Statins for Primary Prevention: Risks Without Benefits

With more than 200 million prescriptions each year in the U.S.[1], statins are one of the most prescribed drug categories here and in much of the world (at least in so-called developed countries). There is little question that for people who have had heart attacks, strokes, angina or peripheral vascular disease, statins are an important component of secondary prevention efforts, or interventions to prevent further (in this case, cardiovascular) risk after a problem has been diagnosed.

Yet about two-thirds of statins are not prescribed for secondary prevention but for primary prevention — that is, to prevent people who have not previously had heart attacks, strokes or other cardiovascular disease from getting such diseases. Over the past decade, especially in the last several years, a number of published studies and reviews have documented the overprescribing of statins for primary prevention, especially for those whose combination of age, medical history, cholesterol levels and other cardiovascular risk factors place them at the lower end of the scale of risk for first-time cardiovascular events. This research has raised serious questions regarding the need for any pharmacological intervention in these lower-risk people. Unfortunately, this majority of statin users are subjected to the risks of these drugs without benefits.

JAMA article overview

In 2012, the Journal of the American Medical Association (JAMA) published an article by Dr. Rita Redberg, editor of JAMA Internal Medicine, and her colleague Dr. Mitchell Katz, with an intriguing but commonsense headline: “Healthy Men Should Not Take Statins.”[2] In their review of the evidence behind this statement, the authors asked:

Should a 55-year-old man who is otherwise well, with systolic blood pressure of 110 mm Hg, total cholesterol of 250 mg/dL, and no family history of premature CHD (coronary heart disease) be treated with a statin?

Their answer: no. The article went on to ask three additional questions:

First, what is the benefit of statins in such people? There is no significant reduction in mortality associated with statin use, even in higher-risk primary prevention populations.

Second, could statins adversely affect healthy people? The authors reviewed the evidence for common adverse effects such as myalgia (muscle pain), fatigue and other minor muscle complaints, many of which are underestimated because studies tend to only collect data on the most serious, quantifiable adverse effects, such as rhabdomyolysis (severe, life-threatening muscle destruction that often causes kidney failure). They also reviewed post-approval studies showing cognitive impairment.

Third, and just as important, they asked if potential benefits of statins outweigh their risks, concluding:

For every 100 patients with elevated cholesterol levels who take statins for 5 years, a myocardial infarction will be prevented in 1 or 2 patients. Preventing a heart attack is a meaningful outcome. However, by taking statins, 1 or more patients will develop diabetes and 20% or more will experience disabling symptoms, including muscle weakness, fatigue, and memory loss.

The article ended with a discussion of nondrug approaches to reducing heart risk in healthy men, such as weight loss through dietary modification and exercise. In addition to their added benefits of improving mood and sexual function, effective nondrug approaches remove the false sense of security people get from taking a statin as a “cure-all” that negates the need for a healthful diet and exercise.

Evidence of overuse

The JAMA article is not alone in questioning the high prevalence of statin use for primary prevention and stressing the resulting potential detrimental effects on patients’ health.

A study from Finland published this year looked at the increased use of statins from 2000 to 2008 in the entire Finnish population of people 70 or older, consisting of 883,051 people.[3] Despite the lack of evidence of a primary prevention benefit of statins for low-risk persons aged 80 years or older, the study found a ninefold increase in statin use in men in this age group as well as a 10-fold increase in women of the same age. The study stated that risk-estimation tools, such as the widely used Framingham Risk Score, are not well applied to the elderly, implying that overestimating risk may lead to overprescribing of statins in low-risk elderly people.

A 2012 review of records of all patients over 55 years of age in a Pennsylvania health care system also examined the prevalence of and reasons for statins use.[4] A large majority of statin prescriptions (71 percent) were for primary prevention. Of the 14,604 patients age 80 or older with a primary prevention indication, 3,145 (22 percent) received a statin. The authors concluded that despite the lack of clear evidence of effectiveness, thousands of patients 80 or over in that health system alone are prescribed a statin for primary prevention.

Lowering cholesterol has some benefits in secondary prevention in the very elderly, but very low cholesterol has been correlated with mortality and morbidity, including risk of Parkinson’s disease.[5] In the Pennsylvania patients being treated with statins for primary prevention, the average LDL cholesterol levels were approximately 80 milligrams per deciliter (mg/dL), almost 20 mg/dL less than the untreated patients — lower levels that are arguably more dangerous.[6]

Another large U.S., mainly primary prevention study involved 10,355 patients 55 years or older with hypertension and elevated cholesterol. Most (86 percent) had no evidence of existing cardiovascular disease. All received usual care — with half randomized to get a statin, the other half a placebo — and were then followed for up to eight years.[7] The conclusion was that the statin did not significantly reduce either all-cause mortality or coronary heart disease when compared with usual care plus a placebo in similar older participants with well-controlled hypertension and moderately elevated LDL cholesterol.

Finally, a recent U.S. study asked 202 physicians their statin-prescribing recommendations for six separately profiled, hypothetical primary prevention patients varying in age, gender, cholesterol levels and other risk factors.[8] For the three lowest-risk hypothetical patients, with 10-year heart attack risks of 5 percent or less, an average of 84 percent of physicians recommended statin use. The authors concluded that physicians do not appear to be adequately considering patients’ actual cardiovascular risks when prescribing statins for primary prevention.

Our conclusion is that the risks of statins are just as likely in patients who are taking the drugs for primary prevention as they are in patients using the drugs for secondary prevention (for whom the acknowledged benefits create more acceptable risks). The large proportion of people using statins for primary prevention are getting the increasingly documented risks of these drugs without any benefit.

References

[1] IMS data on prescriptions filled, 2012.

[2] Redberg R, Katz, M. Healthy men should not take statins. JAMA. 2012;307(14):1491-1492.

[3] Upmeier E, Korhonen MJ, Helin-Salmivaara A, Huupponen R.Statin use among older Finns stratified according to cardiovascular risk. Eur J Clin Pharmacol. 2013; 69:261–267

[4] Chokshi NP, Messerli FH, Sutin D, Supariwala AA, Shah NR. Appropriateness of statins in patients aged ≥ 80 years and comparison to other age groups. Am J Cardiol 2012 Nov 15;110:1477–1481.

[5] Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet 2001 Aug 4; 358: 351–55. Also Huang X, Abbott RD, Petrovitch H, Mailman RB, Ross GW. Low LDL cholesterol and increased risk of Parkinson's disease: prospective results from Honolulu-Asia Aging Study. Mov Disord. 2008 May 15;23(7):1013-8.

[6] Noda H, Iso H, Irie F, Sairenchi T, Ohtaka E, Doi M, Izumi Y, Ohta H. Low-density lipoprotein cholesterol concentrations and death due to intraparenchymal hemorrhage: the Ibaraki Prefectural Health Study. Circulation 2009 Apr 28;119(16):2136-45. Also Huang X, Abbott RD, Petrovitch H, Mailman RB, Ross GW. Low LDL cholesterol and increased risk of Parkinson's disease: prospective results from Honolulu-Asia Aging Study. Mov Disord. 2008 May 15;23(7):1013-8.

[7] ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002 Dec 18;288(23):2998-3007.

[8] Johansen ME, Gold KJ, Sen A, Arato N, Green LA. A national survey of the treatment of hyperlipidemia in primary prevention. JAMA Intern Med. 2013 Apr 8;173(7):586-8.