Who Should Get Statins for Primary Prevention?
What every patient should know about cholesterol-lowering drugs.
With Insights from Pedro Martinez, Keyshawn Johnson, Mike Ditka, and Spike Lee
A statin is a commonly used cholesterol-lowering medication that has been around for decades. Statins go to the liver where they tell cells to draw cholesterol out of the circulation and also to make less cholesterol. Specific types of statins are rosuvastatin (Crestor), atorvastatin (Lipitor), simvastatin (Zocor), pitavastatin (Livalo), pravastatin (Pravachol), fluvastatin (Lescol), and lovastatin (Mevacor). You can read more about some of these individual statins on the CardioSmart website.
There have been mixed messages in the media about statins, which can be confusing to patients and doctors alike. Therefore, we wanted to write directly to patients to make it perfectly clear what 99.9% of physicians, including preventive cardiologists like ourselves, think about statin medications. We wanted to do this in a fun way, so have tried to incorporate some humor, which we hope you enjoy.
First off, in all seriousness, we regard statins as one of the most successful treatments known to protect patients from cardiovascular disease, which means heart attacks and strokes. Prescribing a generic statin to a middle-aged or older adult with high cholesterol and another cardiovascular risk factor, such as high blood pressure, diabetes, or smoking, is viewed by preventive cardiologists as one of the certainties of life—like Bono selling out the Garden (Madison Square or Boston). To paraphrase the legendary pitcher Pedro Martinez, statins are hyperlipidemia's "daddy!"
"Normal" Cholesterol: Loosening the Belt
From an evolutionary standpoint, humans were not intended to have cholesterol levels in the ranges currently considered "normal" in Western culture. Low-density lipoprotein cholesterol (LDL), commonly referred to as "bad cholesterol," generally ranges 50–70 mg/dL in native hunter-gatherers, healthy human neonates, free-living primates, and other wild mammals (1), groups who are notably free of heart attacks and strokes. However, the average adult living in the United States has a "bad cholesterol" (LDL) level in the triple digits!(2) According to the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP), LDL levels 100–129 mg/dL are "near optimal" and levels 130–169 mg/dL are "borderline high."(3, 4) In our cholesterol-filled, overweight, sedentary culture, atherosclerosis (plaque buildup in arteries) abounds, starting early in life.
Statin: When Lifestyle Changes Are Not Enough
Statin treatment is not a replacement for lifestyle changes, but the two are often key components of a comprehensive approach to reducing the risk of heart attacks and strokes. Preventive cardiologists are strong advocates for "primordial prevention," which means promoting healthy lifestyles and avoiding the development of cardiovascular risk factors in the first place. However, when cardiovascular risk factors develop and therapeutic lifestyle changes are not enough for reducing cholesterol, then it is time to talk about the potential beneficial role of statin therapy to alter the progression of plaque build-up in arteries. The role of a statin requires an honest analysis of whether the potential benefits outweigh the possible risks. Therefore, a brief review of statin benefits and risks is warranted.
A patient's future risk of heart attack and stroke clearly goes up as levels of "bad cholesterol" or LDL go up. Over a hundred thousand patients who have already had heart attacks or strokes, or who have risk factors for these problems, have participated in clinical trials in which half of the patients took a statin and the other half did not. Experts can pool all of the information from the participants in these trials in a type of study called a "meta-analysis." This has unequivocally taught us that patients who are at increased risk for cardiovascular disease do better if they take statins.(5) Patients who take statins have fewer heart attacks and strokes. They also have less need for stent procedures and bypass operations. Fewer die of cardiovascular disease, and they live longer overall. As a whole, patients who take statins benefit from a ~40-50% reduction in these major cardiovascular events. Therefore, it is difficult not to consider statin treatment in patients with high cholesterol and other risk factors for heart attack and stroke.
Statin safety has been studied extensively. It is worth emphasizing that an enormous number of patients have taken statins over the last several decades with minimal toxicity. In routine clinical practice, 8-9% of statin-treated versus 4-6% of untreated patients experience muscle aches or mild muscle inflammation.(10) Rhabdomyolysis, meaning a breakdown of muscle, which can lead to kidney damage in its severe form, occurred in just 1-4 per 10,000 patients who participated in statin trials.(5) Liver abnormalities occurred in only 1.1% of patients on statins, a rate that was the same in untreated patients.(11) Statins are also associated with a modest increase in the diagnosis of diabetes mellitus (1 new diabetes event per 1,000 person-years of treatment).(12) Typically, statin side effects are reversible and overall, the safety profile of this treatment class is excellent and is in accordance with other common pharmacologic therapies which are generally accepted as standard of care.
Is a Statin Right for You?
A statin should be used when the benefits outweigh the risks. Therefore, the decision should be based in risk assessment. We know that patients who have had a previous heart attack or stroke are at high risk for another, so these patients should generally be on a statin. In patients who have not had a heart attack or stroke, but are at increased risk for these conditions, the decision to use a statin requires a careful assessment of risks. Given that statins have a very low risk of major side effects, for many patients, the risk-benefit equation will be in favor of treatment. Ways to assess risk include what we call "traditional risk factors," which include basic clinical factors like age, gender, blood pressure, smoking, and cholesterol. Occasionally, the imaging of plaque (e.g., coronary artery calcium scan or carotid ultrasound) can be helpful to more accurately determine a patient's risk. While the best method of determining risk is evolving, physicians in the United States follow guidelines that currently link recommendations to cardiovascular risk assessment by calculation of a person's 10-year risk of a fatal or nonfatal heart attack. This is calculated based on the "traditional risk factors" that we mentioned.
We turn to alternative risk calculators, advanced blood tests, or plaque imaging like coronary calcium scoring when the risk calculator does not seem to adequately capture our patient's risk and does not identify a clear treatment strategy. The JUPITER study demonstrated that many patients who are not considered candidates for a statin by the current guidelines may benefit from treatment.(9) Our research group has shown that coronary artery calcium scoring could be used to identify patients who are expected to derive the most benefit from statin treatment.(13)
Addressing the Opponents
A very small minority of doctors, which we estimate at <0.1%, believe that statin treatment should not be used to prevent heart attacks and strokes in patients who are at risk but have not suffered such an event. Unfortunately, some of these doctors have promoted this message in a prominent medical journal, the Archives of Internal Medicine, and through mainstream media sources like Time magazine.
We appreciate the opportunity to grow from deliberation with our colleagues, but are concerned that these doctors are sending a harmful message to patients and their physicians. We believe that these doctors are stuck in "all or none" logic. They likened the usefulness of statin therapy in patients who have not previously had heart attacks or strokes to that of narcotic and acid-reducing medications. In an article we addressed to them, we jokingly replied: As Keyshawn Johnson and Mike Ditka like to say on the Monday Night Football pregame show, "C'MON MAN!!!"
We are scratching our heads at the notion that the usefulness of statins must be rigidly broken down between primary prevention (patients who have not had a heart attack or stroke) and secondary prevention (patients who have suffered a heart attack or stroke). With all due respect to our colleagues, that logic is as fractured and twisted as Joe Theismann's tibia and fibula after he met Lawrence Taylor in the Redskins backfield on Monday Night Football in 1985. And the message to patients not to use statins is equally as gruesome.
Our expert opinion is that assessment of risk for heart attacks and strokes should occur on a continuum with therapy matched to the level of risk. Regardless of whether a patient has suffered a heart attack or stroke already, if he or she has risk factors like advanced age, male gender, cigarette smoking, high blood pressure, and high cholesterol, then that patient still carries risk from the same underlying disease—atherosclerosis (plaque build-up)—which predictably progresses overtime. Simply observing this predictable disease until the late stage does a particular disservice to the many patients whose first heart attack or stroke is deadly. A late reactionary approach ignores much of what we have learned about cardiovascular risk through rigorous research over decades thanks to all the dedicated doctors and patients who have worked together to understand cardiovascular disease. Leveraging risk information to selectively allocate proven therapy early in the disease course is what patients deserve.
Selective use of statins in the primary prevention setting is simply a matter of doing the right thing for the right patient at the right time based on the convincing totality of evidence. Roger Ebert once said that Spike Lee's 1989 movie Do the Right Thing brought tears to his eyes, but the movie's title particularly rings true in this discussion: Selective use of statins for intermediate and high risk primary prevention patients is the right thing to do.
1. O'Keefe JH, Jr., Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004;43:2142-6.
2. Kuklina EV, Yoon PW, Keenan NL. Trends in high levels of low-density lipoprotein cholesterol in the United States, 1999-2006. JAMA. 2009;302:2104-10.
3. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-97.
4. Grundy SM, Cleeman JI, Merz CN, Brewer HB, Jr., Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004;44:720-32.
5. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-81.
6. Ray KK, Seshasai SR, Erqou S, Sever P, Jukema JW, Ford I, et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch Intern Med. 2010;170:1024-31.
7. Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, Shepherd J, Westendorp RG, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ. 2009;338:b2376.
8. Taylor F, Ward K, Moore TH, Burke M, Davey Smith G, Casas JP, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2011:CD004816.
9. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr., Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-207.
10. Nichols GA, Koro CE. Does statin therapy initiation increase the risk for myopathy? An observational study of 32,225 diabetic and nondiabetic patients. Clin Ther. 2007;29:1761-70.
11. Athyros VG, Tziomalos K, Gossios TD, Griva T, Anagnostis P, Kargiotis K, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet. 2010;376:1916-22.
12. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735-42.
13. Blaha MJ, Budoff MJ, DeFilippis AP, Blankstein R, Rivera JJ, Agatston A, et al. Associations between C-reactive protein, coronary artery calcium, and cardiovascular events: implications for the JUPITER population from MESA, a population-based cohort study. Lancet. 2011;378:684-92.
14. Redberg R, Katz M, Grady D. Diagnostic tests: another frontier for less is more: or why talking to your patient is a safe and effective method of reassurance. Arch Intern Med. 2011;171:619.
15. Redberg RF, Katz M, Grady D. Editor's Note--To Make the Case--Evidence Is Required: Comment on "Making the Case for Selective Use of Statins in the Primary Prevention Setting". Arch Intern Med. 2011;171:1594.