LLTs Exposure Time and Major Vascular Risk Reduction

Key Takeaway

This systematic review and meta-analysis of randomized clinical trials stratified by follow-up time and degree of LDL-C lowering showed that:

• Benefits of LDL-C lowering are not fixed, but increase steadily with longer durations of treatment
• Causal effect of LDL-C on the risk of ASCVD is determined by both the absolute magnitude and the cumulative duration of exposure to LDL-C
• Results from short-term randomized trials were compatible with the very strong associations between LDL-C and cardiovascular events seen in Mendelian randomization (MR) studies

Study findings indicate that current guidelines underestimate the benefits of LDL-C lowering interventions that are continued for longer than 5 years, which has particular relevance to intervention in younger people.

Why This Matters

• Evidence from randomized clinical trials has shown that each mmol/L lower LDL-C* is associated with ≈24% lower risk of major vascular events.
• However, MR studies report that each mmol/L lower LDL-C is associated with >50% lower coronary risk, with the LDL cholesterol difference hypothesized to be attributed to the exposure duration.

This study evaluated the relationship between lipid-lowering drug exposure time and relative risk reduction of major cardiovascular events in randomized clinical trials, by stratifying the analysis to each year of follow-up, by effect size and LDL-C difference.

Study Design

This was a systematic review and meta-analysis of randomized clinical trials of statins, ezetimibe, or PCSK9i that reported LDL-C levels and effect sizes for each year of follow-up

Inclusion criteria

• Studies with a minimum of 1000 patient-years of follow-up
• Trials that reported the effect size/ summary estimate on clinical events per year of follow-up
• Follow-up LDL-C levels per year of follow-up
• Reporting ≥3 years of data

Exclusion criteria

• Trials including dietary therapies
• Patients followed up for <6 months or treatment compared with medications other than cholesterol lowering drugs or placebo

Primary endpoint

• Major vascular events (composite of cardiovascular death, myocardial infarction, stroke, and coronary revascularization).

Statistical analysis

• Meta-regression comparing duration of treatment to log(HR) was used to examine the relationship between treatment duration and risk of major vascular events.
• Effect estimates from meta-analyses of randomized clinical trials were compared with the expected clinical benefit per unit reduction in LDL-C estimated by Ference et al.

Key Results

Overall, 21 trials of LDL-C lowering were included in the analysis; 4 using ezetimibe and statins; 15 using statin therapy only; and 2 for PCSK9i vs placebo. (N = 184,012 patients; average mean follow-up = 4.4 years)

Duration of follow-up and LDL-C reduction

• Each subsequent year of follow-up diminished the mean difference in LDL-C between the treatment and control arms.
• Average difference:
  • After one year = 1.05 mmol/L
  • By 3 years = 0.98 mmol/L
  • By 7 years = 0.54 mmol/L

LDL-C reduction and relative risk reduction in major CV events
After standardizing for the degree of LDL-C reduction, each mmol/L LDL-C reduction was associated with a relative risk reduction in major vascular events after treatment years
After 1 year of treatment	After 3 years of treatment	After 5 years of treatment	After 7 years of treatment
12% (95% CI: 8%–16%)	20% (95% CI: 16%–24%)	23% (95% CI: 18%–27%)	29% (95% CI: 14%–42%)
No significant heterogeneity for individual meta-analyses was observed (I2 between 6% and 39%)

Meta regression and summary estimates

Meta regression	Significantly greater proportional risk reduction of major vascular events per mmol/L LDL-C lowered with each additional year of treatment (P <0.001) This observed consistent trend in sensitivity analyses was restricted to only those trials that contributed to the analyses during every year of follow-up
Summary estimates from randomized clinical trials and MR†	Meta-analyses of short-term randomized clinical trials are consistent with those estimates from MR Proportional risk reduction in major vascular events increases with longer durations of treatment

Limitations

• Analysis was based on trial-level data; more reliable estimates would have arisen from analyses of individual patient data.
• A significant uncertainty existed about the extrapolation from 7 years of treatment in the included meta-analyses to a lifetime of treatment estimated from the MR studies.
• Some differences existed in the definition of major vascular event between the included randomized trials and the outcome used in the MR study by Ference et al.
• Present study was not registered in Prospero.

* Lowered through statins, ezetimibe, and PCSK9i
† From Ference et al. for increasing durations of treatment, stratified to per 1 mmol/L LDL-C lowered

MAT-KW-2200325/V2/Dec 2022