Editor's Note: Commentary based on Maddox TM, Borden WB, Tang F, et al. Implications of the 2013 ACC/AHA cholesterol guidelines for adults in contemporary cardiovascular practice: insights from the NCDR PINNACLE Registry. J Am Coll Cardiol 2014;64:2183-92.

In 2013, the American College of Cardiology (ACC) and the American Heart Association (AHA), at the direction of the National Heart, Lung, and Blood Institute, developed new guidelines on the treatment of blood cholesterol and risk assessment of atherosclerotic cardiovascular disease (ASCVD).^1,2 The new guidelines, using the "highest quality of evidence," concluded a lack of evidence for non-statin therapy in ASCVD risk reduction, identified four groups of patients who would benefit from moderate- and/or high-intensity, fixed-dose statin therapy, introduced a new ASCVD risk assessment tool (Pooled Cohort Equations), and eliminated low-density lipoprotein cholesterol (LDL-C) target levels.

Moving from the 2004 National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) cholesterol guidelines to the 2013 ACC/AHA guidelines has many implications. While NCEP-ATP III focused on coronary heart disease, lipid lowering and risk reduction by several types of medications, and frequent, targeted LDL-C monitoring, the 2013 ACC/AHA guidelines broadened ASCVD endpoints to include stroke, focused almost exclusively on statin therapy for LDL-C lowering and ASCVD risk reduction, and removed LDL-C goals (though testing for compliance and efficacy is recommended). With these findings and recommendations, the new guidelines brought about a wave of controversy. Many were critical of how the guidelines were developed,^3,4 debated the implication of an increasing number of patients eligible for statin therapy, were concerned about the potential overestimation of ASCVD risk, and were unsure of eliminating LDL-C targets.^3-6

These concerns have generated significant attention and have been substantiated in a number of recent studies. Based on the National Health and Nutrition Examination Survey (NHANES) cohort and extrapolated to the U.S. population, a study by Pencina et al. found an additional 12.8 million persons (10.4 million via primary prevention) would be newly eligible for statin therapy under the 2013 guidelines.⁵ Ridker and Cook showed an overestimation of predicted versus observed risk in several study cohorts,⁴ with a more in-depth analysis of overestimation of risk in the Woman's Health Study.⁷ Furthermore, many physicians concerned about the lack of LDL-C monitoring believed in a "lower is better" LDL-C theory, citing evidence found in by the Cholesterol Treatment Trialists' Collaboration showing a 22% reduction rate in major vascular events with each drop in LDL-C of 38.7 mg/dl, and no distinct LDL-C cutoffs for risk reduction.⁸

The controversies surrounding the guidelines left many health care practitioners and patients in a state of confusion. Physicians questioned who should be on statin therapy, if all non-statin lipid lowering therapies should be stopped, and if the practice of monitoring LDL-C levels had passed. However, with an abundant focus on the ASCVD risk prediction and removal of LDL-C targets, the benefit of statin therapy remains clear in patients with ASCVD,^9-11 diabetic patients,¹² and in patients with extremely high LDL-C.⁸

In an article published in The Journal of the American College of Cardiology, "Implications of the 2013 ACC/AHA Cholesterol Guidelines for Adults in Contemporary Cardiovascular Practice: Insights From the NCDR PINNACLE Registry," Maddox et al. offer important and valuable insight into the application of these new guidelines to current cardiovascular practices. The authors' ability to examine cardiovascular practice patters is unique to this analysis. While many previous studies focused on newly "statin eligible" patients, the clinical practice of health care providers will determine how these statin eligible patients are treated.

Maddox et al. showed a lack of both the 2013 ACC/AHA and the 2004 NCEP-ATP III guideline-based therapy in the aforementioned groups for which minimal controversy exists (patients with known ASCVD, patients with diabetes, and LDL-C ≥190 mg/dL). In a nationally represented database of cardiology practices, 91.2% of the population examined had known ASCVD and, thus, fell into a secondary prevention group. Notably, 30.8% of these patients with known ASCVD were not on statin therapy. Additionally, 22.9% were receiving non-statin lipid lowering treatment. Only half of all those with ASCVD in this study were treated with statin monotherapy, as suggested by the 2013 ACC/AHA guidelines. Similar findings were present in the treatment of patients with diabetes and patients with LDL-C ≥190 mg/dL, where 40.6% and 35.5% of patients were not on statin therapy and 20.8% and 26.7% were on non-statin lipid lowering agents, respectively. Finally, less than 2% of the population in these cardiovascular practices were without diabetes mellitus, ASCVD, or LDL-C ≥190 mg/dL and had an ASCVD risk score >7.5%, thus falling into the group categorized by the polarizing Pooled Cohort Equations. Such a low percentage of patients in the primary prevention group likely reflects the population studied and referral bias to cardiovascular practices.

The implications of the 2013 ACC/AHA guidelines on current cardiovascular practice, as examined in Maddox et al.'s study reveal several important findings. First, patients for whom the absolute benefit is greatest, and for whom little controversy on statin therapy exists, may be significantly undertreated. With nearly one-third of those patients with known ASCVD not on lipid lowering therapy in Maddox et al.'s study, a large gap in evidence-based care was identified. It is within this group that health care providers have the greatest ability to reduce future ASCVD burden,¹³ and the prioritizing of statin therapy in the new guidelines should increase the use in these patients (ASCVD, diabetes mellitus, and LDL-C ≥190 mg/dL). Second, the use of non-statin therapy will be greatly reduced with the guidelines emphasis on statins, by far the lipid lowering therapy with the most robust data. However, the overwhelming focus on statin therapy may come under further scrutiny and analysis with recent results, such as those from the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial and promising results of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.¹⁴

While many studies have looked at the number of newly statin-eligible persons under the 2013 ACC/AHA guidelines, this eligibility does not directly translate to treatment. As evidenced in Maddox et al.'s paper, a large percentage of those patients who are "eligible" for statin therapy (or some type of lipid lowering medication) are eligible according to both the 2004 NCEP-ATP III and 2013 ACC/AHA guidelines, and were not on any lipid lowering therapy (27.9% in ASCVD group, 35.9% in patients with diabetes, and 29.3% in patients with LDL-C ≥190 mg/dL). One questions why such a significant portion of patients was not on any lipid lowering therapy and, specifically, statin therapy. Statin intolerance due to experienced, perceived, and fear of side effects is often a significant barrier to therapy.¹⁵ Was the lack of lipid lowering therapy due to side effects, cost, intolerance, lack of motivation, or another unknown reason? Further complicating statin therapy and adherence is the removal of LDL-C targets. By removing LDL-C goals, the 2013 ACC/AHA guidelines may have inadvertently eliminated a motivational tool for goal-directed behavior. Goal setting and goal-directed actions are long standing practices in changing human behavior. Prior studies have shown general poor adherence to statin therapy at one year, even with the elimination of cost as a component.¹⁶ Eliminating LDL-C targets may reduce polypharmacy with lipid lowering medications and reduce the risk of medication side effects to achieve a specific LDL-C level, but patient motivation and adherence may be adversely affected by this change.

Through all the discussion and controversy surrounding the 2013 ACC/AHA guidelines, it is important to remember that these guidelines are a tool for the clinician, and not made to be followed blindly in all patients. These cholesterol guidelines provide a framework in which to further address the discussion of ASCVD risk with patients. As stated in the 2013 ACC/AHA report, "these guidelines are not a replacement for clinical judgment; they are meant to guide and inform decision making."¹ And with that goal, the new guidelines have provided clear recommendations and assessments of ASCVD risk to start the physician-patient dialogue. Questions remain regarding how clinical practice will address newly statin-eligible patients, how medication adherence is affected by removing LDL-C goals, and the efficacy of a new method of predicting ASCVD risk. Additionally, will the discussions around the 2013 guidelines bring awareness to patients, such as those with ASCVD and those with diabetes, for whom little controversy exists for statin therapy? The new guidelines, at minimum, have sparked a renewed look at how the medical community addresses lipid management and the prevention of ASCVD and brings these issues to the forefront of the physician-patient discussion.

References

1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934.
2. Eds. Graham R, Mancher M, Wolman DM, Greenfield S, Steinberg E. Clinical Practice Guidelines We Can Trust. Washington, DC: Institue of Medicine of the National Academies; 2011.
3. Nissen SE. Prevention guidelines: bad process, bad outcome. JAMA Intern Med 2014;174:1972-3.
4. Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 2013;382:1762-5.
5. Pencina MJ, Navar-Boggan AM, D'Agostino RB Sr, et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med 2014;370:1422-31.
6. Martin SS, Abd TT, Jones SR, Michos ED, Blumenthal RS, Blaha MJ. 2013 ACC/AHA cholesterol treatment guideline: what was done well and what could be done better. J Am Coll Cardiol 2014;63:2674-8.
7. Cook NR, Ridker PM. Further insight into the cardiovascular risk calculator: the roles of statins, revascularizations, and underascertainment in the Women's Health Study. JAMA Intern Med 2014;174:1964-71.
8. Cholesterol Treatment Trialists C, Baigent C, Blackwell L, 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.
9. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-1504.
10. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335:1001-9.
11. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35.
12. Cholesterol Treatment Trialists C, Kearney PM, Blackwell L, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008;371:117-25.
13. Naci H, Brugts JJ, Fleurence R, Tsoi B, Toor H, Ades AE. Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials. EurJ Prev Cardiol 2013;20:641-57.
14. Urban D, Poss J, Bohm M, Laufs U. Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. J Am Coll Cardiol 2013;62:1401-8.
15. Kon RH, Russo MW, Ory B, Mendys P, Simpson RJ Jr. Misperception among physicians and patients regarding the risks and benefits of statin treatment: the potential role of direct-to-consumer advertising. J Clin Lipidol 2008;2:51-7.
16. Choudhry NK, Avorn J, Glynn RJ, et al. Full coverage for preventive medications after myocardial infarction. N Engl J Med 2011;365:2088-97.

Keywords: Adenosine Triphosphate, Azetidines, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Cohort Studies, Coronary Disease, Cost of Illness, Diabetes Mellitus, Drug Combinations, Health Personnel, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipoproteins, LDL, Medication Adherence, Motivation, Nutrition Surveys, Polypharmacy, Primary Prevention, Proprotein Convertases, Registries, Risk, Risk Assessment, Risk Reduction Behavior, Secondary Prevention, Simvastatin, Stroke, Subtilisins, Women's Health

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