Discussion

In this analysis, earlier addition of inclisiran to statin therapy in Aboriginal and Torres Strait Islander Australians with established CVD and hypercholesterolaemia was projected to prevent 6401 non-fatal cardiovascular events and gain 23,730 QALYs over 25 years, with an ICER of AUD48,808/QALY. These findings suggest that earlier access to inclisiran may represent a clinically meaningful and potentially cost-effective strategy in a population with substantial unmet cardiovascular need.

With Australian healthcare expenditure rising due to increasing age, frailty, comorbidities and complexity of care, cost-effective interventions have never been more important. Targeting therapies toward populations at highest absolute cardiovascular risk may improve both clinical benefit and economic efficiency [18].

Inclisiran has demonstrated LDL-C lowering efficacy with a favourable tolerability profile in clinical trials and real-world studies to date [4,8,9]. However, its integration into routine practice remains influenced by two key considerations. Firstly, despite patient-level pooled analyses of the ORION-9/10/11 trials trend towards MACE reduction, no long-term dedicated MACE-specific outcomes data exist. Cost-effectiveness analyses published in the literature to-date, use pooled CVD outcome data from the above trials [6,14,[19], [20], [21]]. The pending ORION-4 and VICTORION-2P trials aim to provide these data. Secondly, inclisiran remains a high-cost intervention costing over 40 times more than statins in some cases. Drug acquisition cost is a major determinant of cost-effectiveness, as reflected in prior international evaluations reporting ICERs of USD 157,000/QALY and EUR 72,239/QALY in US and Irish settings, respectively [19,22].

To our knowledge, the only prior Australian cost-effectiveness analysis of inclisiran was reported by Kam et al. using a similar Markov framework [14]. That study did not specifically examine Aboriginal and Torres Strait Islander Australians. Their higher ICER (AUD 125,732/QALY) compared with our findings may reflect differences in baseline cardiovascular risk, population selection, model assumptions, and outcome metrics. Our results support the broader principle that interventions may appear more cost-effective when targeted to populations at higher absolute cardiovascular risk. Apart from our study, up to early 2025 only one study concluded that inclisiran was cost-effective. The UK's National Institute for Health and Care Excellence (NICE) calculated an ICER of <£20,000/QALY. Critically, however, the cost of inclisiran was reduced for this assessment but was not disclosed [20]. Fundamentally, the price of inclisiran would appear to highly elastic, and directly proportional to cost-effectiveness.

Furthermore, our modelling, as has other global models, demonstrates the that earlier inclisiran use, and over longer durations, improves its’ clinical benefit and cost-efficacy [17].

Inclisiran also has practical characteristics that may differentiate it from oral lipid-lowering therapies, particularly its twice-yearly administration by healthcare professionals. This schedule may offer opportunities to integrate treatment delivery with structured secondary prevention follow-up, medication review, and cardiovascular risk reassessment, a concept explored by Nelson et al. [21]. imilar service models have been explored in other chronic disease programs for geographically dispersed and high-risk populations. Whether such approaches improve adherence, persistence, or outcomes in Aboriginal and Torres Strait Islander Australians requires prospective evaluation.

Potential implementation framework could include culturally safe identification of eligible patients during hospitalisation or outpatient review [23], linkage to follow-up registries, optimisation of secondary prevention therapies, and coordinated recall systems including automated messaging and/or transport assistance for 6-monthly review and inclisiran administration [23,24] Partnerships with Aboriginal Community Controlled Health Organisations may be particularly important to maximise accessibility, continuity, and culturally responsive care [23,24]. Furthermore, regular practitioner visitations allow for assessment of ongoing CVD risk and aggressive risk factor modification [25,26]. In rural and remote settings, expanded access pathways may further improve equitable service delivery [27]. These strategies are currently hypothetical and should be tested in implementation studies before wider adoption.

Equity and clinical need are also considered by the PBAC in funding decisions [4]. How health equity gains should be incorporated within conventional willingness-to-pay frameworks remains uncertain and warrants further policy and methodological work. Equity-weighting frameworks propose that health gains achieved in disadvantaged populations may warrant greater societal value. Consequently, interventions with ICERs close to conventional willingness-to-pay thresholds may be viewed more favourably when targeted toward Aboriginal and Torres Strait Islander Australians. Given the disproportionate CVD burden that Aboriginal and Torres Strait Islander Australians carry, and the structural barriers to healthcare that exists in the Australian system preventing equal healthcare use and access [23], there is clinical need for equitable solutions. These findings suggest that, under certain willingness-to-pay thresholds, inclisiran may represent a potentially equitable and clinically effective addition to secondary prevention strategies. However, reimbursement decisions would also require consideration of affordability, budget impact, feasibility, and competing priorities.

This study has several strengths, including use of the best available Australian epidemiological data, transparent modelling assumptions, and a focus on a population with substantial unmet cardiovascular need. Nevertheless, several limitations should be acknowledged. No real-world data currently exist regarding inclisiran uptake, adherence, or effectiveness in Aboriginal and Torres Strait Islander Australians. By assuming equal adherence across treatment arms, the model intentionally isolated pharmacological treatment effects; however, the twice-yearly administration of inclisiran may improve treatment persistence relative to daily oral therapies, potentially underestimating its real-world effectiveness and cost-effectiveness. Long-term cardiovascular outcomes were extrapolated from pooled ORION-9/10/11 trial data in a different population and should therefore be interpreted as modelled rather than observed outcomes. As with all Markov models, simplification of clinical pathways and the memoryless structure may not fully capture recurrent risk trajectories over time. Although deterministic and broader scenario analyses explored uncertainty in key model inputs, probabilistic sensitivity analysis could not be performed because robust parameter uncertainty estimates were unavailable. This is particularly relevant given the base-case ICER lies close to commonly cited Australian willingness-to-pay thresholds, meaning relatively small changes in key assumptions may influence conclusions regarding cost-effectiveness. Accordingly, these findings should be interpreted as exploratory until future studies incorporating robust parameter distributions, population-specific transition probabilities and utility estimates, and dedicated cardiovascular outcomes data permit formal probabilistic sensitivity analysis and more definitive economic evaluation.