Functional Improvement of Coronary Artery Narrowing by Cholesterol Reduction With a PCSK9 Antibody

In a large number of patients presenting with acute coronary syndrome (ACS) multivessel disease is identified. Mechanical treatment of the infarct related artery (IRA) is indisputable, yet mechanical treatment of other bystander lesions in non-infarct related arteries (non-IRAs) is controversial. Some randomized studies have favored preventive complete revascularization during invasive coronary angiography (ICA) over conservative medical treatment with deferred percutaneous intervention (PCI). Yet patient selection and medical treatment in the conservative medical treatment groups were suboptimal.

Revascularization of lesions in the non-IRA can be guided by fractional flow reserve (FFR). In current practice, a value of 0.80 or lower is often used to mark a functionally significant stenosis at a stabilized moment after initial hyperemic response. However, recent evidence suggests that hyperemic response to adenosine is impaired in patients with ACS, which could underestimate how flow-limiting a non-culprit lesion is as measured by FFR. A large patient-level meta-analysis of multiple FFR trials showed that FFR values below 0.67 most evidently identify those at risk of MI or death. Thus, in patients with values above 0.67, mechanical revascularization has less apparent benefit as compared to patients with values below 0.67. The threshold of 0.67 could be a lower safety margin applied for non-IRA lesions, with percutaneous intervention (PCI) as treatment. For values between 0.67 and 0.85, medical treatment could be optimized using the latest generation LDL-C lowering agents on top of current high-intensity statin therapy (HIST) before directly stenting the lesion.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have shown to induce regression of coronary atherosclerotic plaque volume (PV) in patients with coronary artery disease (CAD). As high-risk lesions with large plaque burden (PB) and lipid content are frequently present in ACS, a rapid response on PB and PV can be expected when starting PCSK9-inhibitors on top of HIST. In addition to plaque size, plaque morphology is important in determining residual risk. Lipid-rich plaques have recently again shown to increase the risk of major adverse cardiac events. Lipid rich plaque can be identified using Near-InfraRed Spectroscopy (NIRS). The amount of lipid is represented in the lipid core burden index (LCBI) and is an independent risk factor for future coronary events. A recent study demonstrated the effect on plaque composition in 52 weeks. In this study, an effect in 12 weeks will be evaluated as a potential independent explanation of reduced events in long-term clinical follow-up studies.The change in plaque volume might be closely related to a change in FFR.

Furthermore, it is now well-appreciated that an ACS, a result of atherosclerotic plaque destabilization, initiates a temporary acceleration of atherogenesis in itself. An ACS induces rapid activation of the bone marrow hematopoietic stem- and progenitor cells resulting in monocytosis and activation of innate immune cells, which subsequently accelerate atherosclerosis progression throughout the body. Hypercholesterolemia also activates the innate immune system bone marrow progenitors resulting in long-term activation of the innate immune system. In patients with familial hypercholesterolemia (FH), PCSK9 treatment reduced monocyte CCR2 expression and ex-vivo migratory capacity. Therefore, in the first weeks after an ACS occurred, there is an optimal time window for preventing atherosclerosis progression by powerful lowering of plasma cholesterol.

This pharmaco-invasive strategy with a combination of HIST and a PCSK9-inhibitor could possibly prevent mechanical revascularization (PCI or CABG) in a large cohort of patients. Evolocumab was the first PCSK9-inhibitor approved for clinical use in 2015 for lowering of LDL-C as an adjunct to diet in patients with FH, primary hypercholesterolemia and in patients with homozygous familial hypercholesterolemia (HoFH). Evolocumab has been evaluated in several large scale studies as GLAGOV (N = 968) and FOURIER (N= 27564) on surrogate and clinical endpoints with important benefits and established safety and tolerability.

In this study we want to investigate the effect of maximal LDL-C reduction by evolocumab in addition to HIST compared to placebo on functional impairment of non-IRA lesions, measured by FFR, and the change in NIRS derived lipid core burden index at the 4mm maximal segment (MaxLCBI4mm) from baseline to follow-up in the non-IRA. Secondly, we want to evaluate the change in multiple plaque characteristics, measured by intravascular ultrasound (IVUS). Finally, we will investigate the change in microvascular function, change in pro-inflammatory monocyte phenotype and explore correlations between on treatment LDL-C, LCBI, plaque characteristics and FFR.