EAS Issues New Guidance on Treating Rare Homozygous FH

July 24, 2014

LONDON, UK – The European Atherosclerosis Society (EAS) has released a new statement to aid physicians in detecting and managing patients with homozygous familial hypercholesterolemia (HoFH), a very rare genetic condition characterized by high levels of LDL cholesterol and a premature risk of atherosclerotic CVD[1].

Heterozygous FH (HeFH) occurs in one in 500 individuals, but HoFH is a much rarer condition. Although there is no consensus on prevalence, historical estimates suggest HoFH occurs in one in one million individuals. However, more recent general population studies put the prevalence at one in 160 000 to 300 000 individuals. Untreated individuals often develop atherosclerotic CVD by aged 20 years and die by 30 years, according to EAS.

"Thus, the primary goals of management are prevention of atherosclerosis cardiovascular disease by early and comprehensive control of hypercholesterolemia and early detection of complications, with specific focus on ostial occlusion and aortic stenosis," states the EAS consensus panel on FH. "Unfortunately, HoFH is typically diagnosed when considerable coronary atherosclerosis has already developed, emphasizing the need for optimization of treatment in childhood."

Writing online July 23, 2014 in the European Heart Journal, panel members, including chairs Dr John Chapman (Hôpital de la Pitié, Paris, France) and Dr Henry Ginsberg (Columbia University, New York, NY), state that genetic confirmation can be used as the diagnostic criterion for FH, but an untreated LDL cholesterol >500 mg/dL (or treated LDL cholesterol >300 mg/dL) along with cutaneous or tendon xanthomas before aged 10 years are also sufficient to make an HoFH diagnosis. Untreated LDL-cholesterol levels consistent with HeFH in both parents are also diagnostic criteria for HoFH.

The EAS expert panel says that, once detected, regular screening of HoFH is necessary given the extremely high risk of early-onset, severe atherosclerotic CVD. "This consensus panel recommends that patients receive a comprehensive cardiovascular evaluation at diagnosis, with subsequent Doppler echocardiographic evaluation of the heart and aorta annually, and if available, computed-tomography coronary angiography every five years or more frequently if clinically indicated, taking into account the radiation exposure and severity of subclinical disease."

Treatment and Future Therapies

Treatment of HoFH involves a combination of lifestyle changes, statin therapy (with or without ezetimibe [Zetia, Merck/Schering-Plough]), and lipoprotein apheresis, if available, and should be started as early as possible. LDL apheresis should begin as early as age five years and no later than eight years.

For HoFH patients, the LDL-cholesterol targets are <100 mg/dL for adults, <70 mg/dL for adults with clinical CVD, and <135 mg/dL for children. These targets, admittedly, are ambitious, say the EAS consensus panel, although newer drugs should help physicians get patients closer to goal.

Two novel agents for LDL-cholesterol lowering, lomitapide (Aegerion Pharmaceuticals) and mipomersen (Kynamro, Genzyme), can be considered as adjunctive treatments for patients who do not achieve the recommended LDL-cholesterol targets and remain at high CV risk, according to the panel.

The panel points out that there are LDL-cholesterol-lowering drugs in development, including monoclonal antibodies that target proprotein convertase subtilisin/kexin type 9 (PCSK9). Such agents include evolocumab (Amgen), alirocumab (Regeneron), and bococizumab (Pfizer). In addition, the cholesteryl ester transfer protein [CETP] inhibitors, including evacetrapib (Lilly) and anacetrapib (Merck), have also been shown to lower LDL-cholesterol levels.

"Subject to consideration of benefit vs risk and cost, which may differ from country to country, such pharmacotherapies may ultimately translate to improved clinical outcome for patients with this rare, life-threatening genetic disease," according to the EAS consensus panel.

The EAS consensus panel on FH is supported by unrestricted education grants from Amgen, Aegerion, AstraZeneca, Genzyme, Hoffman-La Roche, Kowa Europe, Novartis, and Sanofi/Regeneron. (The companies were not present at the consensus panel meeting and had no role in the design, content, or approval of the manuscript.) Disclosures for panel members are listed in the paper.


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