Pharmaco-invasive therapy: Early implementation of statins and proprotein convertase subtilisin/kexin type 9 inhibitors after acute coronary syndrome

Abstract

Elevated LDL-cholesterol (LDL-C) plays a major role in atheroma formation and inflammation. Medical therapy to lower elevated LDL-C is the cornerstone for reducing the progression of atherosclerotic cardiovascular disease. Statin therapy, and more recently, other drugs such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have proven efficacy in long-term lowering of LDL-C and therefore diminish cardiovascular risk. During an acute coronary syndrome (ACS), a systemic inflammatory response can destabilize other non-culprit atherosclerotic plaques. Patients with these vulnerable plaques are at high risk of experiencing recurrent cardiovascular events in the first few years post-ACS. Initiating intensive LDL-C lowering therapy in these patients with statins or PCSK9 inhibitors can be beneficial via several pathways. High-intensity statin therapy can reduce inflammation by directly lowering LDL-C, but also through its pleiotropic effects. PCSK9 inhibitors can directly lower LDL-C to recommended guideline thresholds, and could have additional effects on inflammation and plaque stability. We discuss the potential role of early implementation of statins combined with PCSK9 inhibitors to influence these cascades and to mediate the associated cardiovascular risk, over and above the well-known long-term beneficial effects of chronic LDL-C lowering.

Keywords: ACS; LDL-C; MACE; PCSK9 inhibition therapy; statins.

FIGURE 1

Plot of statin, ezetimibe, and PCSK9 trials depicting the relationship between mean LDL-cholesterol (LDL-C) reduction and the proportional reduction of major vascular events (MVE) at one year (MVE: composite of death from coronary heart disease, myocardial infarction, stroke, or revascularization more than 30 days after randomization). Squares represent single trials, the size of the squares represent the number of endpoints in the study. The vertical lines represent one standard error (SE). The regression line represents the event rate reduction per mmol/l LDL-C reduction. AFCAPS/TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; ALERT, Assessment of Lescol in Renal Transplantation; ALLHAT-LLT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid Lowering Trial; ASCOT-LLA, Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm; CARDS, Collaborative Atorvastatin Diabetes Study; CARE, Cholesterol and Recurrent Events; FOURIER, Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; GISSI, Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico; HPS, Heart Protection Study; IMPROVE-IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial; JUPITER, Justification for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin; LDL, low density lipoprotein; LIPID, Long-term Intervention with Pravastatin in Ischemic Disease; LIPS, Lescol Intervention Prevention Study; MVE, major vascular events; ODYSSEY, Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; Post CABG, Post–Coronary Artery Bypass Graft; PROSPER, Long-term Intervention with Pravastatin in Ischemic Disease; SE, standard error; WOSCOPS, West of Scotland Coronary Prevention Study; 4S, Scandinavian Simvastatin Survival Study. Figure edited from Cannon et al. (98), with permission.

FIGURE 2

Schematic showing the role of local intraplaque proprotein convertase subtilisin/kexin type 9 (PCSK9) in atherosclerosis progression. Figure reprinted from Luquero et al. (99) with permission from the authors.

FIGURE 3

Proposed mechanism of the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme in the promotion of vulnerable plaque and recurrent acute coronary syndrome (ACS). ACS and statin therapy can both upregulate plasma PCSK9. Plasma PCSK9 can promote inflammation, increasing the risk for recurrent ACS. Local inflammation in the vessel wall can upregulate local PCSK9 production by smooth muscle cells (SMCs). Local PCSK9 can downregulate macrophage low density lipoprotein-cholesterol (LDL-C) receptors, decreasing LDL-C uptake and increasing the pool of extracellular lipid. This extracellular LDL-C is transformed to oxLDL, which activates pro-inflammatory genes and pro-inflammatory cytokine production, and induces SMC and endothelial cell apoptosis. Macrophages take up oxLDL via scavenger receptors, thus promoting foam cell formation and necrotic core formation. This process might increase vulnerable plaque and risk for recurrent ACS. PCSK9 inhibitors lower plasma PCSK9 and might also lower local PCSK9 in the vessel wall, inhibiting this process.