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Novel AI algorithm could help personalise the prevention of cardiovascular disease

Causal AI presented in a Hot Line Session today at ESC Congress 2022

e-Cardiology and Digital Health

Barcelona, Spain – 28 Aug 2022: A novel artificial intelligence (AI) algorithm accurately estimates the risk of heart disease caused by cumulative exposure to cholesterol and blood pressure levels and the benefits of lowering both – thus providing the essential information needed to make individual treatment decisions. The late breaking research is presented in a Hot Line session today at ESC Congress 2022.1

“This study shows for the first time how to embed the causal effects of low-density lipoprotein (LDL) cholesterol and systolic blood pressure (SBP) into AI algorithms,” said principal investigator Professor Brian Ference of the University of Cambridge, UK. “These algorithms could be used to inform decisions for individual patients on the optimal timing, intensity and duration of LDL and SBP lowering to most effectively prevent atherosclerotic cardiovascular events.”

Atherosclerotic cardiovascular disease is a chronic progressive disease that begins early in life and slowly progresses over time. Randomised trials have demonstrated that lowering LDL and SBP reduces the risk of atherosclerotic cardiovascular events.2,3 However, Mendelian randomisation studies show that lifelong exposure to lower LDL and SBP is associated with much larger reductions in the risk of cardiovascular events compared to the reductions observed in randomised trials from lowering LDL and SBP starting later in life.4-6 This suggests that lowering LDL and SBP earlier in life may substantially improve the prevention of cardiovascular disease. However, the optimal timing, duration and intensity of LDL and SBP lowering to prevent cardiovascular events is unknown.

Clinicians use risk estimating algorithms to select persons with an elevated likelihood of heart disease who may benefit from therapy. However, these algorithms do not include the effects of LDL and SBP observed in randomised trials or Mendelian randomisation studies and thus may not capture the true benefit of lowering LDL or SBP. Therefore, the objectives of this study were twofold. First, to evaluate whether current risk scores accurately estimate the baseline risk of cardiovascular events caused by LDL and SBP and the benefit of lowering LDL and SBP beginning at any age and extending for any duration. Second, to evaluate, using an AI algorithm, whether adding the causal effects of LDL and SBP more accurately estimates cardiovascular risk and benefit. 

The Causal AI algorithm was used to estimate the effects of LDL and SBP in discrete time units of exposure (conditional on previous exposure to reflect the biology of how atherosclerosis develops) among 1.8 million individuals, including 1,320,974 enrolled in Mendelian randomisation studies evaluating 140 variants associated with LDL and 202 variants associated with SBP, and 527,512 participants enrolled in 76 randomised trials evaluating LDL or SBP lowering therapies.

The accuracy of the Joint British Societies’ (JBS3) algorithm was evaluated, both alone and after adding Causal AI effects of LDL and SBP in: 1) an independent sample of 445,771 participants in the UK Biobank to assess how well these algorithms estimated lifetime risk and benefit; and 2) 48,315 participants in LDL and SBP lowering trials7 to assess how well these algorithms estimated the short-term benefit of lowering LDL, SBP or both observed in the trials. The primary outcome was major coronary events (MCE), defined as the first occurrence of a fatal or nonfatal myocardial infarction, or coronary revascularisation. The secondary outcome was major cardiovascular events (MCVE), defined as the first occurrence of a major coronary event or nonfatal ischaemic stroke.

The study had three main findings. One, the JBS3 algorithm systematically underestimated the risk of MCE among persons with lifelong higher LDL, SBP or both; and systematically overestimated risk among those with lifelong exposure to lower LDL, SBP or both. Professor Ference said: “This finding explains why current risk algorithms lead to the biologically implausible conclusion that LDL and SBP – the two main modifiable causes of atherosclerotic cardiovascular events – do not meaningfully contribute to the risk of cardiovascular events. By contrast, including the causal effects of LDL and SBP, derived from the Causal AI algorithm, accurately estimated the risk of MCE at all ages among persons with both higher and lower lifetime exposure to LDL, SBP or both.”

Two, the JBS3 algorithm systematically underestimated the benefit of maintaining lifelong lower LDL, SBP, or both on MCE. In contrast, including the causal effects of LDL and SBP accurately estimated the benefit of maintaining lifelong lower LDL and SBP at all ages. Three, the JBS3 algorithm systematically underestimated the benefit of lowering LDL, SBP or both starting later in life as compared to randomised trials of LDL and SBP lowering therapies. By contrast, including the causal effects of LDL and SBP accurately estimated the benefit of lowering LDL, SBP, or both starting later in life during every month of follow-up observed in randomised trials.

Professor Ference said: “Current risk estimating algorithms are biased against prevention because they systematically underestimate the benefit of lowering LDL and SBP. This may lead to the false conclusion that waiting to lower LDL and SBP until later in life is more effective and costs less than lowering LDL and SBP at a younger age. Replacing these algorithms with Causal AI has the potential to personalise the prevention of cardiovascular disease and illustrate the public health and economic value of investing in cardiovascular prevention.”



Notes to editor

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This press release accompanies both a presentation and an ESC press conference at ESC Congress 2022. It does not necessarily reflect the opinion of the European Society of Cardiology.


Funding: No direct funding was provided for the study.


Disclosures: Prof BA Ference reports receiving research grants from Novartis, Amgen, Pfizer, Merck, and Esperion Therapeutics. In addition, the author reports receiving personal fees for consulting, advisory board participation and lectures from Novartis, Amgen, Regeneron, Sanofi, Merck, Pfizer, Eli Lilly, Novo Nordisk, AstraZeneca, Viatris, The Medicines Co, Mylan, Daiichi Sankyo, dalCOR, CiVi Pharma, KrKa Phamaceuticals, the American College of Cardiology, the European Society of Cardiology, and the European Atherosclerosis Society.


References and notes

1Causal AI will be discussed during Hot Line Session 6 on Sunday 28 August at 14:00 to 15:15 CEST in the Barcelona auditorium.

2Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–1681.

3The Blood Pressure Lowering Treatment Trialists’ Collaboration. Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis. Lancet. 2021;397:1625–1636.

4Ference BA, Yoo W, Alesh I, et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol. 2012;60:2631–2639.

5Ference BA, Julius S, Mahajan N, et al. Clinical effect of naturally random allocation to lower systolic blood pressure beginning before the development of hypertension. Hypertension. 2014;63:1182–1188.

6Ference BA, Bhatt DL, Catapano AL, et al. Association of genetic variants related to combined exposure to lower low-density lipoproteins and lower systolic blood pressure with lifetime risk of cardiovascular disease. JAMA. 2019;322:1381–1391.

7The trials were the Heart Protection Study (HPS), the Systolic Blood Pressure Intervention Trial (SPRINT), and the Heart Outcomes Prevention Evaluation (HOPE)–3 trial.


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