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EAS 2017 April 24: FOURIER up for discussion

25 April 2017   (1 Comments)
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EAS Congress Prague provided the first opportunity to discuss the results of the FOURIER cardiovascular outcomes trial with evolocumab in Europe.

A recap on the data was presented by Professor Terje Pedersen (UiO Institute of Clinical Medicine, Faculty of Medicine, Oslo, Norway). Briefly, FOURIER included 27,564 very high risk patients with established cardiovascular disease on maximally tolerated lipid lowering therapy (95% statin monotherapy).1 Lowering LDL cholesterol from a mean of 92 mg/dl at baseline to 30 mg/dl was associated with a significant 15% reduction in the primary endpoint (a composite of cardiovascular death, MI, stroke, hospitalisation for unstable angina, and coronary revascularisation), as well as 20% reduction in the key secondary ‘hard’ endpoint (a composite of cardiovascular death, MI and stroke) over the 26 month follow-up. There was no significant mortality benefit, consistent with findings observed in a number of other studies including IMPROVE-IT, SEARCH and IDEAL, reflecting the duration of the study. The cardiovascular benefit of FOURIER was consistent across the range of baseline LDL-C levels. Landmark analysis showed that benefit accrued over time, from 16% reduction in the first year to 25% in the second year for the key secondary outcome. This response has also been shown for statins.2 Treatment was generally well tolerated, and in the EBBINGHAUS substudy there was no evidence to suggest any detrimental effect on neurocognitive function. In an accompanying presentation, Professor Steve Nicholls (University of Adelaide, Australia) discussed the findings of GLAGOV and FOURIER.

So what were the key take home messages from the discussion?

  • Is there a threshold LDL value for benefit?

FOURIER adds to the evidence that LDL is causal for ASCVD, showing that the relationship between LDL cholesterol lowering and reduction in cardiovascular risk extends to very low LDL cholesterol levels with no evidence of a threshold for benefit. According to Professor John Chapman (University of Pierre and Marie Curie, Pitié-Salpêtrière University Hospital, Paris, France)the data pose a key question: do we need minimal levels of circulating LDL cholesterol? ‘We have known for more than 30 years that the brain can fulfil all of its needs for cholesterol from endogenous synthesis.’

  •  How variable was the LDL lowering response?

The limited available data underline the need for further study of the pharmacogenomic variability with evolocumab and alirocumab and how this impacts the cardiovascular benefit.

  • How do we translate the data to real world practice?


This question raises a number of uncertainties in how best to target this treatment to very high risk patients most likely to derive benefit. Whether imaging may play a role is a moot point that is not without practical and cost considerations. Additionally, it is important to ensure that treatment with a PCSK9 inhibitor is justified on the basis of lack of adequate response to statin and ezetimibe therapy; monitoring statin response over a 4-6 week period was suggested by Professor Chris Packard (University of Glasgow, UK).

LDL cholesterol goals were also under scrutiny. According to Professor Alberico Catapano (University of Milan, Italy) lead author of the ESC/EAS dyslipidaemia guidelines, any changes are likely to await the results of the ODYSSEY Outcomes study.

Finally, a point was made for the need for further data in women. While there was no evidence of any difference in response between the genders in FOURIER, the much larger proportion of men than women (75% versus 25%), together with evidence that the atherosclerotic process may be accelerated in post-menopausal women raises issues about the translation of data.

  • What is the long-term safety of very low LDL cholesterol levels?

According to Professor Nicholls, one in four of the FOURIER population treated with evolocumab attained an LDL cholesterol value <20 mg/dl and some patients attained LDL cholesterol levels <10 mg/dl. Even at these very low levels, there was no evidence to suggest any adverse effect. In support, Professor Packard added that recent data from the IMPROVE-It trial provide reassurance about the safety of very low LDL cholesterol levels.3 However, the issue will not be fully resolved without long-term surveillance in clinical use. The need for consideration of long-term safety with other modes of PCSK9 inhibition that act intracellularly, such as the siRNA inclisiran, is highly relevant.

Finally, despite the evidence from FOURIER and GLAGOV that PCSK9 inhibition on top of maximally tolerated statin therapy is effective in inducing regression and reducing cardiovascular events, these very well treated patients continue to experience events.

Does the GLAGOV study provide any insights into the compositional characteristics of the plaque that may favour benefit? We look forward to these data to provide some clues.  

References

1. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017 Mar 17. doi: 10.1056/NEJMoa1615664. [Epub ahead of print]

2. Collins R, Reith C, Emberson J et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532-61.

3. Giugliano RP, Wiviott SD, Blazing MA et al. Long-term Safety and Efficacy of Achieving Very Low Levels of Low-Density Lipoprotein Cholesterol : A Prespecified Analysis of the IMPROVE-IT Trial. JAMA Cardiol 2017 Mar 14. doi: 10.1001/jamacardio.2017.0083. [Epub ahead of print]

Comments...

Paul D. Rosenblit says...
Posted 25 April 2017
Are VLDL- and Chylomicron- remnants more atherogenic than LDL-C, since they do not seem to require modification prior to macrophage uptake? Are particle numbers of atherogenic cholesterol-containing lipoproteins more important; more particles more atherosclerosis?

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