Vascular and myocardial inflammation are significantly increased in Acute Coronary Syndrome (ACS) patients, are closely correlated to LDL-C levels, and are associated with these adverse consequences in the post-ACS patient population. Serum proprotein convertase subtilisin/kerin type 9 (PCSK9) levels are also increased in ACS, may raise LDL-C, and the investigators\' pre-clinical studies indicate that PCSK9 is also a potent inducer of vascular inflammation. The addition of the PCSK9 antibody evolocumab, currently approved to lower LDL-C in certain patient populations, to current medical therapies would appear to be of particular benefit in an important subset of ACS patients, those with non-ST elevation myocardial infarction (NSTEMI) by markedly reducing LDL-C, stabilizing vulnerable plaque, and limiting inflammation-associated myocardial cell loss and resultant dysfunction.

The recently published IMPROVE‐IT trial was the first to demonstrate that in high‐risk patients, reduction of low density cholesterol (LDL‐C) beyond current treatment goals by addition of ezetimibe to statin therapy leads to a further improvement of cardiovascular (CV) outcomes. The results of this study provide strong support for the concept that it is lower LDL‐C levels that is key to achieving better outcomes, and that it is possible to achieve these on top of statin therapy (despite the much debated potential "pleiotropic" effects of statins). However, ezetimibe has only limited ability to reduce LCL‐C further (‐24% lower compared with statin alone in the IMPROVE‐IT trial). Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a new treatment paradigm for hypercholesterolemia. The normal function of PCSK9 is to bind to the low density cholesterol (LDL‐C) receptor, and to promote its lysosomal destruction in the hepatocyte. Thus, inhibition of PCSK9 protects the LDL‐C receptor from lysosomal destruction, resulting in increased recirculation of the LDL‐C receptor to the hepatocyte cell surface, and as a consequence, increased hepatic uptake and lower circulating levels of LDL‐C. The PCSK9 inhibitor evolocumab has been approved in 2015 for the treatment of patients with homocygote familial hypercholesterolemia (FH), as well as for treatment of patients with heterocygote familial or non‐familial hypercholesterolemia in which target LDL‐C levels cannot be achieved by standard cholesterol‐lowering therapy, or who are statin‐intolerant. Evolocumab achieves a reduction in LDL‐C regardless of background therapy in the order of 50‐70% (including those on a statin). This therapy substantially increases the number of patients achieving lower LCL‐C target levels. Recently, the results of a large prospective study (FOURIER) in 27.500 patients at high CV risk have been published. This study showed that evolocumab lowered LDL cholesterol in patients already on optimized lipid lowering therapy including a statin to a median of 30 mg per deciliter and substantially reduced CV events (hazard ratio 0.85, confidence interval 0.79 to 0.92; P<0.001). However, the mechanisms mediating the improvement of CV outcomes under therapy with evolocumab are unclear at present. Intact function of the endothelium is a key component of vascular health. Conversely, impaired endothelial function has been linked with increased future CV event rates. Intact endothelium has many protective and anti‐atherosclerotic effects on the vasculature. At least in part, these protective effects are due to endothelial release of nitric oxide (NO). A well‐established and non‐invasive method of assessing endothelial function in humans is by measurement of flow‐mediated vasodilation (FMD). In addition, recent evidence suggests concurrent assessment of low flow‐mediated vasoconstriction (L‐FMC) improves characterization of underlying CV and coronary disease compared with each parameter alone. Further, endothelial function has been found to impact large artery function. Endothelial dysfunction leads to vasoconstriction, greater peripheral wave reflection and arterial stiffness, and as a consequence, augmentation of central (aortic) systolic blood pressure (BP). This is of prognostic relevance, since aortic stiffness (e.g. determined by pulse wave velocity [PWV]), central systolic BP (cSBP) and central BP augmentation have been identified as strong and independent predictors of CV events in several patient cohorts. Exciting technical developments of recent years have now made the ambulatory (24‐h) measurement of arterial stiffness possible. The investigator group has been amongst the first to show that statin treatment improves endothelial function in patients with elevated LDL‐C, which at least in part serves to explain the beneficial effects of statins on CV outcomes. The investigator Group was also able to show that an improvement in endothelial function during statin therapy is linked with an improvement of pulse wave reflection. Rapid improvement of endothelial and large artery function is considered to be particularly important in patients at high CV risk, such as those that have suffered a recent CV event. The investigator Group hypothesize that the beneficial effects of evolocumab, such as recently demonstrated in the FOURIER trial, are linked to a rapid improvement of endothelial and large artery function, even in patients already on optimized lipid lowering therapy including a statin. Of note, improvement of basal NO activity in the renal circulation and NO‐dependent vasodilation of the peripheral vasculature occurs already 3 days after initiating treatment of statins. In the current study we focus on FMD of the brachial artery as the primary objective parameter. This parameter, which is widely accepted as an integrated measure of vascular function, is partly dependent on endothelial NO production. These data would help to explain the results of IMPROVE‐IT and FOURIER, and add to the evidence that it is lower cholesterol levels that matter most for CV outcomes.

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BACKGROUND:

Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain.

METHODS:

We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years.

RESULTS:

At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%).

CONCLUSIONS:

In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets. (Funded by Amgen; FOURIER ClinicalTrials.gov number, NCT01764633 .).

BACKGROUND:

Proprotein convertase subtilisin/kexin type 9 inhibitor therapy is a treatment option for patients with familial hypercholesterolemia (FH) who are unable to reach low-density lipoprotein cholesterol (LDL-C) goals.

OBJECTIVES:

The aim of this study was to provide long-term safety and efficacy data for evolocumab in patients with homozygous FH (HoFH) and severe heterozygous FH (HeFH).

METHODS:

In this open-label, single-arm study, patients with HoFH or severe HeFH ≥12 years of age and on stable lipid-lowering therapy began subcutaneous evolocumab 420 mg monthly or 420 mg every 2 weeks if on lipoprotein apheresis. After 12 weeks, those not on apheresis could be up-titrated to 420 mg every 2 weeks. The primary endpoint was the incidence of treatment-emergent adverse events; secondary endpoints were changes in LDL-C and other lipids.

RESULTS:

In total, 300 patients (106 with HoFH, including 14 <18 years of age at enrollment) received evolocumab for a median of 4.1 years. Adverse events occurred in 89.3% of patients, the most common of which were nasopharyngitis, influenza, upper respiratory tract infection, and headache. Mean change in LDL-C from baseline to week 12 was -21.2% (-59.8 mg/dl) in patients with HoFH and -54.9% (-104.4 mg/dl) in those with severe HeFH and was sustained over time. Of 48 patients with HoFH who were up-titrated, mean change in LDL-C improved from -19.6% at week 12 to -29.7% after 12 weeks of 420 mg every 2 weeks. The adjudicated cardiovascular event rate was 2.7% per year. Of 61 patients receiving apheresis at enrollment, 16 discontinued apheresis.

CONCLUSIONS:

Evolocumab was well tolerated and effectively reduced plasma LDL-C levels in patients with HoFH and severe HeFH over a median of 4.1 years.

This study seeks to identify morphologic changes, such as increase in FCT in atherosclerotic plaques associated with treatment with evolocumab and maximally tolerated statin therapy with or without additional lipid‐modifying medication in patients presenting with NSTE‐ACS using optical coherence tomography (OCT; primary, secondary, and exploratory endpoints).

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BACKGROUND:

Baseline imbalances have been identified in randomized trials of evolocumab and alirocumab. Our aim was to quantitatively assess (1) the presence of systematic baseline differences, and (2) the relationship of baseline differences with effects on low-density lipoprotein-cholesterol (LDL-c) and clinical outcomes in the trials.

METHODS:

We performed a meta-epidemiological study. PubMed, Embase, regulatory reports, ClinicalTrials.gov and company websites were searched for trials. Seven baseline characteristics (mean age, LDL-c, BMI, percentage males, diabetics, smokers, and hypertensives) and five outcomes (LDL-c, major adverse cardiac events, serious adverse events, any adverse events, all-cause mortality) were extracted. We calculated (1) range and distribution of baseline imbalances (sign-test), (2) pooled baseline differences and heterogeneity (meta-analysis), (3) differences in SDs around continuous variables (sign-test and pooling), and (4) the relationship of baseline differences with outcomes (meta-regression). The comparisons of PCSK9-inhibitor groups with either placebo or ezetimibe were analysed separately and combined.

RESULTS:

We identified 43 trials with 63,193 participants. Baseline characteristics were frequently missing. Many trials showed small baseline imbalances, but some large imbalances. Only baseline BMI showed a statistically significant lower pooled mean for the drug versus placebo groups (MD -0.16; 95% CI -0.24 to -0.09). Heterogeneity in baseline imbalances was present in six placebo- and five ezetimibe-comparisons. Heterogeneity was statistically significant for BMI, males, diabetics and hypertensives in the combined comparisons. There was a statistically significant preponderance for larger SDs in the PCSK9-inhibitor versus control groups (sign-test age 0.014; LDL-c 0.014; BMI 0.049). Meta-regression showed clinically relevant relationships of baseline imbalances in age, BMI and diabetics with the risk of any adverse events and the risk of mortality. Two relationships were statistically significant: A higher mean BMI in the drug versus control group with a decreased risk of mortality (beta - 0.56; 95% CI -1.10 to -0.02), and a higher proportion of diabetics with an increased risk of any adverse events (beta 0.02; 95% 0.01 to 0.04).

CONCLUSIONS:

Heterogeneous baseline imbalances and systematically different SDs were present in evolocumab and alirocumab trials, so study groups cannot be assumed to be comparable. These findings raise concerns about the design and conduct of the randomization procedures.

The effects of cholesterol-lowering drugs, including those that reduce cholesterol synthesis (statins) and those that reduce cholesterol absorption (ezetimibe), on cholesterol absorption and synthesis are well understood. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a novel class of cholesterol-lowering drugs that robustly reduce LDL-cholesterol (LDL-C), but little is known about their effects on cholesterol absorption and synthesis. We evaluated how treatment with evolocumab, a fully human monoclonal IgG2 antibody to PCSK9, affects markers of cholesterol synthesis and absorption by measuring these markers in patients from an evolocumab clinical trial. At 2 weeks, changes in β-sitosterol/total cholesterol (TC) from baseline were 4% for placebo, 10% for evolocumab 140 mg (nonsignificant vs. placebo), and 26% for evolocumab 420 mg (P < 0.001 vs. placebo). Changes in campesterol/TC at week 2, relative to baseline between placebo and evolocumab, were all nonsignificant. Evolocumab had a modest effect on markers of cholesterol synthesis. At 2 weeks, changes in desmosterol/TC were 1% for placebo, 7% for evolocumab 140 mg (nonsignificant vs. placebo), and 15% for evolocumab 420 mg (P < 0.01 vs. placebo). Changes from baseline in lathosterol/TC at week 2 between placebo and evolocumab were nonsignificant. These results suggest that evolocumab has a modest effect on cholesterol synthesis and absorption despite significant LDL-C lowering.

BACKGROUND:

Incremental low-density lipoprotein (LDL) cholesterol lowering with the proprotein convertase subtilisin kexin type 9 inhibitor evolocumab regresses coronary atherosclerosis in statin-treated patients.

OBJECTIVES:

The purpose of this study was to evaluate the effect of adding evolocumab to statin therapy on coronary plaque composition.

METHODS:

A total of 968 statin-treated coronary artery disease patients underwent serial coronary intravascular ultrasound imaging at baseline and following 76 weeks of treatment with placebo or evolocumab 420 mg monthly. Plaque composition changes were determined in 331 patients with evaluable radiofrequency analysis of the ultrasound backscatter signal.

RESULTS:

Compared with statin monotherapy, evolocumab further reduced LDL cholesterol (33.5 mg/dl vs. 89.9 mg/dl; p < 0.0001) and induced regression of percent atheroma volume (-1.2% vs. +0.17%; p < 0.0001) and total atheroma volume (-3.6 mm3 vs. -0.8 mm3; p = 0.04). No difference was observed between the evolocumab and placebo groups in changes in calcium (1.0 ± 0.3 mm3 vs. 0.6 ± 0.3 mm3; p = 0.49), fibrous (-3.0 ± 0.6 mm3 vs. -2.4 ± 0.6 mm3; p = 0.49), fibrofatty (-5.0 ± 1.0 mm3 vs. -3.0 ± 1.0 mm3; p = 0.49), and necrotic (-0.6 ± 0.5 mm3 vs. -0.1 ± 0.5 mm3; p = 0.49) volumes. An inverse correlation was observed between changes in LDL cholesterol and plaque calcification (r = -0.15; p < 0.001).

CONCLUSIONS:

The addition of evolocumab to a statin did not produce differential changes in plaque composition compared with statin monotherapy. This suggests that evaluation of plaque morphology using virtual histology imaging may provide no incremental information about the plaque effects of evolocumab beyond measurement of plaque burden. (GLobal Assessment of Plaque reGression With a PCSK9 antibOdy as Measured by intraVascular Ultrasound [GLAGOV]; NCT01813422).