Using a Markov Model and Real-World Evidence to Identify the Most Cost-Effective Cholesterol Treatment Escalation Threshold for the Secondary Prevention of Cardiovascular Disease

Alfredo Mariani (), Syed Mohiuddin, Patrick Muller, Eleanor Samarasekera, Sharon A. Swain, Joseph Mills, Riyaz Patel, David Preiss, Eduard Shantsila, Beatrice C. Downing, Michael Lonergan, Shaun Rowark, Nicky J. Welton, Rachael Williams and David Wonderling
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Alfredo Mariani: National Institute for Health and Care Excellence
Syed Mohiuddin: National Institute for Health and Care Excellence
Patrick Muller: National Institute for Health and Care Excellence
Eleanor Samarasekera: National Institute for Health and Care Excellence
Sharon A. Swain: National Institute for Health and Care Excellence
Joseph Mills: Liverpool Heart and Chest Hospital
Riyaz Patel: Barts Health NHS Trust, University College London Hospitals NHS Foundation Trust
David Preiss: University of Oxford
Eduard Shantsila: University of Liverpool
Beatrice C. Downing: University of Bristol
Michael Lonergan: Medicines and Healthcare Products Regulatory Agency
Shaun Rowark: National Institute for Health and Care Excellence
Nicky J. Welton: University of Bristol
Rachael Williams: Medicines and Healthcare Products Regulatory Agency
David Wonderling: National Institute for Health and Care Excellence

Applied Health Economics and Health Policy, 2025, vol. 23, issue 5, No 9, 869-883

Abstract: Abstract Background Despite the decreased risk of cardiovascular disease (CVD) with statins, there remains an unfulfilled clinical need to prevent CVD events and premature mortality through further cholesterol-modifying interventions. In people with established CVD taking a statin, lipid therapy escalation to reduce low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) levels may lower the risk of CVD hospital admissions and improve survival. However, the cost-effectiveness of different cholesterol treatment escalation thresholds is uncertain. Objective This study aimed to identify the most cost-effective cholesterol threshold for escalating lipid therapy in people with established CVD who are taking a statin, to support the 2023 update of the NICE guideline on CVD in England. Methods A cohort Markov model with a yearly cycle length was developed to compare the lifetime costs and quality-adjusted life years (QALYs) of various LDL-C treatment escalation thresholds (0–4.0 mmol/L), using a combination of treatment effects from an original network meta-analysis of randomised controlled trials (RCTs), real-world data for estimating baseline cholesterol levels and CVD event rates from a published meta-analysis of statin RCTs. The model used the following CVD events: ischaemic stroke; transient ischaemic attack; peripheral artery disease; myocardial infarction; unstable angina; coronary revascularisation; and mortality. The model also used evidence-based estimates of resource use and costs, and published quality of life data. Baseline LDL-C levels and CVD hospital admission rates were estimated through a bespoke analysis of the English primary care data from Clinical Practice Research Datalink (CPRD), linked to Hospital Episode Statistics Admitted Patient Care (HES) and Office for National Statistics (ONS) death registrations. Results Data from 590,917 adult individuals (61.7% men) with CVD on a statin in primary care between 1 January 2013 and 28 February 2020 were included in the CPRD-HES-ONS analysis. The most cost-effective threshold for lipid therapy escalation was an LDL-C of 2.2 mmol/L (or equivalent non-HDL-C of 2.9 mmol/L) at NICE’s lower cost per QALY of £20,000. An LDL-C of 2.0 mmol/L (or equivalent non-HDL-C of 2.6 mmol/L) was the most cost-effective treatment escalation threshold in a significant proportion (38%) of probabilistic simulations and produced more health. At this threshold, the model predicted that 42% of people with CVD would require combination therapy with ezetimibe while 19% would require an injectable drug such as inclisiran. At NICE’s upper cost per QALY of £30,000, the most cost-effective LDL-C treatment escalation threshold was 1.7 mmol/L (or equivalent non-HDL-C of 2.2 mmol/L). Conclusions The results demonstrate the importance of establishing evidence of cost-effectiveness for cholesterol treatment escalation thresholds. The study’s findings support the updated NICE guideline recommending a threshold of 2.0 mmol/L LDL-C (or equivalent non-HDL-C of 2.6 mmol/L) for secondary prevention of CVD.

Date: 2025
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DOI: 10.1007/s40258-025-00977-6

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