For decades, prevention in Coronary Artery Disease has hinged on risk calculators, lipids, and lifestyle. While these pillars remain fundamental, the field increasingly asks whether earlier anatomic and biologic evidence of plaque can fine-tune who benefits from intensive therapy. In this context, the VICTORION-PLAQUE randomized clinical trial design foregrounds plaque imaging as a decision-relevant signal in Primary Prevention. Inclisiran, a small interfering RNA that silences hepatic PCSK9 production, offers durable LDL Cholesterol reduction with twice-yearly maintenance dosing, making it an archetypal candidate for long-horizon risk modification. The strategic question is whether modifying lipids early translates into measurable changes in Atherosclerosis before clinical events occur.

LDL particles penetrate the arterial intima, become retained, and trigger inflammatory cascades that drive plaque growth and vulnerability. PCSK9 enhances LDL receptor degradation; inhibiting it increases hepatic LDL receptor recycling and accelerates LDL clearance. Monoclonal antibodies validated the pathway for secondary prevention and high-risk primary prevention, while inclisiran extends the same biology via RNA interference with infrequent dosing. By targeting PCSK9 synthesis rather than circulating PCSK9 protein, inclisiran achieves sustained receptor upregulation over months. That durability aligns with the slow kinetics of plaque biology, where structural change unfolds over quarters to years and intermittent measurement can still capture meaningful trajectories.

LDL-C is an outstanding causal biomarker, but it is a step removed from arterial wall biology. Imaging-derived plaque metrics offer a tangible complement: they quantify burden and, in some modalities, composition and surface characteristics. When used judiciously, these readouts can reduce uncertainty around who has biologically active disease despite acceptable lab profiles, or who might require intensified therapy even without ischemia. The central premise is that the artery wall is the stage on which risk accrues; by watching that stage directly, clinicians may refine decisions without waiting for events. Importantly, the field continues to interrogate which plaque markers best predict outcomes and how much change is clinically meaningful.

Noninvasive modalities each capture different aspects of plaque. Coronary computed tomography angiography can quantify stenosis severity, nonobstructive plaque burden, and specific high-risk features such as low attenuation or positive remodeling. Vascular ultrasound can follow intima-media thickness, focal plaque presence, and, in some protocols, echogenicity surrogates of composition. While differing in cost, radiation, and accessibility, both are deployable in subclinical populations and are well suited to longitudinal follow-up. A trial like VICTORION-PLAQUE leverages these strengths by focusing on reproducible measures of Plaque Burden and, where feasible, composition, to serve as surrogate endpoints of therapeutic effect. Such endpoints have face validity and growing empirical support, but still require careful interpretation alongside clinical outcomes evidence.

The VICTORION-PLAQUE primary prevention trial is notable for its enrollment of individuals without a prior cardiovascular event and with no flow-limiting lesions identified during in-hospital screening. That design isolates a population where baseline risk is often underestimated and where anatomic signal can meaningfully alter management. Participants are randomized to inclisiran or usual care background therapy, and followed with standardized imaging to track plaque evolution over time. This approach is well aligned with the mechanism and dosing cadence of inclisiran, which is administered with an initial series followed by maintenance doses at extended intervals. By embedding imaging into the protocol, the trial aspires to show that lowering LDL-C early can shift arterial trajectories before symptoms or ischemia emerge.

Eligible participants represent a pragmatic cross-section of asymptomatic adults identified through hospital-based screening with evidence of atherosclerotic plaque but without flow-limiting stenoses. Randomization balances conventional risk factors and background preventive therapies to reduce confounding. The intervention strategy centers on inclisiran, leveraging its siRNA mechanism to provide durable LDL-C lowering with infrequent dosing, a practical advantage for long-term adherence in real-world settings. Comparator care continues to reflect guideline-directed prevention, including statins as appropriate, ensuring the question pertains to incremental benefit rather than substitution. Such a pragmatic frame improves interpretability and potential applicability of imaging changes to routine practice.

Primary and key secondary endpoints focus on reproducible, quantitative changes in plaque burden and, where available, features associated with vulnerability. Serial imaging allows assessment of within-person change, which generally requires smaller samples than hard clinical endpoints to demonstrate biologic effect. Though the precise schedule and modality mix are protocol-defined, noninvasive methods such as coronary CT angiography and vascular ultrasound are well matched to the subclinical profile of the cohort. The central analytic question is whether inclisiran shifts plaque trajectories relative to comparator, and whether those shifts track with anticipated LDL-C reductions. Positive signals would bolster the case for earlier intervention and set the stage for longer-term clinical outcomes follow-up.

Surrogate endpoints reduce sample size and duration, but they demand robust validation and transparent interpretation. Regulators generally expect biologic plausibility, consistent correlation with outcomes, and, ideally, randomized evidence linking surrogate change to event reduction under the same mechanism. In a field where LDL-C already meets causal and interventional criteria, plaque imaging can function as a mechanistic bridge that contextualizes early changes and supports health technology assessments. Trialists must predefine analysis plans, specify handling of missing imaging data, and guard against regression to the mean when serial measures are used. If outcomes are not captured, careful discussion is needed to avoid overstating what imaging alone can tell us about event risk.

Translating an imaging-centric design into clinical workflows requires attention to risk selection, logistics, cost, and equity. Not every primary prevention patient should be imaged, nor would broad imaging be feasible or value-adding. Instead, imaging can be positioned as a second-line risk clarifier in those with intermediate risk, discordant markers, or family history suggestive of elevated lifetime risk. By deploying imaging selectively, clinicians can reclassify risk for a subset and align therapy intensity with visible biology. These decisions must be paired with conversations about benefits, uncertainties, and preferences, given that some features of plaque carry nuanced implications for event risk and downstream management.

Traditional calculators average risk over populations; imaging personalizes it. Candidates for plaque imaging in primary prevention often include those with borderline or intermediate 10-year risk, younger individuals with strong family history, and patients with risk-enhancing factors such as metabolic syndrome where lifetime risk may be high. In these groups, visible plaque can recalibrate conversations around intensifying therapy, adding an agent like inclisiran, or prioritizing lifestyle change with measurable targets. The alignment with Risk Stratification frameworks is compelling: when biology and risk scores diverge, imaging can adjudicate. The VICTORION-PLAQUE design underscores how surrogate endpoints might ultimately support more granular recommendations in guidelines.

Prevention economics hinge on adherence and durability of effect. Twice-yearly maintenance dosing is a practical advantage of inclisiran, potentially addressing nonadherence that erodes effectiveness of more frequent regimens. From a payer perspective, an imaging-derived demonstration of slowed plaque progression can strengthen the value proposition by linking cost to biologic benefit. That said, any expansion of imaging should be evaluated for downstream utilization, including incidental findings and follow-on testing. Models that integrate drug costs, imaging cadence, and projected event reduction will be needed to determine cost-effectiveness across different baseline risk strata and health systems. Transparent assumptions and sensitivity analyses will be essential.

Operational feasibility matters. Coronary CT angiography is increasingly available, with improving protocols for radiation and contrast management, while vascular ultrasound remains widely accessible with low cost and no radiation. Standardization is crucial: reproducible acquisition protocols, centralized or rigorously trained readers, and consistent software are necessary to detect modest changes over time. Scheduling cadence must balance sensitivity to change with patient burden; for many endpoints, annual or multi-year intervals are reasonable. Ultimately, a learning health system approach can help institutions identify which modalities and schedules provide the most decision-relevant information for their populations. Local data, combined with trial insights, can guide scalable pathways.

Guideline committees and payers respond to converging signals from mechanistic biology, clinical outcomes, and practical utility. Imaging-based evidence of plaque modification adds weight to mechanistic plausibility, especially when aligned with LDL-C reductions known to reduce events in higher-risk settings. Over time, such data can inform coverage policies for therapies like inclisiran in specific subgroups, particularly when accompanied by structured pathways that ensure appropriate use. For clinicians, having both laboratory and anatomic targets can facilitate shared decision-making and documentable therapeutic goals. If VICTORION-PLAQUE demonstrates coherent, reproducible plaque benefits, it may accelerate a shift toward imaging-informed primary prevention strategies.

Methodologically, imaging-guided trials emphasize assay fidelity as much as pharmacology. Reliability, calibration drift, and inter-reader variability can dominate signal detection at the margins where early disease evolves. Protocols must specify image quality criteria, adjudication rules, and prespecified sensitivity analyses using different plaque definitions. Trials can also explore composite imaging endpoints that integrate burden and high-risk features, provided they are clinically interpretable. Importantly, imaging should be framed not as a replacement for outcomes, but as an acceleration tool that narrows uncertainty and guides which populations and regimens warrant larger outcomes trials.

Visualizing disease changes conversations. Showing a patient nonobstructive plaque on a scan can contextualize discussions about intensifying LDL-C lowering, adding a twice-yearly injection, or refining lifestyle targets. However, communication must avoid overstating certainty, particularly when discussing surrogate endpoints. Emphasizing that imaging reveals biology, while outcomes reflect lived risk over time, helps calibrate expectations. Shared decision aids that integrate images, risk trajectories, and therapy options can support understanding and adherence. Thoughtful communication is a clinical intervention in its own right.

Several questions follow naturally. Which imaging features most reliably forecast outcomes in asymptomatic populations, and what magnitude of change is clinically relevant? How do imaging-guided strategies perform across diverse groups, including those historically underrepresented in trials? Where does imaging add value beyond traditional markers like hsCRP, lipoprotein(a), and family history? Trials like VICTORION-PLAQUE can inform these questions by pairing biologic plausibility with practical endpoints and describing operational playbooks. They can also clarify how durable LDL-C lowering interacts with other risk-modifying therapies over the long term.

In sum, imaging-guided primary prevention is not a rejection of risk scores and lipids but an integration of anatomy and biology into a more precise approach. Inclisiran, by virtue of durable PCSK9 silencing and infrequent dosing, aligns with the slow timescale of atherosclerosis and the practicalities of real-world adherence. The VICTORION-PLAQUE design, accessible via https://pubmed.ncbi.nlm.nih.gov/40769373/, embodies this trajectory by using standardized imaging endpoints to infer near-term biologic benefit in a cohort without overt events. If serial noninvasive imaging demonstrates consistent plaque modification, early intervention strategies may become more justifiable for carefully selected patients. The field should pair such findings with outcomes data and thoughtful economic analyses to ensure that innovation translates into equitable, high-value prevention.