All guidelines recommend that patients be treated with high-efficacy statin therapy after myocardial infarction (MI).^1,2 Reduction of low-density lipoprotein cholesterol (LDL-C), the guideline-recommended marker of the atherogenic lipoproteins, is the primary target of lipid therapy post MI.

The "LDL hypothesis," that high levels of LDL-C are associated with elevated risk of atherosclerotic cardiovascular disease (CVD), has now been tested by Mendelian randomization studies and clinical trials of both statins and non-statin lipid-modifying agents. In genetic studies, persistent exposure to lower LDL-C beginning early in life, due to inherited genetic variants in numerous genes, has been shown to confer a three-times-greater reduction in risk of coronary heart disease (CHD) for each 1 mmol/L decrement in LDL-C than treatment with a statin started later in life.^3-5 In a large meta-analysis of 8 randomized controlled statin trials including a total of 38,153 patients, individuals who achieved very low LDL-C levels (<50 mg/dL or 50 to <70 mg/dL) had a lower risk for major CVD events than those who achieved moderately low levels (75 to <100 mg/dL).⁶ This meta-analysis also showed large interindividual variation in response to statin therapy.⁶

The 2013 ACC/AHA guidelines did not specify LDL-C treatment goals but focused on the intensity of statin therapy and percentage reductions of LDL-C levels.¹ As a result, there has been confusion about the role of LDL-C levels in residual risk assessment and the need for treatment with additional lipid-modifying agents in high-risk patients.^7,8

In IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), in patients with recent acute coronary syndrome and LDL-C levels of 50–100 mg/dL on therapy (50–125 mg/dL untreated), patients treated with ezetimibe combined with simvastatin had a 6% relative reduction in CVD events compared with those treated with simvastatin monotherapy. This demonstrated that further decreasing LDL-C levels (to 54 mg/dL vs. 70 mg/dL) with non-statin therapy was beneficial in lowering CVD event rates.⁹

Recognizing the potential advantages that measurement of LDL-C levels provides to physicians in guiding secondary prevention, the "Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk"¹⁰ outlined the framework for adding non-statin therapies in patients with inadequate LDL-C lowering on statin therapy. The consensus pathway also specified LDL-C levels for patients based on individual risk and provided "thresholds" at which additional non-statin therapies, including ezetimibe and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors, may be initiated.

Recent studies of PCSK9 inhibitors in addition to statin therapy have shown that LDL-C levels can be reduced beyond those achieved by using statins alone.^11,12 In the ODYSSEY LONG TERM trial (Long-term Safety and Tolerability of Alirocumab Versus Placebo on Top of Lipid-Modifying Therapy in High Cardiovascular Risk Patients With Hypercholesterolemia), which studied patients with heterozygous familial hypercholesterolemia or with at least one CHD risk equivalent, patients treated with alirocumab in addition to statin had significantly greater reduction in LDL-C levels at 78-week follow-up than patients treated with placebo plus statin (58 mg/dL vs. 123 mg/dL),¹³ and a post-hoc analysis from this trial suggested a beneficial effect of PCSK9 inhibition on major CVD events compared with placebo.¹³ In another long-term study of PCSK9 inhibitor added to statins, GLAGOV (Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound), patients with angiographic CHD achieved lower mean LDL-C levels with the addition of evolocumab compared with placebo (37 mg/dL vs. 93 mg/dL) and a significant decrease in percent atheroma volume as measured by serial intravascular ultrasound (–0.95% with evolocumab vs. +0.05% with placebo) after 76 weeks of treatment.¹⁴ The first completed outcome study of PCSK9 inhibitor plus statin, FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk), which compared the effect of adding evolocumab or placebo to statin therapy on the incidence of major adverse cardiovascular events in 27,564 patients with prior CVD and LDL-C levels of ≥70 mg/dL or non-high-density lipoprotein cholesterol ≥100 mg/dL on optimized statin therapy,¹⁵ was recently announced to have met both its primary composite endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, or coronary revascularization) and the even more rigorous key secondary composite endpoint (cardiovascular death, nonfatal MI, or nonfatal stroke).¹⁶ Results were presented at ACC.17.

For physicians treating high-risk patients, measuring and acting upon LDL-C levels are critical for optimizing lipid therapy to reduce recurrent CVD event risk. Using specific levels of LDL-C as a "threshold" for initiation of therapy or a "goal" for monitoring response to therapy is useful in patient-physician discussions about lifestyle, adherence to medication, and potential benefits and risks of intensifying statin therapy or adding non-statin therapy. Persistent elevations in LDL-C may be related to poor adherence to pharmacotherapy or lifestyle recommendations or to a variable response to the prescribed therapy. Assessing both CVD risk and LDL-C level identifies patients who are most likely to benefit from therapy¹⁷ and should guide treatment decisions regarding the need for and intensity of therapy to achieve optimum CVD outcomes in high-risk patients.

References

1. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2935-59.
2. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315-81.
3. Ference BA, Yoo W, Alesh I, et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol 2012;60:2631-9.
4. Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.
5. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532-61.
6. Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol 2014;64:485-94.
7. Ray KK, Kastelein JJ, Boekholdt SM, et al. The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. Eur Heart J 2014;35:960-8.
8. 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.
9. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015;372:2387-97.
10. Writing Committee, Lloyd-Jones DM, Morris PB, et al. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2016;68:92-125.
11. Koren MJ, Giugliano RP, Raal FJ, et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation 2014;129:234-43.
12. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9.
13. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.
14. Nicholls SJ, Puri R, Anderson T, et al. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA 2016;316:2373-84.
15. Sabatine MS, Giugliano RP, Keech A, et al. Rationale and design of the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk trial. Am Heart J 2016;173:94-101.
16. Amgen Inc. Amgen Announces Repatha® (Evolocumab) Significantly Reduced The Risk Of Cardiovascular Events In FOURIER Outcomes Study (Amgen website). 2017. Available at: http://www.amgen.com/media/news-releases/2017/02/amgen-announces-repatha-evolocumab-significantly-reduced-the-risk-of-cardiovascular-events-in-fourier-outcomes-study/. Accessed 02/17/2017.
17. Stone NJ, Robinson JG. Potential for Net Benefit Should Guide Preventive Therapy. Circulation 2017;135:630-2.

Keywords: Acute Coronary Syndrome, Angina, Unstable, Antibodies, Monoclonal, Atherosclerosis, Cardiovascular Diseases, Cholesterol, LDL, Coronary Artery Disease, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Myocardial Infarction, Plaque, Atherosclerotic, Proprotein Convertases, Risk Assessment, Risk Factors, Secondary Prevention, Stroke, Subtilisins

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