Insights from Robert Browning, Pedro Martinez, Keyshawn Johnson, Mike Ditka, and Spike Lee.

We greatly admire Drs. Rita Redberg, Mitchell Katz, and Deborah Grady and commend them on the “Less is More” series in the Archives of Internal Medicine. We agree with these three academic leaders on the vast majority of issues and we understand that there are many examples of overuse of medical care in modern medicine that may result in harm and in which less care is truly more. The phrase “Less is More” has been attributed to the 1855 poem Andrea del Sarto (the faultless painter) by Robert Browning, the dramatic English poet to whom is also attributed the phrase, “faultless to a fault.” While we are perpetual proponents of rigorous science and evidence-based medicine, we pose the question: is demanding further evidence prior to using statin therapy in primary prevention being faultless to a fault?

Statins are among the most successful therapies known to reduce cardiovascular risk and are rightfully commonplace in the personalized treatment of asymptomatic adults with coronary risk factors or known atherosclerotic vascular disease. Prescribing a generic statin to a middle-aged or older adult with hyperlipidemia and another risk factor 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 lipid levels in the ranges currently considered “normal” in Western culture. Low-density lipoprotein cholesterol (LDL-C) 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 atherosclerotic vascular disease, whereas the average adult living in the United States has a low-density lipoprotein cholesterol level (LDL-C) in the triple digits.⁽²⁾ According to the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP), LDL-C levels 100-129 mg/dL are “near optimal” and levels 130-169 mg/dL are “borderline high.”^{(3, 4)} In our lipid-laden, overweight, sedentary culture, atherosclerosis 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 multifactorial approach to cardiovascular risk reduction. We are strong advocates for primordial prevention efforts dedicated to promoting healthy lifestyles and avoiding the development of cardiovascular risk factors. However, when cardiovascular risk factors develop and therapeutic lifestyle changes are insufficient, then it is time to talk about the potential beneficial role of statin therapy to change the natural history of the atherosclerotic disease process. Deciding whether adults with an elevated risk of a subsequent CVD event over the next decade might benefit from a generic 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.

Statin Benefits

Future atherosclerotic risk tracks predictably with lipoprotein elevation and statins can potently lower lipoproteins. Over a hundred thousand patients who have participated in randomized clinical statin trials have unequivocally taught us that the proportional benefit of therapy, or relative risk reduction, is relatively constant across a wide array of primary and secondary prevention patient subgroups. This point was demonstrated in the Cholesterol Treatment Trialists’ prospective meta-analysis of data from 170,000 participants in 26 randomized clinical trials.⁽⁵⁾

This meta-analysis demonstrates the clinical benefit of statin therapy in both primary and secondary prevention settings in patients treated over an average of five years (Figure 1). Lipid lowering with statin therapy produced similar proportional reductions in major cardiovascular events per each 1.0 mmol/L (39 mg/dL) LDL-C reduction: 13% reduction in coronary death or non-fatal myocardial infarction (95% CI 7-19; p<0.0001), 19% reduction in coronary revascularization (95% CI 15-24; p<0.0001), and 16% reduction in ischemic stroke (95% CI 5-26; p=0.005). All-cause mortality was reduced by 10% per 1.0 mmol/L LDL-C reduction (RR 0.90, 95% CI 0.87-0.93; p<0.0001) primarily due to protection from cardiovascular death (RR 0.80, 99% CI 0.74-0.87; p<0.0001).

Two of the three recent dedicated primary prevention meta-analyses support these findings.^(6-8) One of these meta-analyses narrowly explored only all-cause mortality,⁽⁶⁾ whereas the other two of meta-analyses more comprehensively examined^(7,8) additional cardiovascular endpoints that patients and physicians care about, including heart attacks and strokes. For example, in the meta-analysis by Brugts et al.⁽⁷⁾ concentrating on primary prevention patients (at least 80% or more participants did not have established cardiovascular disease in the included trials), after an average of 4.1 years of follow-up in 70,388 patients, statin treatment significantly reduced coronary events (odds ratio 0.70, 95% CI 0.81-0.96) and major cerebrovascular events (odds ratio 0.81, 95% CI 0.71-0.93). A simple table of raw events from major primary prevention trials also tells the story (Table 1). The JUPITER trial was 100% primary prevention patients and also showed a significant reduction in myocardial infarction (hazard ratio 0.46, 95% CI 0.30-0.70, p=0.0002) and stroke (hazard ratio 0.52, 95% CI 0.34-0.79, p=0.002) amongst other clinically relevant endpoints including death from any cause (hazard ratio 0.80; 95% CI 0.67-0.97).⁽⁹⁾ Therefore, in line with the totality of evidence and clinical guidelines, statin therapy is justifiably the standard of care for primary prevention patients at sufficient cardiovascular risk.

Table 1: Number of clinical events in three primary prevention statin trials in the control versus statin-allocated group
	WOSCOPS		AFCAPS/TexCAPS		MEGA
	Control	Statin	Control	Statin	Control	Statin
Primary endpoint*	248	174	183	116	101	66
CHD death	52	38	15	11	15	7
PTCA/CABG	80	51	157	106	66	39
Stroke	51	46	NA	NA	62	50
Total mortality	135	106	77	80	79	55
*WOSCOPS: CHD death + nonfatal MI; AF/Tex: uAP, CHD death, nonfatal MI, sudden cardiac death; MEGA: fatal/nonfatal MI, AP, cardiac/sudden death, coronary revascularization. (Adapted from Matsuzawa Y et al; Atherosclerosis Supplements 2007; 8: 19-24)

The role of clinicians is to use the best available evidence to help prevent patients reduce their risk of cardiovascular morbidity and mortality. It is difficult not to consider statin use in dyslipidemic persons at intermediate or high risk of a CVD event over the next decade. Patients should be informed about all appropriate treatment options such as statin therapy as well as the associated risks so that they can be active participants in their medical care. Not providing this information to our patients could lead to mistrust of their physicians and to their detriment.

Statin Risks

There is extensive literature on statin safety. 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 myopathic events, of which 95% were myalgias or mild myositis.⁽¹⁰⁾ Rhabdomyolysis occurred in just 1-4 per 10,000 participants in 26 randomized statin trials.⁽⁵⁾ Liver-related adverse effects 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 incidence of diabetes mellitus (1 new diabetes event per 1000 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 Your Primary Prevention Patient?

A statin should be used in primary prevention when the benefits outweigh the risks. Therefore, the decision should be based in risk assessment. Given that statins have a very low risk of major side effects, for many patients, the risk-benefit equation will be in favor of therapy. Modes of risk assessment include traditional risk factors and occasionally atherosclerosis imaging. While the best method of determining risk and the threshold of risk beyond which therapy should be instituted are evolving, physicians in the United States may center their assessment in the NCEP-ATP guidelines, which currently link recommendations to cardiovascular risk assessment by calculation of a person’s 10-year risk of a fatal or nonfatal MI.

We turn to alternative risk calculators, advanced biomarker testing, or coronary calcium scoring when the Framingham risk model does not seem to adequately capture our patient’s risk and does not identify a clear treatment strategy. The JUPITER study demonstrated that many primary prevention patients who are not considered candidates for a statin by the current guidelines may benefit from treatment.⁽⁹⁾ Our group has shown that coronary artery calcium scoring robustly risk stratifies JUPITER-like primary prevention patients and therefore could be used to identify subgroups of patients who are expected to derive the most benefit from statin treatment.⁽¹³⁾

Addressing the Opponents

We appreciate the opportunity to grow from deliberation with our colleagues, but are concerned that uncompromising opponents of statin treatment in primary prevention are sending a harmful message. Stuck in what seems to be “all or none” logic, Dr. Redberg and her colleagues at UCSF and the Archives of Internal Medicine have concluded that statins are warranted strictly in secondary prevention, but are without evidence for use in primary prevention.^{(14, 15)} They likened the usefulness of statin therapy in primary prevention to that of opioids in patients with nonmalignant pain or PPIs in persons with nonulcer dyspepsia. 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 dichotomized between primary and secondary prevention. With all due respect to the academicians from UCSF, 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.

We submit that risk assessment should occur on a continuum with therapy matched to the level of risk. Regardless of whether a patient with cardiovascular risk factors has suffered a previous cardiovascular event, he or she still carries risk from the same insidious, progressive underlying disease: atherosclerosis. Observing the natural history of this predictable disease until the late stage does a particular disservice to the many patients whose first myocardial infarction or stroke is fatal. A late reactionary approach ignores much of what we have learned about cardiovascular risk through rigorous research over the preceding decades. Leveraging risk information to selectively allocate proven therapy early in the disease course is what our patients deserve.

In the past, some of our Cardiology colleagues have taken extreme views about topics such as the initial use of ICDs, nesiritide, glitazones, and the COURAGE and OAT trials. Once we had more data on these controversial topics, most of the Cardiology and Internal Medicine thought leaders reached a consensus about these issues. The AHA, ACC, Canadian, and European guidelines have endorsed selective use of statin therapy for at-risk primary prevention adults for more than a decade. It is time for the senior editors of the Archives to reassess their extreme position and take into account the huge evidence base supporting selective use of statin therapy in the primary prevention setting.

Selective use of statins in the primary prevention setting is simply a matter of doing the right thing in 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.

We applaud the senior editors of the Archives for re-energizing their journal and for their landmark work in the fields of cost-effectiveness and proper utilization of limited healthcare resources. We agree with their views more than 95% of the time. But comparing the usefulness of a generic statin in an adult with another risk factor in primary prevention to that of a PPI or a narcotic … C’mon man! And women!

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References

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.

Keywords: Adenosine Triphosphate, Atherosclerosis, Cholesterol, LDL, Lipoproteins, LDL, Overweight

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