"Inclisiran First" Strategy Leads to 60% Reduction in LDL-C vs 7% for Usual Care: VICTORION-INITIATE Findings

Michael J Koren, MD

A pragmatic study that used an “inclisiran first” strategy for treatment of adults with atherosclerotic cardiovascular disease (ASCVD) not at LDL-C goal despite maximally tolerated statin therapy found that immediate addition of inclisiran led to a 60% reduction in LDL-C from study baseline to day 330 vs a reduction of 7% observed among study participants treated with usual care.¹

These findings from the VICTORIAN-INITIATE randomized trial were announced at a late breaking clinical trial session at the American College of Cardiology Annual Scientific Sessions on Saturday, April 6, 2024, in Atlanta, GA. Lead and presenting author Michael Koren, MD, CEO of ENCORE Research Group in Jacksonville, FL, also reported that study participants in the inclisiran first group were 4 to 8 times more likely to reach guideline recommended LDL-C targets at the end of the study than those treated with usual care.

“What we were asking in this study was how can we do better in treating cholesterol issues in people that have cardiovascular disease?” said Koren in an interview with Patient Care. “The sad reality is that only 2% of our patients who have cardiovascular disease actually get to their LDL goals.” The reasons, according to Koren and colleagues, are many and include nonadherence to medication, clinical inertia, and also poor access to therapy. Inclisiran, a small-interfering RNA molecule, is dosed twice yearly and has been shown to reduced LDL-C by an additional ~50% when added to background lipid-lowering therapy. The “simplified” semi-annual treatment implementation may also support reaching LDL-C goals, wrote authors in the study abstract. 

VICTORIAN-INITIATE was a phase 3b prospective, randomized, open label trial to evaluate the effect on LDL-C lowering of initiating treatment with twice-yearly inclisiran in addition to usual care compared to usual care alone, usual care being defined as any lipid-lowering therapy prescribed or titrated at a treating physician’s discretion. Participants had prior ASCVD and LDL-C of 70 mg/dL or greater on maximal statin therapy or were statin intolerant. They were randomly assigned in a 1:1 ratio to inclisiran 284 mg at study days 0, 90, and 270 plus usual care or usual care alone. The study’s primary endpoints were change in LDL-C from baseline to day 330 and statin discontinuation, defined as no statin use for 30 days or more before the end of the study (noninferiority margin of 15%).

The study cohort numbered 450 participants with a median age of 67 years; 30.9% were women, 12.4% were Black, and 15.3% were Hispanic. Prior or current ASCVD included coronary heart disease, reported by 91.8%, cerebrovascular disease by 18.2%, and peripheral artery disease by 14.7%.

RESULTS

Koren and colleagues reported, as above, that the strategy of initiating inclisiran immediately when it is clear that statin therapy alone is inadequate to reach LDL-C targets led to a significantly greater mean LDL-C reduction from baseline to day 330 than a usual care approach (P <.001). V-INITIATE was an open label study, Koren said in the interview. “So even though we randomized patients to reduce any selection biases, we actually wanted to observe the effect of bias in the system; we wanted to see whether or not this structured approach of implementing this product would make a difference in terms of people getting to their goals.” He added that when there is a plan “to get a very effective therapy to patients sooner in the pathway, it makes a huge difference in the first year.”

“So even though we randomized patients to reduce any selection biases, we actually wanted to observe the effect of bias in the system; we wanted to see whether or not this structured approach of implementing this product would make a difference in terms of people getting to their goals.”

Speaking about the second primary endpoint – statin discontinuation – Koren said the findings were different from what they had anticipated “but really fascinating” They had thought that if someone is taking a new drug that is highly effective, the inclination might be to stop taking their statin medication. What they found was an opposite effect. There was no statistical difference between the proportion of participants in either group that discontinued statin therapy 30 days or more before the end of the study period. However, Koren explained, “numerically more people in the usual care arm stopped their statins than in the inclisiran group. The actual numbers were that in the usual care arm 16.7% of all participants who were on statins at the start, stopped them. In the inclisiran first arm, just 6% stopped their statins.” And that’s what was surprising about the outcome, he said.

It's likely that the effects of the clinical trial structure led to better adherence than is typically seen in the real world, Koren observed. “I think if it wasn't a clinical trial, the dropout rate would be more than 16.7% in the usual care group. I think just an unfortunate reality of what happens in our usual clinical care settings.”

According to the study abstract, treatment-emergent adverse event (TEAE) and serious TEAE rates were similar for inclisiran first (62.8% and 11.5%) and usual care (53.7% and 13.4%). TEAEs leading to study drug withdrawal occurred in 6 (2.6%) and 0 pts for inclisiran first and usual care, respectively.

“What we're finding here is that instead of just trusting ‘usual care,’ we should be putting systems in place that structure our approach” to lowering LDL-C, so people are treated more aggressively, earlier in the process,” Koren said concluding the interview. “And that's the key

take home message for clinicians.”

Source: Comparison of an "inclisiran first" strategy with usual care in patients with atherosclerotic cardiovascular disease: results from the VICTORIAN-INITIATE randomized trial. Abstract presented at: American College of Cardiology 73rd Scientific Sessions; April 6-8, 2024; Atlanta, GA.