Background: Elevated Lp(a) (lipoprotein[a]) is a risk marker for atherosclerotic disease, but the underlying mechanisms remain elusive. We examined the association of Lp(a) with changes in coronary atherosclerosis following intensive lipid-lowering therapy., Methods: In the PACMAN-AMI trial (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction), 300 patients with acute myocardial infarction were randomized to receive biweekly alirocumab 150 mg or placebo in addition to high-intensity statins. Patients underwent serial 2-vessel intravascular ultrasound, optical coherence tomography, and near-infrared spectroscopy in the non-infarct-related arteries at baseline and after 52 weeks. The main end points were percent atheroma volume by intravascular ultrasound, minimum fibrous cap thickness by optical coherence tomography, and maximum lipid core burden index within 4 mm (maxLCBI 4mm ) by near-infrared spectroscopy., Results: A total of 265 patients had serial intravascular ultrasound data (mean age, 58±9 years; 16% women). Alirocumab resulted in greater reductions in percent atheroma volume and maxLCBI 4mm , as well as a greater increase in minimum fibrous cap thickness, compared with placebo. In the alirocumab group, the reduction in maxLCBI 4mm was smaller in patients with higher baseline Lp(a), defined by the highest quartile (Q4, ≥98 nmol/L; n=30), than in those with lower baseline Lp(a) (Q1-Q3, <98 nmol/L; n=99; -40.2 [-91.1 to 10.7] versus -91.4 [-113.9 to -68.9], respectively; P =0.01 after adjustment for clinically relevant baseline variables), and was comparable to the maxLBI 4mm reduction in the placebo group (-37.60 [-57.40 to -17.80]; n=134). These findings were consistent when higher baseline Lp(a) was defined by cut-off values of ≥75 versus <75 nmol/L (n=35 versus 94, respectively, in the alirocumab group) and ≥125 versus <125 nmol/L (n=23 versus 106, respectively). Changes in percent atheroma volume and minimum fibrous cap thickness did not differ in relation to baseline Lp(a)., Conclusions: In patients with acute myocardial infarction, elevated Lp(a) at baseline is associated with attenuation of plaque lipid regression despite intensive treatment with alirocumab plus high-intensity statin. This finding may explain the residual cardiovascular risk associated with high Lp(a) despite optimal control of lipid levels., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03067844., Competing Interests: Dr Koskinas has received speaker fees from Amgen, Sanofi, and Daiichi Sankyo. Dr Kakizaki has received speaker fees from Abbott Medical, Boston Scientific, Philips, OrbusNeich Medical, Terumo, Eli Lilly, Mochida Pharmaceutical, Novartis, Kowa, Takeda Pharmaceuticals, Ono Pharmaceutical, Boehringer Ingelheim, Daiichi Sankyo, Mitsubishi Tanabe Pharma, AstraZeneca, and consulting fees from Infraredx. Dr van Geuns reported grants and personal fees from Boston Scientific, Abbott Vascular, Astra Zeneca, Amgen, and grants from InfraRedx. Dr Praz has received travel expenses from Abbott Vascular, Edwards Lifesciences, Polares Medical, Medira, and Siemens Healthineers. Dr Spirk reports personal fees from Sanofi-Aventis (Switzerland), outside the submitted work. Dr Lanz has received speaker fees to the institution from Abbott and Edwards Lifesciences. Drs Heg and Losdat are employed by CTU Bern, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees; however, CTU Bern is involved in the design, conduct, or analysis of clinical studies funded by not-for-profit and for-profit organizations. Dr Windecker has received research and educational grants to the institution from Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Corflow Therapeutics, CSL Behring, Daiichi-Sankyo, Edwards Lifesciences, Guerbet, Infraredx, Janssen-Cilag, Johnson & Johnson, Medicure, Medtronic, Merck Sharp & Dohme, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Swiss, Pfizer, Polares, Regeneron, Sanofi, Servier, Sinomed, Terumo, Vifor, and V-Wave. He serves as an unpaid advisory board member and unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, V-Wave, and Xeltis but has not received personal payments from pharmaceutical companies or device manufacturers. Dr Engstrøm has received speaker fees from Abbott Vascular. Dr Lang has received consultancy fees and research grants from AOP Health, Johnson & Johnson, MSD, United Therapeutics, Sanofi, Medtronic, Novo Nordisk, Neutrolis, and Pulnovo. Dr Räber has received grants from Sanofi, Regeneron, and Infraredx to the institution, speaker fees from Sanofi, and grants from Abbott, HeartFlow, Boston Scientific, and Biotronik to the institution, as well as grants from Abbott, Amgen, AstraZeneca, Occlutech, Sanofi, Canon, and Medtronic for speaker and consultation fees outside the submitted work. The other authors report no conflicts.