The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial showed that among those with stable atherosclerotic cardiovascular disease, lowering LDL-cholesterol (LDL-C) levels beyond current targets through addition of the PCSK9 inhibitor evolocumab to background therapy with a statin resulted in a 15% relative risk reduction in the composite primary endpoint of cardiovascular (CV) death, myocardial infarction (MI), stroke, hospitalization for unstable angina or coronary revascularization (9.8% vs. 11.3%, P < 0.001).¹ Additionally, a 20% relative risk reduction for the harder key secondary endpoint of cardiovascular death, myocardial infarction or stroke was noted (5.9% vs. 7.4%, P < 0.001).

Although patients with prior MI have the potential to benefit from LDL-C lowering, trials such as the 4S (Scandinavian Simvastatin Survival Study) and IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) trials have demonstrated that patients with high-risk features may derive greater benefit from intensive lipid lowering compared to those without these features.^2-7 Utilizing data from the FOURIER trial, Sabatine et al. examined whether readily ascertainable features of coronary artery disease (CAD) severity and extent can identify MI patients who may derive greater benefit from PCSK9 inhibition with evolocumab.⁸

The authors analyzed data from 22,351 patients with prior MI on statin therapy enrolled in FOURIER. Three markers of CAD severity and extent were collected, namely 1) the number of prior MIs, 2) time since the last MI, and 3) presence of residual multivessel disease defined as ≥40% stenosis in ≥2 large epicardial vessels. The median follow-up was 2.2 years.

In this analysis, MI within 2 years of randomization, history of ≥2 prior MIs and residual multivessel disease were all independent predictors of worse outcomes. More specifically, these groups had 37%, 78% and 39% higher relative risks of developing the primary endpoint and 36%, 90% and 34% higher relative risks of developing the key secondary endpoint compared to those without these characteristics.

Evolocumab reduced LDL-C to a similar degree in each of these high-risk groups with a median post-treatment LDL-C of ~30 mg/dL. Evolocumab yielded a greater reduction in the relative risk of the primary endpoint in those with an MI <2 as compared to ≥2 years previously (20% vs. 5%, P_interaction= 0.04), multiple MIs as compared to only one MI (18% vs. 8%, P_interaction= 0.15), and residual multivessel disease compared to no multivessel disease (21% vs. 7%, P_interaction= 0.07). Similar results were noted for the key secondary endpoint, supporting the notion of evolocumab's incremental value in those with high-risk features.

Patients with prior MI and at least one high-risk feature had a 17% relative risk reduction in the primary composite endpoint (14.4% vs. 17.3%, P < 0.001) and a 22% relative risk reduction in the key secondary endpoint (8.6% vs. 11.0%, P < 0.001) with evolocumab compared to those with no high-risk features. Those with no high-risk features did not demonstrate benefit in the primary or secondary endpoints during the trial follow-up period.

In the overall FOURIER trial, treatment with evolocumab was associated with a number needed to treat (NNT) of 74 for the primary end point over 2.2 years.¹ The presence of any high-risk feature in those with prior MI translated into a NNT of 27-30 during the same timeframe. In comparison, the absence of any high-risk feature resulted in an appreciably higher NNT of 79-130.

Importantly, this study highlights the value of risk-stratifying an already at-risk population with prior MI. It also shows that MI patients at highest risk of worse outcomes benefit the most from LDL-C lowering. Such findings were noted in the 4S trial, where the absolute benefit of simvastatin was greater in those with highest compared to lowest predicted risk.² Similar findings were noted in the IMPROVE-IT trial, where even greater benefit was noted with the addition of ezetimibe to statin therapy in those with prior coronary artery bypass graft surgery (5),⁵ stroke and diabetes.^6,7 Among those without diabetes, ezetimibe's benefit was largely restricted to those with a high Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention.⁴ Finally, patients in the FOURIER trial with higher baseline levels of high-sensitivity C-reactive protein had greater absolute risk reduction with evolocumab compared to those with lower levels.⁹

Several factors likely account for more pronounced risk reduction with lipid lowering in high-risk patients. MI patients with high-risk features have higher residual risk, usually resulting from advanced atherosclerosis, vulnerable plaque pathology and more extensive coronary artery involvement. Data from the GLAGOV (GLobal Assessment of Plaque regression With a PCSK0 antibOdy as Measured by intraVascular Ultrasound) trial supports this notion, with greater reduction in percent atheroma volume among those with higher plaque burden.¹⁰ Furthermore, there exists a greater opportunity to attenuate CV risk among those with higher event rates, especially during shorter periods of follow up.

In FOURIER, the median follow-up period of 2.2 years is shorter than some other trials of lipid lowering therapy.^2,3,11 Consistent with prior studies such as 4S,² LIPID (Long-Term Intervention With Pravastatin in Ischemic Disease) and IMPROVE-IT,^3,11 CV benefits with lipid lowering therapy may take at least 1.5 years to manifest. While the Kaplan-Meier curves in the FOURIER trial began to diverge as early as 6 months in those at highest risk, such findings were pushed out to nearly 2 years in those at lower risk. This observation underscores the potential of even greater benefit with evolocumab in the lower risk group had the trial continued for a longer period.

In this analysis, the effect of evolocumab on the individual components of the primary and key secondary endpoints was not reported. The absence of a mortality benefit with evolocumab in the overall population may be the result of both lower case fatality rates and the relatively short duration of the trial.¹

In conclusion, this analysis provides support for the notion that tailoring of lipid lowering therapy in MI patients with a PCSK9 inhibitor is likely to be of greatest benefit in those with additional high-risk features. It also provides the rationale to enrich future trials with patients at highest baseline risk. The current high cost of PCSK9 inhibitors represents a major barrier to greater use.¹² Targeting those likely to derive greater benefit may improve the cost-effectiveness of this drug class. Updated estimates of cost-effectiveness should take these new findings into account.

References

1. 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.
2. Wilhelmsen L, Pyorala K, Wedel H, Cook T, Pedersen T, Kjekshus J. Risk factors for a major coronary event after myocardial infarction in the Scandinavian Simvastatin Survival Study (4S). Impact of predicted risk on the benefit of cholesterol-lowering treatment. Eur Heart J 2001;22:1119-27.
3. Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-57.
4. Bohula EA, Morrow DA, Giugliano RP, et al. Atherothrombotic risk stratification and ezetimibe for secondary prevention. J Am Coll Cardiol 2017;69:911-21.
5. Eisen A, Cannon CP, Blazing MA, et al. The benefit of adding ezetimibe to statin therapy in patients with prior coronary artery bypass graft surgery and acute coronary syndrome in the IMPROVE-IT trial. Eur Heart J 2016;37:3576-84.
6. Bohula EA, Wiviott SD, SGiugliano RP, et al. Prevention of stroke with the addition of ezetimibe to statin therapy in patients with acute coronary syndrome in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation 2017;136:2440-50.
7. Giugliano RP, Cannon CP, Blazing MA, et al. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation 2018;137:1571-82.
8. Sabatine MS, De Ferrari GM, Giugliano RP, et al. Clinical benefit of evolocumab by severity and extent of coronary artery disease: an analysis from FOURIER. Circulation 2018. [Epub ahead of print]
9. Bohula EA, Giugliano RP, Leiter LA, et al. Inflammatory and cholesterol risk in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk). Circulation 2018. [Epub ahead of print]
10. 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.
11. 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.
12. Kazi DS, Penko J, Coxson PG, et al. Updated cost-effectiveness analysis of PCSK9 inhibitors based on the results of the FOURIER trial. JAMA 2017;318:748-50.

Keywords: Dyslipidemias, Simvastatin, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Pravastatin, Antibodies, Monoclonal, Plaque, Atherosclerotic, Cholesterol, LDL, Coronary Artery Disease, Secondary Prevention, Cost-Benefit Analysis, Constriction, Pathologic, Factor IX, Risk Factors, Atherosclerosis, Angina, Unstable, Coronary Artery Bypass, Myocardial Infarction, Stroke, Diabetes Mellitus, Risk Reduction Behavior, Outcome Assessment, Health Care

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