The following are key points to remember from this European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) update on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in patients with atherosclerotic cardiovascular disease (ASCVD) or in familial hypercholesterolemia (FH):

1. The 2017 ESC/EAS Task Force provides clinical guidance and novel clinical decision algorithms when considering a PCSK9 inhibitor, and monitoring treatment efficacy to statin, ezetimibe, and PCSK9 inhibitors. Gaps in knowledge for PCSK9 inhibition are also discussed.
2. In the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial of evolocumab (a fully human monoclonal PCSK9 antibody) in 27,564 patients with ASCVD, low-density lipoprotein cholesterol (LDL-C) levels were lowered by 59% (from mean 93 mg/dl to 55 mg/dl) and significantly reduced the risk of major CV events (absolute event rates 9.8% vs. 11.3% on placebo over 2.2 years, relative risk reduction of 15%). The clinical benefit of treatment was due to reduction of nonfatal events, largely driven by reduction in myocardial infarction (MI) and coronary revascularization. This benefit was generally consistent across all major patient subgroups, including age, sex, and type of clinical presentation of ASCVD (coronary artery disease [CAD] with history of MI, ischemic stroke, and symptomatic peripheral arterial disease [PAD]), and accrued over time. When adjusted for duration of treatment, the results from FOURIER were superimposable with those observed with statin therapy.
3. While there was no significant benefit on CV and all-cause mortality, the findings are consistent with a meta-analysis of four high- versus low-dose statin trials that found a reduction mainly in nonfatal CV events in patients allocated to the high-dose regimen. Moreover, while reduced mortality was observed in earlier statin placebo-controlled trials, this was only seen after prolonged treatment and not after 2.2 years against a background of contemporaneous, predominantly high-dose statin therapy as in the FOURIER trial. It will be of great interest to see whether longer follow-up of patients treated with a PCSK9 inhibitor results in reduction in mortality.
4. As exemplified by FOURIER, patients with documented clinical ASCVD are at very high CV risk, with an annual absolute risk of a major CV event >3%. The recommended first approach to the management of elevated LDL-C levels in these patients is intense statin therapy. Clinicians should allow sufficient time to achieve the maximum tolerated regimen of statin therapy with concomitant ezetimibe, depending on clinical judgement and local guidance.
5. On the basis of currently available evidence, the Task Force recommends that a PCSK9 inhibitor should be considered in the following:
• Patients with ASCVD, by definition at very high risk, who have substantially elevated LDL-C levels despite maximally tolerated statin with or without ezetimibe therapy, and thus are considered at particularly high risk of an adverse prognosis.
• Patients with ASCVD and at very high risk who do not tolerate appropriate doses of at least three statins and thus have elevated LDL-C levels.
• FH patients without clinically diagnosed ASCVD, at high or very high CV risk, and with substantially elevated LDL-C.
6. Additional indices of risk severity are defined for patients with clinical ASCVD including concomitant presence of FH; diabetes mellitus with target organ damage or with a major risk factor such as marked hypertension; severe or extensive ASCVD; or rapid progression of ASCVD (repeated acute coronary syndrome, unplanned coronary revascularizations, or ischemic stroke within 5 years of the event). For FH patients without clinical ASCVD, additional indices of risk severity are diabetes mellitus with target organ damage or with a major risk factor such as marked hypertension; lipoprotein(a) >50 mg/dl; major risk factors such as smoking, marked hypertension; >40 years without treatment; premature ASCVD (<55 years in males and <60 years in females) in first-degree relatives; and imaging indicators of increased risk.
7. The Task Force recommends an LDL-C threshold for consideration of PCSK9 inhibitor treatment of 140 mg/dl, despite statin with or without ezetimibe therapy or inability to tolerate appropriate doses of at least three statins. Reduction of LDL-C levels by 50% with this treatment offers the possibility of attainment of the guideline-recommended LDL-C goal or 70 mg/dl, resulting in >1% annual reduction in absolute CV risk. In addition, the presence of additional indices of risk severity, such as rapidly progressive ASCVD, in particular after an ACS, diabetes mellitus, or complex multivessel or polyvascular atherosclerotic disease, exacerbates absolute risk and would qualify for lowering the LDL-C threshold to 100 mg/dl.
8. In addition, further risk assessment imaging may help to identify those patients with severe and/or extensive ASCVD who are at particularly high risk. These include carotid artery plaque (defined as either focal wall thickening >50% compared with the surrounding vessel wall or a focal region with an intima-media thickness measurement >1.5 mm); coronary artery calcium score >400; or extent, severity, location, and composition of plaque on coronary computed tomography angiography.
9. Monitoring treatment includes monitoring the LDL-C lowering response to statin and ezetimibe at 4 weeks and checking adherence before considering a PCSK9 inhibitor, as well as assessing the LDL-C lowering response to the PCSK9 inhibitor at 2 weeks after first injection of either the monthly or 2-weekly regimen (before the next injection).
10. The Task Force did not provide discussion of cost-effectiveness. However, they stressed that absolute CV risk together with absolute LDL-C levels are the key determinants of the number needed to treat (NNT) to prevent a CV event. In patients with ASCVD, who have substantially elevated LDL-C levels despite maximally tolerated statin plus ezetimibe therapy, or inability to tolerate statins, data from the FOURIER trial suggest that adding a PCSK9 inhibitor to lower LDL-C levels by 50% might be expected to reduce the 5-year NNT to <30 in patients with a baseline LDL-C <140 mg/dl. It would be presumptive to model the impact of adding a PCSK9 inhibitor on the NNT until longer-term follow-up data are available to assess the potential of these treatments to modify the trajectory of ASCVD.
11. Gaps in knowledge concerning PCSK9 inhibitor therapy include:
• Interindividual variability in LDL-C lowering response to alirocumab and evolocumab.
• Dedicated trials in patients with recent (<1 month) CV events.
• Impact of PCSK9 inhibition in patients with chronic kidney disease (not requiring dialysis).
• Long-term efficacy and safety of PCSK9 inhibitors in clinical use.
• Long-term safety of very low LDL-C levels.
• Long-term impact of PCSK9 inhibition on disability and CV mortality.
• Long-term evaluation of risk for type 2 diabetes.
• Impact of sustained and marked LDL-C lowering to very low levels on plaque composition and stability.
• Long-term impact of reduction in elevated lipoprotein(a) with PCSK9 inhibition.
• Cost-effectiveness of PCSK9 inhibition added to maximally tolerated statin with or without ezetimibe therapy.

Perspective:

The ESC/EAS guidelines are for the most part supported by evidence. However, the complexity of the decision trees which encourage further expensive testing in patients with known ASCVD, and failure to reduce the LDL-C to <140 mg/dl with maximal statin + ezetimibe, is more stringent than presently accepted by most third-party payers in the United States prior to FOURIER trial results—particularly strict considering that the treatment benefit in FOURIER was present in patients with an LDL-C <70 mg/dl on maximally tolerated statin therapy. Similarly, approval for patients with FH without ASCVD is an LDL-C >100 mg/dl despite maximal tolerated doses of statin + ezetimibe and >70 mg/dl with ASCVD or high risk defined as elevated Lp(a), high level of high-sensitivity C-reactive protein, and high coronary calcium score.

Keywords: Acute Coronary Syndrome, Atherosclerosis, Carotid Intima-Media Thickness, Carotid Stenosis, Cholesterol, LDL, Coronary Angiography, Coronary Artery Disease, Diabetes Mellitus, Type 2, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Hypertension, Lipoprotein(a), Myocardial Infarction, Peripheral Arterial Disease, Plaque, Atherosclerotic, Primary Prevention, Proprotein Convertases, Renal Insufficiency, Chronic, Risk Assessment, Risk Factors, Smoking, Stroke, Subtilisins, Treatment Outcome

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