ACC.24 – Results from the VICTORION-INITIATE study showed that an “inclisiran first” strategy led to greater LDL-c lowering at day 330 compared to usual care in patients with ASCVD enrolled in representative US clinical settings

This summary is based on the presentation of Michael J. Koren, MD (Jacksonville, Florida, US) at the ACC.24 Scientific Session – Comparison of an “Inclisiran First” Strategy With Usual Care in Patients With Atherosclerotic Cardiovascular Disease: Results From the VICTORION-INITIATE Randomized Trial

Introduction and methods

Evidence-based guidelines recommend risk-based LDL-c goals of <55 mg/dL and <70 mg/dL in patients with ASCVD to improve outcomes. Most patients however fail to achieve these goals. Studies with inclisiran -an siRNA that inhibits PCSK9 production- have shown additional lowering of LDL-c of ~50%, with most patients reaching their LDL-c goals.

In this study, an “inclisiran first” strategy, meaning adding inclisiran immediately if patients failed to reach LDL-c < 70 mg/dL despite receiving maximally tolerated statins, was examined.

The VICTORION-INITIATE was a prospective, randomized, open-label, phase 3b trial enrolling 450 patients with a history of ASCVD, LDL-c ≥70 mg/dL or non-HDL-c ≥100 mg/dL and fasting triglycerides <500 mg/dL on maximally tolerated statin therapy or with documented statin intolerance in representative US clinical settings. Patients were randomized to “inclisiran first” strategy (inclisiran added immediately upon failure to reach LDL-c < 70 mg/dL on maximally tolerated statins) or to usual care (any lipid-lowering therapy directed/titrated at the treating physician’s discretion). Inclisiran was administered at day 0, day 90 and day 270. The coprimary endpoints were percent change in LDL-c from baseline to day 330, and the discontinuation of statin therapy (no statin use ≥30 days before the end-of-study visit).

Main results

• The mean percent change in LDL-c from baseline at day 330 was -60.0% (97.5%CI: -64.7 to -55.2) with ‘inclisiran first” and -7.0% (97.5%CI: -12.0 to -1.9) with usual care (LS mean difference -53.0%, 97.5%CI: -60.0 to -46.0, P<0.001).
• Statin discontinuation was 6.0% (1.9, 10.2) in the “inclisiran first” strategy group and 16.7% (10.2, 23.1) in the usual care group. The non-inferiority margin (15%) was met when comparing the two groups (-10.6%, 97.5%CI: -18.3% to -3.0%).
• At day 330, a significant greater proportion of patients in the “inclisiran first” group achieved LDL-c goals compared with the usual care arm (81.8% vs. 22.2% for LDL-c goal of <70 mg/dL and 71.6% vs. 8.9% for LDL-c goal of < 55 mg/dL).
• At day 330, 88.4% of patients in the “inclisiran first” group were on statins as only background LLT. In the usual care group, 73.4% of patients were on statins only, 12.6% received statin combination therapy, and 2.5% received a PCSK9 mAb without concomitant statins.
• The safety profile of the “inclisiran first” strategy was similar with usual care, except for injection-site treatment emergent adverse events (TEAEs).

Conclusion

Results of the VICTORION-INITIATE study showed that LDL-c lowering with the “inclisiran first” strategy resulted in a sustained LDL-c lowering with most ASCVD patients reaching their LDL-c goals at day 330. In contrast, in the usual care group in which physicians were given access to patients’ LDL-c levels and encouraged to treat according to lipid management guidelines, few patients achieved LDL-c goals.

These findings demonstrate the clinical value of initiating inclisiran earlier in the treatment pathway and highlight the urgent need to improve usual care for US patients with ASCVD, according to Michael Koren.

- Our reporting is based on the information provided at the ACC.24 Scientific Session -

The findings of this study were simultaneously published in J Am Coll Cardiol