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Cardiovascular event rate modifies response to pharmacologic LDL-C lowering in primary prevention: implications of a
Irene Karungi1, Christophe A T Stevens1, Julia Brandts1,2
1Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom.
Insights
Lower-risk individuals gain greater relative benefits from LDL-C lowering therapies. Achieving a 25% relative risk reduction for major adverse cardiovascular events requires larger LDL-C reductions in higher-risk populations.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Epidemiology
Background:
- Initiating LDL-C lowering therapies in lower-risk primary prevention is often delayed due to modest absolute benefits.
- Greater relative benefits observed in lower-risk individuals may strengthen the rationale for earlier intervention.
Purpose of the Study:
- To quantify the relative risk reduction (RRR) for 3P-MACE per 1 mmol/L LDL-C lowering across different baseline risk levels.
- To determine the absolute LDL-C reduction needed to achieve a 25% RRR at various risk thresholds.
Main Methods:
- A systematic review and meta-analysis of randomized, placebo-controlled lipid-lowering trials.
- Included populations had low (<20%) prevalence of atherosclerotic cardiovascular disease.
- Mixed-effects meta-regression assessed the effect of placebo event rate on RRR and absolute LDL-C reduction for 25% RRR.
Main Results:
- 17 trials (105,879 participants) were analyzed, with LDL-C reduction ranging from 0.38-1.95 mmol/L.
- RRR per 1 mmol/L LDL-C reduction decreased from 36% at a 1%/year event rate to 13% at a 3%/year event rate.
- Absolute LDL-C reductions needed for a 25% RRR increased with baseline risk, from 0.36 mmol/L to 3.09 mmol/L.
Conclusions:
- Lower-risk primary prevention populations experience significantly greater relative benefits from LDL-C lowering.
- Higher-risk populations require greater absolute LDL-C reductions to achieve similar relative treatment benefits.
Background:
LDL-C lowering is often delayed in lower-risk primary-prevention settings as absolute benefits appear modest. Trial evidence for greater relative benefits from pharmacologic LDL-C lowering in lower-risk individuals, supporting genetic studies, could strengthen the rationale for initiating LDL-C-lowering therapies at lower-risk levels.
Objectives:
To quantify i) how RRR for 3P-MACE per 1mmol/L LDL-C-lowering varies by baseline risk, ii) the absolute LDL-C reduction required to achieve 25 % RRR at varying risk thresholds.
Methods:
Systematic review and meta-analysis using EMBASE, MEDLINE, and CENTRAL searches for randomized, placebo-controlled lipid-lowering trials in populations with no or low (<20 %) prior atherosclerotic cardiovascular disease prevalence, reporting 3P-MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke). Effect modification of placebo event rate on RRR/1mmol/L was assessed using mixed-effects meta-regression. A second meta-regression plotted the absolute LDL-C reduction associated with 25 % RRR across event-rates.
Results:
17 trials (105,879 participants) reporting 6076 3P-MACE were included (12 statins only, 5 non-statins); mean age 63.0y, median follow-up 4.4y. LDL-C reduction ranged from 0.38-1.95 mmol/L and placebo event-rate ranged from 0.52 %/year-3.78 %/year. RRR per 1mmol/L LDL-C reduction attenuated from 36 % at 1 %/year event-rate to 13 % at 3 %/year (p < 0.0001). Absolute LDL-C reductions required to achieve 25 % RRR increased with baseline-risk, ranging from 0.36 mmol/L at 1 %/year-risk to 3.09 mmol/L at 3 %/year-risk (p = 0.0001).
Conclusion:
Lower-risk primary prevention populations derive significantly greater relative benefits per 1mmol/L LDL-C lowering. Conversely, higher-risk populations derive less benefit per 1mmol/L LDL-C lowering and hence require greater absolute LDL-C reductions to achieve comparable relative treatment benefits. PROSPERO (CRD420251155320).
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