The 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults identified patients with clinical atherosclerotic cardiovascular disease (ASCVD) as a group in whom the benefit of statin therapy outweighs the risk of adverse events.¹ The guideline recommended the initiation of high-intensity statin therapy for those ASCVD patients 40 to ≤75 years of age with no major safety concerns and moderate-intensity statins for those >75 years of age or with major safety concerns related to the use of high-intensity statins. The goal of therapy for those treated with high-intensity statins was achievement of ≥50% reduction from baseline LDL-C and for those taking moderate intensity therapy, 30-49% reduction. Based upon the lack of randomized controlled trial (RCT) data at the time of publication, non-statin therapy was advised to be considered only in patients who exhibited a less-than-anticipated LDL-C lowering response to statin therapy when the clinician felt that ASCVD risk reduction benefits outweighed the potential for adverse effects.

Since the publication of the 2013 guideline, randomized controlled trials have demonstrated ASCVD risk reduction benefit in certain groups of ASCVD patients in whom non-statins were added to baseline statin therapy. In patients who had suffered a recent acute coronary syndrome and were followed for a median of 6 years, combined therapy with simvastatin 40 mg daily and ezetimibe 10 mg daily was demonstrated to more effectively reduce the incidence of a composite of adverse cardiovascular outcomes (cardiovascular death, nonfatal myocardial infarction, unstable angina requiring re-hospitalization, coronary revascularization ≥30 days after randomization, or nonfatal stroke) than simvastatin plus placebo.² A subsequent study applied a 9-point ASCVD risk stratification tool, the Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention, to 17,717 patients enrolled in the above trial to determine which post-acute coronary syndrome patients would derive the greatest potential for benefit from the addition of ezetimibe to statin therapy.³ Nine variables, including congestive heart failure, arterial hypertension, age ≥75 years, diabetes mellitus, prior stroke, prior coronary artery bypass surgery, peripheral arterial disease, estimated glomerular filtration rate <60 ml/minute/1.73 m2 and cigarette smoking were noted to be independent risk predictors for cardiovascular death/myocardial infarction and ischemic stroke. When subjects were divided into high (≥3 of these variables), intermediate (2 variables) and low (0-1 variable) risk groups, those in the high-risk category derived a 19% relative and 6.3% absolute reduction in risk of cardiovascular death, MI or ischemic stroke (number needed to treat [NNT] 16 to prevent one event) with ezetimibe plus simvastatin as compared to simvastatin plus placebo. Those at intermediate risk had a 11% relative and 2.2% absolute risk reduction (NNT 45). Subjects at low risk derived no benefit from the addition of ezetimibe. This study showed that risk indicators other than the absolute level of LDL-C may be useful to help the clinician to decide when ezetimibe therapy could provide additional ASCVD risk reduction benefit as compared to statin monotherapy.

Two 2015 efficacy and safety studies of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in high-risk patients showed a significant 57-61% additional LDL-C reduction on top of baseline statin therapy and an excellent safety profile.^4,5 A 2016 intravascular ultrasound study of the administration of evolocumab to patients with stable coronary artery disease, 60% of whom were taking a high-intensity statin, 38% a moderate intensity statin, and only 2% receiving ezetimibe, showed that evolocumab produced an additional significant 60% LDL-C reduction, as compared to the addition of placebo, in the time-weighted mean LDL-C. The primary efficacy measure, the percent coronary atheroma volume, was significantly reduced in the evolocumab group and did not change in the placebo group. A greater percentage of evolocumab-treated subjects demonstrated percent atheroma regression and total atheroma volume regression than those receiving placebo.⁶

The first PCSK9 inhibitor trial with cardiovascular event endpoints was Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER), a randomized, double-blind placebo-controlled trial of 27,564 subjects with ASCVD and LDL-C levels ≥70 mg/dL or non-HDL-C >100 mg/dL while on maximally tolerated statin therapy.⁷ The subjects were randomly assigned to receive subcutaneously administered evolocumab (either 140mg every 2 weeks or 420 mg monthly) or placebo injection. The primary endpoint of the study was the composite of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary endpoint was the composite of cardiovascular death, MI, or stroke. The median duration of follow-up was 2.2 years.

The patients enrolled in FOURIER were at very high ASCVD risk. Entry criteria included MI or non-hemorrhagic stroke or symptomatic peripheral arterial disease and the concomitant presence of at least one major risk factor (diabetes [type I or type II]; age ≥65 years at randomization [and ≤85 years at the time of informed consent]; MI or non-hemorrhagic stroke within 6 months of screening; additional diagnosis or MI or non-hemorrhagic stroke excluding qualifying MI or non-hemorrhagic stroke; current daily cigarette smoking; or history of symptomatic PAD if eligible by MI or stroke history); or two minor risk factors (history of non-MI-related coronary revascularization; residual coronary artery disease with ≥40% stenosis in ≥2 large vessels; most recent HDL-C <40 mg/dL for men and <50 mg/dL for women; most recent hs-CRP >2.0 mg/L; most recent LDL-C ≥ 130 mg/dL or non-HDLC ≥160 mg/dL before randomization; or the presence of the metabolic syndrome).

The least squares mean percentage reduction in LDL-C at 48 weeks in those receiving evolocumab, compared with placebo, was 59%, from a median baseline of 92 mg/dL to 30 mg/dL (P < .001). Relative to placebo, evolocumab therapy was associated with a significant reduction in the risk of the primary endpoint (1344 subjects [9.8%] vs. 1563 subjects [11.3%]; hazard ratio 0.85; 95% CI, 0.79-0.92; P < .001) and the key secondary endpoint (816 [5.9%] vs. 1013 [7.4%]; hazard ratio 0.80; 95% CI, 0.73-0.88; P < .001), in all key subgroups, including those with low baseline LDL-C (median, 74 mg/dL). While injection site reactions were encountered more frequently in those receiving evolocumab than placebo, there was otherwise no significant difference between the two groups in the incidence of adverse events.

Based upon the above studies, the use of additive non-statin therapy should optimally be considered for those ASCVD patients with: 1) additional ASCVD risk factors or other clinical indicators associated with increased cardiovascular risk; 2) less-than-anticipated reductions in LDL-C despite lifestyle counseling and maximally-tolerated statin therapy; and 3) achievement of anticipated LDL-C reduction with maximally-tolerated statin therapy, but persistent elevation of LDL-C.

How does the clinician incorporate the above findings into practice to improve preventive care for patients with established ASCVD? A detailed discussion of these patient care considerations was provided in the 2017 Focused Update of the 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.⁸ A synthesis of their recommendations is provided in the steps outlined below:

1. Continue to emphasize the importance of lifestyle interventions, regardless of drug therapy employed.
2. Identify and treat secondary causes of dyslipidemia, whenever present.
3. Employ the maximal intensity statin tolerated by the patient, using clinical judgment to guide a decision to employ less intense statin regimens based upon individual patient factors.
4. Monitor and follow LDL-C levels (and in hypertriglyceridemia patients, non-HDL-C levels) to assess adherence and responsiveness to therapy and facilitate clinical decision-making about the need for statin intensification or the addition of non-statin therapy. Use these levels as factors in the decision- making process about treatment intensification, rather than as absolute goals of pharmacotherapy.
5. Address statin-related adverse effects whenever present, in order to maximize the intensity of statin that the patient can receive.
6. If, after a clinician patient discussion, the decision is made to employ non-statins: A) reinforce the importance of continuing statin therapy; B) consider the expected LDL-C lowering efficacy of the agent to be added (ezetimibe: generally 20% reduction; PCSK9 inhibitors generally ≥50% reduction), recognizing the potential for variability of responsiveness in individual patients; and C) consider and carefully discuss with the patient the expected benefits, potential side effects and cost of therapy, particularly before prescribing costly non-generic drug therapy for ASCVD risk reduction.

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. 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.
3. Bohula EA, Morrow DA, Giugliano RP, et al. Atherothrombotic risk stratification and ezetimibe for secondary prevention. J Am Coll Cardiol 2017;69:911-21.
4. 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.
5. 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.
6. 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.
7. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
8. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2017 focused update of the 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 Expert Consensus Decision Pathways. J Am Coll Cardiol 2017;70:1785-1822.

Keywords: Primary Prevention, Secondary Prevention, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Cholesterol, LDL, Risk Factors, Coronary Artery Disease, Plaque, Atherosclerotic, Incidence, Peripheral Arterial Disease, Metabolic Syndrome, Acute Coronary Syndrome, Numbers Needed To Treat, Lipoproteins, HDL2, Double-Blind Method, Glomerular Filtration Rate, Least-Squares Analysis, Constriction, Pathologic, Consensus, Brain Ischemia, Follow-Up Studies, Stroke, Antibodies, Monoclonal, Atherosclerosis, Angina, Unstable, Coronary Artery Bypass, Myocardial Infarction, Diabetes Mellitus, Hypertension, Life Style, Risk Reduction Behavior, Hospitalization, Patient Care, Heart Failure, Outcome Assessment, Health Care, Subtilisins

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