Survival in homozygous familial hypercholesterolemia is determined by the on-treatment level of serum cholesterol

Literature - Thompson GR, Blom DJ, Marais DA, et al. - Eur Heart J 2017; published online ahead of print

Background

Homozygous FH leads to extreme elevations of LDL-C from birth, accelerated atherosclerosis and premature death from acute coronary syndrome [1,2]. Two recent retrospective surveys described outcomes in FH homozygotes. Although most patients were treated with statins, the first study with 149 individuals of South Africa, included 15% of patients that were treated with plasmapheresis or lipoprotein apheresis, and reduced serum cholesterol by 24% [3]. Moreover, the second study with 44 individuals in the UK, included 60% of patients that were treated with plasmapheresis of lipoprotein apheresis, and reduced serum cholesterol by 45% [4].

Results of these studies suggest that chances of survival in homozygous FH depend on the extent of reduction in serum cholesterol.

This hypothesis was tested in a combined analysis of data from South African and UK homozygotes treated with various lipid-lowering measures, including statins, ezetimibe, lipoprotein apheresis and evolocumab, between 1990 and 2014. For this purpose, 133 patients who were statin-naïve at baseline, were subdivided into three quartiles according to their on-treatment serum total cholesterol levels: quartile 1: <8.1 mmol/L, quartile 2&3: 8.1–15.1 mmol/L and quartile 4: >15.1 mmol/L.

Main results

• More than 50% of patients in quartile 4 had null/null or null/defective LDLR mutations, whereas three-quarters of those in quartiles 1 and 2&3 had defective/defective LDLR or LDLRAP1 mutations (P=0.01).
• The mean total cholesterol levels on treatment were 6.3, 11.6 and 18.5 mmol/L in quartiles 1, 2&3 and 4, with corresponding reductions from baseline of 58%, 29% and 10% (P< 0.001).
• There was a significant association between on-treatment total cholesterol levels and time to any death. The unadjusted analysis showed that risk of death was 11.5 times greater in quartile 4 compared to quartile 1 (P<0.001). After adjustment, this was reduced to 6.2 times greater (P=0.04).
• The risk for cardiovascular death in quartile 4 was 12.8 times higher compared with quartile 1 (P<0.001). After adjustment, the risk was still 3–4 times higher, with borderline statistical significance.
• Most common MACE were coronary artery bypass grafting, aortic valve replacement and percutaneous coronary intervention with or without stenting. Risk of MACE was approximately 2 times higher in quartile 4 compared with quartile 1 (P=0.01), but the difference lost its statistical significance after adjustment.
• Patients with a MACE were older (36 vs. 24 years, P=0.0001), more often Caucasian (83.5% vs. 63.0%, P=0.008) and more likely to have pre-existing cardiovascular disease (21.5% vs. 0%, P=0.0001). They started treatment later (at 21 vs. 10 years of age, P=0.0001) and had less reduction in total cholesterol on treatment (-29% vs. -39%, P=0.004).

Conclusion

References

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