Early and short-term use of proprotein convertase anti-subtilisin-kexin type 9 inhibitors on coronary plaque stability in acute coronary syndrome

Abstract

Aims: Proprotein convertase anti-subtilisin-kexin type 9 inhibitors (PCSK9Is) improve plaque volume and composition and reduce major adverse coronary events in chronic coronary artery disease. We evaluated the effects of the short-term use of PCSK9Is on coronary plaque stability in patients with acute coronary syndrome (ACS) using optical coherence tomography (OCT).

Methods and results: This is a multicentre, open-label randomized controlled trial. The enrolled 80 subjects met the inclusion criteria. Of these, 52 patients (age 60 ± 11 years, 38 men, 14 women) with ST-elevated ACS had undergone successful primary percutaneous coronary intervention with LDL-cholesterol (LDL-C) levels > 70 mg/dL while receiving high-intensity statins. Participants were randomly assigned to the PCSK9I group (evolocumab 420 mg for 3 months, n = 29) or the standard of care (SoC) group (n = 23). Optical coherence tomography was performed at baseline (BL) and 3 and 9 months after randomization to assess lipid-rich plaques in non-culprit lesions. The change in the minimum fibrous cap thickness (MFCT) from BL to 9 months was the primary endpoint. The percentage change in LDL-C levels from BL to 3 months was significantly greater in the PCSK9I group (-67.8 ± 21.5% in the PCSK9I group vs. -16.3 ± 21.8% in the SoC group; P < 0.0001), and the difference between the two groups disappeared from BL to 9 months (-20.0 ± 37.8% in the PCSK9I group vs. -6.7 ± 34.2% in the SoC group; P = 0.20). The changes in MFCT from BL to 9 months were significantly greater in the PCSK9I group, even after PCSK9I discontinuation {100 μm [interquartile range (IQR): 45-180 μm] vs. 50 μm [IQR: 0-110 μm]; P = 0.032}.

Conclusion: Combination treatment with PCSK9Is and statins resulted in more marked plaque stabilization after ACS than SoC alone, and this effect persisted for 6 months after PCSK9I discontinuation.

Registration: Adage-Joto study, UMIN ID No. 26516.

Keywords: Acute coronary syndrome; LDL-cholesterol; Optical coherence tomography; PCSK9 inhibitor; Statin.

Graphical Abstract

We evaluated the effects of the short-term use of PCSK9Is on coronary plaque stability in patients with ACS using OCT. Participants were randomly assigned to the PCSK9I group (evolocumab 420 mg for 3 months) or standard of care group. Optical coherence tomography was performed at baseline and 3 and 9 months after randomization to assess lipid-rich plaques in non-culprit lesions. Change in the MFCT from baseline to 9 months was the primary endpoint. ACS, acute coronary syndrome; MFCT, minimum fibrous cap thickness; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; PCSK9Is, proprotein convertase anti-subtilisin–kexin type 9 inhibitors; SoC, standard of care; STEMI, ST-elevation myocardial infarction.

Figure 1

Study profile. Eighty subjects met the inclusion criteria. Of these, 62 participants were randomized at a 1:1 ratio to receive proprotein convertase anti-subtilisin–kexin type 9 inhibitor therapy or standard care. Of these, eight individuals who did not undergo serial optical coherence tomography examinations at baseline and 3 and 9 months were excluded. Ultimately, 52 patients underwent serial optical coherence tomography examinations in accordance with the protocol, with 29 in the proprotein convertase anti-subtilisin–kexin type 9 inhibitor group and 23 in the standard of care group.

Figure 2

Change in the minimum fibrous cap thickness by optical coherence tomography measurement. (A) Change in the minimum fibrous cap thickness from baseline to the 9-month follow-up was significantly greater in the proprotein convertase anti-subtilisin–kexin type 9 inhibitor group than in the standard of care group. (B) Minimum fibrous cap thickness was significantly greater at 3 and 9 months than at baseline in the proprotein convertase anti-subtilisin–kexin type 9 inhibitor and the standard of care groups.

Figure 3

The percentage change in optical coherence tomography measurements. (A) The percentage change in the maximum fibrous cap thickness from baseline to the 3-month follow-up and from baseline to the 9-month follow-up was significantly greater in the proprotein convertase anti-subtilisin–kexin type 9 inhibitor group than in the standard of care group. (B) The percentage change in maximum lipid arc from 3 to 9 months and from baseline to 9 months was significantly reduced.

Figure 4

Representative optical coherence tomography images in the proprotein convertase anti-subtilisin–kexin type 9 inhibitor group. Fibrous cap thicknesses (white arrows) were increased from baseline (80 mm) to the 3-month follow-up (350 mm) and from the 3-month follow-up to the 9-month follow-up (500 mm); lipid (asterisk) arcs were decreased during the follow-up period.

Figure 5

Representative optical coherence tomography images in the standard of care group. Fibrous cap thicknesses (white arrows) were mildly increased from baseline (80 mm) to the 3-month follow-up (140 mm) and from the 3-month follow-up to the 9-month follow-up (220 mm); lipid (asterisk) arcs were slightly decreased during the follow-up period.