Introduction

Reducing inequities in cardiovascular outcomes remains a major public health priority. In Australia, the national Closing the Gap strategy seeks to eliminate disparities in life expectancy between Aboriginal and Torres Strait Islander Australians and non-Indigenous Australians [1]. Despite this commitment, Aboriginal and Torres Strait Islander Australians continue to experience a substantially higher burden of cardiovascular disease (CVD), with excess premature mortality, recurrent hospitalisation, disability, and healthcare expenditure [2]. CVD remains one of the leading contributors to the persistent life expectancy gap, highlighting the need for more effective and scalable preventive strategies.

Hypercholesterolaemia is a major modifiable driver of atherosclerotic cardiovascular disease (ASCVD). The Australian Institute of Health and Welfare has estimated that the population attributable fraction of hypercholesterolaemia to CVD risk among Aboriginal and Torres Strait Islander Australians is 29% [2]. Elevated low-density lipoprotein cholesterol (LDL-C) is causally associated with ASCVD, and extensive evidence demonstrates that lowering LDL-C proportionally reduces major adverse cardiovascular events [3]. Accordingly, contemporary international guidelines consistently recommend early and intensive LDL-C lowering, particularly in secondary prevention populations [3].

Although efficacious at reducing LDL-C and MACE, the utility of first-line lipid-lowering statins and second-line lipid-lowering Ezetimibe are impeded by adherence, pill-burden, adverse effects, clinical inertia and prescribing barriers [4]. Subsequently, many patients remain at-risk, particularly Aboriginal and Torres Strait Islander Australians who have well-defined decreased access to, and utilisation of, healthcare resources despite increased need driven by the social determinants of health [5].

Inclisiran, a Proprotein Convertase Subtilisin–kexin Type 9 (PCSK9) Small-interfering Ribonucleic Acid (siRNA), offers rapid, safe, durable and tolerable LDL-C reduction [6]. The recent VICTORION-INITIATE trial demonstrated improved LDL-C therapeutic goal attainment and lower risk of MACE with earlier inclisiran initiation [7]. A further unique differentiatior over other lipid-lowering therapies is its’ 6-monthly dosing, which reduces pill-burden, improves adherence and reduces clinical inertia to LDL-C lowering in real-world studies which may ultimately reduce MACE [4,8]. Whilst subsidised by the Australian governments Pharmaceutical Benefits Advisory Committee (PBAC) for patients with CVD and hypercholesterolaemia, inclisiran remains distant third-line lipid-lowering therapy subject to meeting multiple onerous strict criteria thereby limiting access for high-risk patients who may derive the greatest absolute benefit (Table 1) [9].

Current PBS indications for Inclisiran | Our proposed strategy for Inclisiran
Symptomatic CVD AND trialled diet/exercise AND trialled high-dose Statin for 3 months (or developed intolerance) AND trialled Ezetimibe for 3 months (or developed intolerance) AND have either:•Atherosclerotic-CVD in >2 vascular territories OR•2 CVD events in the last 5 years OR•Diabetes with microalbuminuria OR•Diabetes and >60 years old OR•Aboriginal and Torres Strait Islander Australian with diabetes OR•TIMI (thrombolysis in Myocardial Infarction) score of >4AND LDL-C still >1.8 mmol/L | Early, first-line with standard Statin therapy IF:Aboriginal and Torres Strait Islander Australian AND diagnosed with atherosclerotic CVD AND LDL-C >1.8 mmol/L

Whether earlier use of inclisiran could represent a clinically effective and economically efficient strategy for populations with disproportionate cardiovascular risk remains unknown. We therefore evaluated the cost-effectiveness of early addition of inclisiran to statin therapy for secondary prevention in Aboriginal and Torres Strait Islander Australians with established CVD and hypercholesterolaemia, using a long-term Markov model from the Australian healthcare system perspective. We hypothesised that an earlier, equity-focused treatment strategy may reduce cardiovascular burden and provide value-based guidance for future preventive cardiology policy.