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Cholesterol lowering with a strategy using the short interfering RNA agent, inclisiran, earlier in the treatment pathway led to significantly better long-term low-density lipoprotein (LDL) reduction compared with usual care in patients with atherosclerotic cardiovascular disease (ASCVD), in a new "real world" study.

While most patients in the "inclisiran first" arm reached LDL goals at day 330, few patients in the usual care arm achieved these goals.

"Results from 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," lead author Michael J. Koren, MD, concluded.

Koren, medical director and CEO of the Jacksonville Center for Clinical Research, Jacksonville, Florida, presented the study on April 6 at the recent 2024 American College of Cardiology's Annual Scientific Session. It was simultaneously published in the Journal of the American College of Cardiology.

Discussant of the study at the ACC meeting, Jorge Plutzky, MD, director of preventive cardiology at Brigham and Women's Hospital, Boston, Massachusetts, called this "an important study that provides another important example of stunning under-treatment of high-risk patients and coupled that with a really innovative approach."

"We are excited to have this new approach available, which is currently very underutilized but can have such an important impact."

In his presentation, Koren noted that extensive evidence supports intensive LDL lowering to improve cardiovascular outcomes in patients with ASCVD, and guidelines recommend LDL goals of < 55 mg/dL or < 70 mg/dL, depending on individual risk. However, most US patients with ASCVD fail to achieve these goals due to factors such as clinical inertia, medication nonadherence and side effects, and/or poor healthcare access.

Inclisiran, which inhibits hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) production and increases LDL receptor expression and LDL cholesterol (LDL-C) clearance, has been shown to lower LDL by around 50% with a twice-yearly subcutaneous dosing schedule.

The VICTORION-INITIATE study compared an inclisiran first strategy, adding inclisiran immediately if patients fail to reach LDL-C < 70 mg/dL despite receiving maximally tolerated statins, to usual care in patients with ASCVD in representative US clinical settings.

The study involved 450 patients with a history of ASCVD and with LDL > 70 mg/dL or non-high-density lipoprotein cholesterol > 100 mg/dL and fasting triglycerides < 500 mg/dL who were receiving maximally tolerated statin therapy or had documented statin intolerance.

Patients had a median age in the mid-to-upper 60s, 30% were female, 12%-14% were African American, 14%-17% were Latino, and 25% had a history of statin intolerance. The mean LDL at baseline was 97 mg/dL.

Managing physicians provided lab/lipid results and were encouraged to follow AHA/ACC guidelines and add therapies at their discretion.

Results showed that at day 330, the mean change in LDL from baseline was −60.0% with the inclisiran first strategy compared with −7.0% with usual care (P < .001).

The strategy of inclisiran first was not inferior to usual care in terms of statin discontinuation. In fact, inclisiran first patients were less likely to discontinue statins (6% vs 16.7% in the usual care arm).

At day 330, a significantly greater proportion of patients in the inclisiran first arm achieved LDL goals of < 70 mg/dL (81.8% vs 22.2%) or < 55 mg/dL (71.6% vs 8.9%) compared with the usual care arm.

Changes in background therapy showed that 88.4% of patients in the inclisiran first group and 73.4% of those in the usual care group were on statins as the only background therapy at day 330.

"While we didn't expect to see many changes in background therapy in the inclisiran first arm, we did expect to see some action on additional therapies in the usual care arm, but unfortunately, there was very little action in this regard, with advancement in therapy rarely used in the usual care group," Koren noted.

Only 12.6% of patients in the usual care group received statins in combination with ezetimibe, anti-PCSK9 monoclonal antibodies (Mabs), and/or bempedoic acid, and only 2.5% received a PCSK9 MAb without concomitant statins.

The only difference in adverse events was injection site reactions, with six patients stopping therapy with inclisiran because of injection site reactions vs none in the control group.

Koren pointed out that the study was designed to more accurately represent the general US population, with real-world US clinical practice as a control comparator. But further analysis was required to establish whether the lack of lipid therapy use and intensification in the usual care arm reflected an inadequately resourced population with limited access to non-statin therapy.

"The usual care arm in this study is not necessarily a best practice arm, but it shows what is actually happening," he said.

The study design permitted the use of inclisiran in the usual care arm leading to 10 patients in the usual care arm receiving inclisiran, which may have underestimated the effect of the "inclisiran-first" strategy.

Koren noted that inclisiran had a high compliance rate as it was driven by healthcare providers, so the doses were scheduled at day 1 and day 90 and then 6 months thereafter.

He said an important message from the study was: "We need to do a better job as clinical cardiologists in explaining to patients the urgency of getting their LDL down to target levels."

He pointed out that at least 80% of the patients in this study would fall into the category of very high risk, with a target LDL of < 55 mg/dL, but they started out with average LDL levels at 97 mg/dL.

"So, there is a lot of work to be done," he said. "We need to be more aggressive with patients, and we are being kind when we tell them that they need to take additional medications and work on their diet."

Plutsky suggested that inclisiran could be started even earlier — straight after the event. "So, we could know when we are discharging a patient that going forward, their LDL is going to come under control rather than just hoping that another therapy will be added down the line."

He added that this "would be such an opportunity to be able to initiate this treatment earlier and not wait for worse outcomes."

The VICTORION-INITIATE study was funded by Novartis. Koren is an employee of a company that received fees for his participation in the VICTORION-INITIATE trial and that has received study grants and consulting fees from multiple manufacturers of PCSK9 inhibitors and other treatments for lipid disorders.