‘Inclisiran-first’ strategy yields greater LDL reductions vs. usual care for patients with CVD
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Key takeaways:
- For patients who could not achieve their LDL goal on statins alone, an inclisiran-first strategy lowered LDL more than usual care.
- The inclisiran-first strategy did not cause more statin discontinuations.
ATLANTA — For patients with atherosclerotic CVD, an inclisiran-first strategy was associated with greater lowering of LDL compared with the usual care, researchers reported at the American College of Cardiology Scientific Session.
The inclisiran-first strategy involves adding inclisiran (Leqvio, Novartis), a small interfering RNA PCSK9 inhibitor, immediately after a patient is unable to reach an LDL goal of less than 70 mg/dL despite maximally tolerated statin therapy, Michael J. Koren, MD, CEO and director of the Jacksonville Center for Clinical Research, said during a presentation.
For the pragmatic VICTORION-INITIATE trial, Koren and colleagues randomly assigned 450 patients (median age, 67 years; 31% women; 12% Black; mean LDL at baseline, 97.4 mg/dL) with ASCVD and LDL greater than 70 mg/dL despite maximally tolerated statin therapy to the inclisiran-first strategy. Per the strategy, inclisiran 284 mg was administered at days 0, 90 and 270, plus usual care based on lipid management at the discretion of the treating physician, or usual care alone. The results were simultaneously published in the Journal of the American College of Cardiology.
“Extensive evidence supports intensive LDL lowering in patients with ASCVD,” Koren said here. “Unfortunately, most of these patients in the U.S. don’t achieve LDL goals for reasons such as clinical inertia, medication nonadherence, side effects and/or poor health care access. We evaluated an inclisiran-first implementation strategy ... to ascertain if the unique properties of the drug would translate to U.S. clinical settings that were reflective of normal practice.”
The primary outcomes were percentage change in LDL and statin discontinuation from baseline to day 330.
One-quarter of patients reported a history of statin intolerance, 90% were taking statins at baseline (88.9% statin monotherapy) and of the 45 patients not on statins, all but one were not taking any lipid-lowering therapy. In addition, 91.8% had prior or current CHD and the rest had cerebrovascular disease or peripheral artery disease.
The mean LDL percentage change from baseline to day 330 was –60% (97.5% CI, –64.7 to –55.2) in the inclisiran-first group and –7% (97.5% CI, –12 to –1.9) in the usual care group (between-group difference, –53 percentage points; 97.5% CI, 60 to 46; P < .001), the researchers reported.
Among the patients with no history of statin intolerance, statin discontinuation rates were 6% in the inclisiran-first group and 16.7% in the usual care group, meeting the prespecified noninferiority margin of 15% (–10.6%; 97.5% CI, –18.3 to –3), Koren said during the presentation.
The results were consistent across all prespecified subgroups, he said.
Rates of treatment-emergent adverse events were similar (inclisiran-first, 62.8%; usual care, 53.7%), as were rates of serious treatment-emergent adverse events (11.5% and 13.4%, respectively).
“The inclisiran-first strategy led to sustained LDL lowering consistent with prior studies of inclisiran,” Koren said. “Most patients with ASCVD reached their LDL goal by day 330. Despite the study giving treating physicians access to LDL levels and encouraging concordance with the management guidelines, few patients in the usual care arm reached guideline-recommended LDL goals. No new safety concerns were identified. The results of the VICTORION-INITIATE study demonstrate the clinical value of initiating inclisiran earlier in the treatment pathway and the urgent need to improve usual care of patients in the U.S. with ASCVD.”
Reference:
Perspective
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Alexander J. Blood, MD, MSc, FACC
This was an interesting, well-done implementation study. It demonstrated that an inclisiran-first strategy significantly improves LDL control compared with standard of care, even in a situation where patients and providers were notified that they were under observation. This hearkens back to the notion of “strike while the iron is hot.” If you know a patient is interested and motivated, getting them to target is much more likely to be effective by using inclisiran up front, with other therapies in concert, as opposed to a more wait-and-watch kind of strategy. The researchers showed over a relatively long follow-up that the control arm did not significantly intensify therapy, even with much cheaper options.
A criticism is that the study drug was provided for free. That does not exactly replicate real-world practice, where there are significant prior authorization and cost barriers for many patients. However, if you look at the outcomes and think about the value-based world to which many think that we are shifting, especially in high-risk patients, this could make a significant difference in reducing the incidence of recurrent events through better LDL control. It should be considered in statin-intolerant patients or in patients for whom some of these therapies are not as easy to access.
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Koren MJ, et al. Featured clinical research I. Presented at: American College of Cardiology Scientific Session; April 6-8, 2024; Atlanta.
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