‘Inclisiran first’ strategy in ASCVD reduces LDL-C

Among patients with atherosclerotic cardiovascular disease (ASCVD) who fail to achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals despite receiving maximally tolerated statins, initiating inclisiran immediately resulted in significant reductions in LDL-C, according to the VICTORION-INITIATE trial presented at ACC.24.

“Studies have shown that twice-yearly inclisiran, administered by a healthcare provider, lowers LDL-C by approximately 50 percent, with most patients achieving their LDL-C goal,” said lead author Dr Michael Koren from Jacksonville Center for Clinical Research, Jacksonville, Florida, US.

Hence, using an “inclisiran first” implementation strategy, Koren and his team sought to determine whether the efficacy of twice-yearly inclisiran could be translated to US clinical settings that reflect “real-world” practice.

The “inclisiran first” implementation strategy refers to adding inclisiran immediately upon failure to reach LDL-C <70 mg/dL on maximally tolerated statins among ASCVD patients. [J Am Coll Cardiol 2024:doi.org/10.1016/j.jacc.2024.03.382]

The researchers conducted a phase IIIb, prospective, open-label, pragmatically designed trial, involving 450 patients (median age 67 years, 30.9 percent female) with ASCVD and LDL-C ≥70 mg/dL on maximally tolerated statin therapy recruited from 45 sites in the US. Participants were randomized in a 1:1 ratio to receive inclisiran 284 mg at days 0, 90, and 270 ("inclisiran first" strategy) plus usual care (any LLT* directed/titrated at the treating physician’s discretion) or usual care alone.

At day 330 or end-of-study (EOS) visit, LDL-C level was significantly reduced by 60 percent from baseline with the “inclisiran first” strategy compared with 7 percent with usual care alone (least squares mean difference, -53 percent; p<0.001). [ACC.24, Featured Clinical Research I]

Among patients without a history of statin intolerance, those in the "inclisiran first" group were less likely to discontinue their statins ≥30 days before the EOS visit, a coprimary endpoint, compared with those receiving usual care alone (6 percent vs 16.7 percent; treatment difference, ‒10.6 percent, 97.5 percent confidence interval, -18.3 to -3.0), which met the noninferiority margin of 15 percent, Koren noted.

In addition, the percentage of patients who achieved an LDL-C goal of <70 mg/dL was higher in the "inclisiran first" group compared with the usual care group (71.6 percent compared to 8.9 percent). More patients in the "inclisiran first" group also attained an LDL-C goal of <55 mg/dL (71.6 percent vs 8.9 percent).

In terms of safety, the rates of treatment-emergent adverse events (TEAEs) and serious TEAE were comparable between the two groups, said Koren. However, injection site reactions occurred more frequently in the “inclisiran first” group, whereas none were reported in the usual care group.

“Nevertheless, no new safety concerns have been identified with twice-yearly inclisiran administration in a real-world clinical setting,” Koren noted.

“Overall, LDL-C lowering with the “inclisiran first” strategy led to sustained LDL-C lowering, consistent with prior clinical studies of inclisiran, … [which resulted in] most patients with ASCVD reaching LDL-C goals at day 330,” he said.

“VICTORION-INITIATE study [results] 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,” Koren added.