Physicians' Academy for Cardiovascular Education

An algorithm based on causal and cumulative effects of LDL and SBP to accurately calculate lifetime CV risk and benefit

News - Sep. 2, 2020

Cumulative Exposure to Lipoproteins and SBP Determines Optimal Age and Intensity to Initiate Lipid and BP Lowering Therapy to Minmize Lifetime Risk of Cardiovascular Disease

Presented at the ESC congress 2020 by Brian Ference (Cambridge, UK)

Introduction and methods

Although atherosclerosis starts early in life and slowly progresses over time, current guidelines focus on identifying those with short-term risk of acute CV events. This strategy has a huge limitation for those patients who have already developed sufficient atherosclerotic burden and at high risk of developing an acute event before therapy is initiated. Development of lifetime risk equations may help to encourage younger patients to initiate prevention earlier in life. Mendelian randomization studies have demonstrated that LDL and SBP, two modifiable risk factors for CVD, have causal and cumulative effects on risk of ASCVD, that are independent and additive. Lowering of LDL and SBP earlier in life could potentially reduce the risk of lifetime risk of CVD.

The objectives of this study were to examine whether LDL and SBP have cumulative effects on risk of ASCVD and use the cumulative and causal effects of LDL and SBP on risk of ASCVD to construct a risk algorithm that can predict risk and benefit of lowering LDL and SBP, over any time horizon.

The causal effect of each mmol-year of increase in exposure to LDL and of each mmHg-year in exposure to SBP was estimated. This was done by Mendelian randomization using 60,801 CAD cases and 123.504 controls in the CARDIoGRAMplusC4D consortium. The validity was tested by assessing the effect of random allocation to higher levels of LDL and SBP during each year of life in 445,765 participant in the UK Biobank. The Mendelian randomization estimates were used to empirically develop a risk and benefit algorithm that estimates remaining life time risk for a person who survives to a given age free of CVD as a function of the average remaining life time risk among persons in the population who also survived to that age without any CVD, and a person’s cumulative exposure to LDL and SBP. Estimates of CV risk and benefits using the lifetime exposure model were compared to risk and benefit derived from existing life time risk equations, and 10-year risk equations.

Main results


This study using data from the CARDIoGRAMplusC4D consorti and UK Biobank demonstrated that the effect of LDL and SBP on risk ASCVD increases with increased duration of exposure, thereby confirming the cumulative exposure hypothesis. An algorithm based on causal and cumulative effects of LDL and SBP was constructed to estimate lifetime risk and benefit. This algorithm overcomes the limitations of current life time risk and 10-year risk models and can estimate risk of ASCVD over any horizon and clinical benefit of lowering LDL and SBP over any time horizon.

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