,^6,7 and rosuvastatin⁸. The landmark WOSCOPS trial was the first to show positive results for primary prevention of CAD.¹ Subsequently, the AFCAPS/TexCAPS⁵ and JUPITER⁸ trials also showed significant reduction in major adverse cardiovascular events, including mortality. These trials were stopped prematurely because significant reductions in primary composite outcomes were observed.^5,6,8

As a whole, the available data suggest that moderate-intensity statin therapy lowers the risk of nonfatal myocardial infarction and CAD-related death by approximately 20–30% without increasing non-cardiovascular death. The clinical investigators who conducted these trials are to be commended for their landmark work. However, great caution must be taken before extending statin therapy, as tested in published trials, into the general population.

It is important to realize that some of the primary prevention trials contained a significant incidence of individuals with established atherosclerotic cardiovascular disease or other high-risk cardiovascular features, such as diabetes mellitus, peripheral artery disease, or positive family history of CAD. For example, in the ASCOT-LLA Trial all patients had hypertension and approximately 10% had history of stroke or transient ischemic attack (TIA) at the time of enrollment. Exclusion of patients with diabetes mellitus, established atherosclerosis, and other CAD risk factors from primary prevention trials certainly would have decreased the number of cardiovascular events, and hence lessened the absolute benefit of statin therapy on cardiovascular endpoints. In fact, a meta-analysis of 11 statin trials involving >60,000 patients who were free of known cardiovascular disease at enrollment did not find a significant reduction in all-cause mortality in statin-treated patients vs. controls.⁹ For low-risk adults, statin therapy is probably not necessary, nor cost-effective.¹⁰

While statin therapy has been shown to reduce cardiovascular risk by 20–30% regardless of baseline cholesterol profile, for an individual patient the predicted absolute benefit of statin therapy depends on his/her cardiovascular risk profile—i.e. patients with low-risk profiles will tend to derive lesser absolute benefit from statin therapy than patients with high-risk profiles.

For example, based on Framingham Heart Study data, a 45-year old non-smoking woman who is not taking antihypertensive medications, has no known cardiovascular disease, and has total cholesterol of 210 mg/dL, HDL cholesterol of 40, and systolic blood pressure 130 mmHg has a predicted 10-year risk of developing CAD of 1.0%. Moderate-intensity daily statin therapy would be anticipated to reduce this risk to approximately 0.75%--i.e. an absolute risk reduction of 0.25%. Do the cost, hassle, and potential side-effects of long-term statin therapy justify this degree of absolute risk reduction? Many individuals would answer “no” to this question. Conversely, a non-smoking 55 year-old man with drug-treated hypertension who has total cholesterol of 250 mg/dL, an HDL cholesterol of 30 mg/dL, and a systolic blood pressure of 150 mmHg has a predicted 10-year risk of developing cardiovascular disease of 21%. Statin therapy would be anticipated to reduce this individual’s risk to approximately 15%, i.e. an absolute risk reduction of 6%. For this individual primary preventive therapy with a statin would appear to be much more reasonable, both from the patient’s and physician’s perspective.

Recently, 10-year risk prediction models have been questioned as adequate guides for initiation of statin therapy.¹¹ This is because for many young adults with active atherosclerosis risk factors the predicted incidence of developing clinically-manifest CAD within 10 years is <10% (i.e. below the threshold of initiating statin therapy), yet their lifetime risk of developing atherosclerotic cardiovascular disease may be quite high, often exceeding 50%.

However, individuals with low lifetime risk of ischemic heart disease can be identified. For example, Framingham Heart Study data suggest that individuals who reach age 50 years and have optimal cardiovascular risk factors (defined as total cholesterol <180 mg/dL, blood pressure <120/80, non-smoker, and non-diabetic) have a low lifetime risk of developing cardiovascular disease (5.2% for men, 8.2% for women).¹² It would seem unwarranted in such individuals to initiate what could amount to several decades of statin therapy.

In terms of lowering risk of developing cardiovascular disease, it is also important to note that medical therapy (i.e. pills) is not the only option. A recent clinical trial involving >7000 individuals showed that dietary intervention can reduce the risk of developing cardiovascular disease.¹³ In this study, which involved patients with diabetes mellitus or at least 3 other cardiovascular risk factors, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events over a follow-up period of several years (median 4.8) by approximately 30% compared to a control diet, which involved avoidance of dietary fat. Hence, dietary modification may achieve a relative benefit in primary cardiovascular disease prevention similar to that of moderate-intensity statin therapy. These results suggest that a preferred initial strategy to reduce cardiovascular risk for many individuals should be dietary and other lifestyle modifications (particularly physical activity), as opposed to statin therapy. While we all know that long-term adherence to dietary and lifestyle modification will be suboptimal for many individuals, adherence to long-term primary prevention oral medications has also been problematic.¹⁴

Conclusion

In conclusion, we do not advocate routine administration of statins to healthy adults to reduce the risk of developing CAD. This recommendation parallels the approach advocated for patients with atrial fibrillation. While oral anticoagulant drugs significantly reduce the risk of developing a first stroke in patients with non-valvular atrial fibrillation, current guidelines do not advocate that all patients with atrial fibrillation be treated with warfarin or another oral anticoagulant drug. This is because low-risk patients can be identified by easily applied risk-prediction tools, such as the CHADS² score. In low-stroke-risk patients long-term oral anticoagulant therapy is not justified. Similarly, for the primary prevention of CAD we advocate a quantitative strategy that is based upon office-based history and physical examination, fasting lipid profile data, and use of simple risk-prediction tools, such as the Framingham Heart Study risk calculator (http://hp2010.nhlbihin.net/atpiii/calculator.asp). With this readily retrievable, low-cost information the health care provider and patient can discuss the potential benefits of statin therapy (as well as other pharmacological and non-pharmacological interventions) and decide together how to proceed.

Biography

Mayank Mittal, MD, (left) and William P. Fay, MD, (right) are in the Department of Internal Medicine, University of Missouri School of Medicine, and the Harry S. Truman Memorial Veterans Hospital, in Columbia.

Contact: fayw@missouri.edu