Effect of 5-lipoxygenase-activating protein inhibiton on coronary atherosclerosis progression in patients with recent acute coronary syndrome: the PASSIVATE randomised clinical trial

Abstract Background Anti-inflammatory therapies have shown promise in reducing major adverse cardiovascular events (MACE) in patients with coronary atherosclerosis. AZD5718, a selective 5-lipoxygenase-activating protein (FLAP) inhibitor, has been shown in small and large animal models of atherosclerosis to reduce leukotriene production, decrease neutrophil chemotaxis and attenuate atherosclerosis progression but its efficacy in coronary plaque regression of patients with recent acute myocardial infarction (AMI) has not been evaluated. Purpose The PASSIVATE trial evaluated whether treatment with 125 mg of AZD5718 daily for 12 months, compared with matching placebo, reduces non-calcified plaque volume (NCPV) progression on computed tomography coronary angiography (CTCA) in patients with recent AMI. Methods This randomised, double-blind, placebo-controlled trial was conducted across 8 sites in Singapore and New Zealand. We included participants who were hospitalised for an AMI, defined according to the 4th Universal Definition of MI, underwent invasive coronary angiography showing at least ≥50% stenosis in one epicardial coronary artery and ≥20% in a second artery and a baseline white blood cell count ≥ 7.0 X 103/uL. We excluded patients with eGFR50 mL/min/1.73 m2, abnormal liver or thyroid function tests, asthma or who were on treatment with other leukotriene antagonists. The primary efficacy endpoint was the absolute change from baseline to 12 months in total non-calcified (130 HU) coronary plaque volume (mm3) measured on CTCA. Key secondary endpoints included the 12-month change in high-sensitivity C-reactive protein (hs-CRP) and peri-coronary adipose tissue attenuation (PVAT), a marker of peri-coronary inflammation on CTCA. All baseline and 12-month CTCA scans were analysed centrally at a core imaging facilty in Singapore. Results Baseline demographics, NCPV and hs-CRP were not significantly different between groups (Table 1). At 12 months, compared with baseline, mean NCPV increased by 55.46 ± 210.24 mm³ in the placebo group and increased by 48.47 ± 166.53 mm³ in the AZD5718 group (P=0.78) (Figure 1). Compared with the placebo group, the AZD5718 group had a more attenuated increase in neutrophil count (placebo group 0.49 ± 14.41 x10⁹/L vs. AZD5718 group 0.16 ± 6.04 x10⁹/L ; P=0.012) over 12 months. Other secondary efficacy endpoints, including hs-CRP (Figure 1), PVAT (Figure 1), total plaque volume, fibrofatty plaque volume and calcified plaque volume, showed no significant differences in change over 12 months between the placebo and AZD5178 groups. There were no significant differences in adverse or serious adverse events between the placebo and AZD5718 groups. Conclusions Treatment with AZD5718, a FLAP inhibitor, did not reduce NCPV or hs-CRP compared with placebo over 12 months in patients with recent AMI. These findings suggest limited efficacy of AZD5718 in modulating plaque progression or systemic inflammation in this population.Table 1:Baseline characteristics Figure 1:12-month change in endpoints