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EAS2018 Late Breaking Clinical Trial: New insights from FOURIER

Tuesday 8 May 2018   (0 Comments)
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New insights from FOURIER: Benefit from lipoprotein(a) lowering with evolocumab

Lipoprotein(a) has been a focus of news at EAS Congress Lisbon. This new analysis from the FOURIER study,1 not only confirms the high risk associated with elevated lipoprotein(a) levels, but also shows that patients with the highest lipoprotein(a) levels together with high LDL cholesterol concentration obtained maximum clinical benefit from treatment with the PCSK9 inhibitor evolocumab.

Dr Michelle O’Donoghue (Brigham and Women’s Hospital, Boston, USA) reported the results of this analysis. Briefly, lipoprotein(a) was measured at baseline, and weeks 12 and 48 using an isoform independent assay. The association between lipoprotein(a) and cardiovascular risk was assessed in the placebo arm. Subsequently, the effect of evolocumab on lipoprotein(a), LDL cholesterol and cardiovascular outcomes was assessed based on Kaplan Meier rates at 3 years.

Not surprisingly, there was a skewed distribution of lipoprotein(a) levels at baseline, ranging from 13-165 nmol/L (median 37 nmol/L). Quartile analysis of lipoprotein(a) levels showed that, in the placebo group, patients with the highest levels had a 26% increase in risk for coronary heart disease death or MI, and a 12% increase in risk for the combined hard endpoint of cardiovascular death, MI and stroke (the key secondary endpoint in FOURIER) compared with patients with the lowest levels.

Treatment with evolocumab lowered lipoprotein(a) by a median of 26.9% (absolute change 11 nmol/L). In patients with baseline lipoprotein(a) levels > the median of 37 nmol/L, this translated to an absolute reduction in major cardiovascular events of 2.8% (number needed to treat 36). By comparison, patients with baseline lipoprotein(a) levels at or below the median value, had an 1.2% absolute reduction in cardiovascular risk.

The key take home message is that patients in FOURIER with the highest baseline lipoprotein(a) levels derived the greatest absolute benefit from evolocumab treatment. The findings are important in the context of ongoing development of novel agents that specifically target apo(a) to lower lipoprotein(a) levels by up to 90%.2 Direct comparison with the findings of the Mendelian randomization study reported yesterday are limited due to differences in assay reporting (nmol/L versus mg/dl) and the lack of conversion calibration.

Dr. O’Donoghue discusses the results of this FOURIER analysis in this video >

References

1. Sabbatine MS, Giuliano RP, Keech AC et al. Vedolizumab and clinical outcomes in patients with cardiovascular disease. N Engle J Med 2017; 376:1713-22.

2. Vinay NJ, van Appellees JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomized, double-blind, placebo-controlled, dose-ranging trials. Lancet 2016; 388:2239-2253.


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