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Introduction: Incliciran, a small interfering ribonucleic acid (siRNA), is the new modulator of the proprotein convertase subtilisin kexin 9 (PCSK9) that has proven safe and effective in reducing LDL-C and ASCVD. However, it is unclear if incliciran is superior to the already established PCSK9 monoclonal antibodies (mAb) in reducing major adverse cardiac events (MACE). Methods: We performed a meta-analysis of randomized controlled trials of patients with high cardiovascular risk who underwent PCSK9 inhibition by either mAb or siRNA. The primary outcome was the reduction of MACE. Results: Thirty RCTs with a total of 92,775 patients were included. For patients with a high cardiovascular risk profile, the modulation of PCSK9 by mAb decreases the risk of MACE (HR 0.84, 95% CI 0.8 - 0.89, p<0.0001) compared with statins and/or ezetimibe. Similar effects occurred when siRNA (HR 0.78, 95% CI 0.63 - 0.97, p=0.024) was compared to statins alone. The impact on MACE was no different between mAb and siRNA modulation of PCSK9 (p=0.49) (figure 1). When PCSK9 inhibitors were compared to statins monotherapy, only evolocumab and incliciran were statistically significant in reducing MACE (p<0.0001 and p=0.024, respectively). An additional analysis of all studies, including those with statins plus ezetimibe, showed that all therapies except bococicimab (p=0.309) reduced MACE (figure 2). Conclusions: This study suggests that PCSK9 inhibition by siRNA is as effective as mAb PCSK9 for reducing MACE in patients with a high cardiovascular risk profile, with the convenience of being administered twice a year.

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