Findings of a study on the largest global cohort of HoFH patients
Worldwide experience of homozygous familial hypercholesterolemia: retrospective cohort study
Introduction and methods
Studies of relatively small sample size with patients from high-income countries largely determine our view on the clinical characteristics and natural history of homozygous familial hypercholesterolemia (HoFH). There is not much known about differences worldwide in detection, management and outcomes in patients with HoFH.
Therefore, a global consortium was set up of researchers and clinicians caring for HoFH patients.
Aim of the study
To provide a contemporary, systematic assessment of the characteristics, diagnosis, treatment and outcomes of HoFH patients, on a global scale and by country income status.
The HoFH International Clinical Collaborators (HICC) is a global consortium of clinicians and researchers that take care of patients with HoFH. Eligible patients for the registry had a clinical or genetic diagnosis of HoFH.
Patients with HoFH who were alive and being followed up in of after 2010 were eligible for the study. Definition of baseline was the point at which HoFH was diagnosed. Individual-level data on 751 patients from 38 countries were available, with 20 countries classified as high-income, 12 as upper-middle-income and 6 as lower-middle-income countries (latter two are referred to as non-high-income countries).
Major adverse cardiovascular events (MACE), a composite of CV death, non-fatal MI, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG).
- Median age of diagnosis was 12.0 years (IQR 5.5-27.0); 16.0 years (IQR 6.0-33.0) in high-income countries vs. 10.0 years (5.0-20.0) in non-high-income countries.
- Untreated LDL-c levels were 14.7 mmol/L (IQR 11.6-18.4) and lower in patients from high-income countries than those from non-high-income countries.
- 150 Patients (30%) had a first-degree family member with HoFH who was also in the registry.
- Majority of those with available genetic information were homozygous or compound heterozygous carriers of LDLR variants (83%). These patients had higher untreated LDL-c levels than patients with other genetic variants.
- Nearly all patients (92%) were on statin therapy, usually high intensity (83%).
- Ezetimibe was used by 72% of patients from high-income countries and 54% of patients from non-high-income countries.
- LLTs as PCSK9 inhibitors, lomitapide and evinacumab were used infrequently, and predominantly in patients from high-income countries.
- 78% were on combination therapy with 2 of more therapies and 42% used 3 or more LLT types.
- Percentages of patients taking LLT combinations were higher in high-income countries.
- Lipoprotein apheresis was performed in 39% of patients, at a median age of 15.0 years (IQR 10.0-28.0), once per week (25%) or every other week (54%).
- Attainment of guideline-recommended LDL-c levels was low; 12% of patients reached an LDL-c level <2.6 mmol/L (primary prevention) or <1.8 mmol/L (secondary prevention).
- LDL-c reduction was 30% in patients on monotherapy, 45% with 2 classes of LLT, and >65% in patients using 3 or more LLT.
- LDL-c goals were more frequently attained in patients from high-income countries (21%) compared with non-high-income countries (3%).
- 5% of the overall population achieved the LDL-c goal of <1.8 mmol/L (primary prevention) and <1.4 mmol/L (secondary prevention).
- Median age at which MACE occurred was 31.0 years (IQR: 22.0-42.0)
- At diagnosis of HoFH, 9% of patients had already suffered a non-fatal MI, had undergone PCI or CABG or with aortic valve stenosis.
- There were 37 deaths of which 28 from CV causes (median 28.0 years, IQR 17.0-45.5).
- In those with a recorded non-fatal coronary events, a recurrent event occurred in 28% of patients.
- Peripheral arterial disease occurred in 6% of patients and cerebrovascular disease in 3%.
- Supravalvular aortic stenosis was reported in 29% of patients and aortic valve replacement had been performed in 7% (median 31.0 years, IQR 24.8-41.0).
- MACE-free survival was shorter in patients in non-high-income countries (24.5 years, IQR 17.0-34.5) compared with high-income countries (35.0 years, IQR 25.0-49.0) (HR 2.10, 95%CI:1.40-2.88), with a stepwise attenuation after adjustment for treatment with 3 or more LLT, age of diagnosis and sex (HR 1.64, 95%CI:1.31-2.38).
- Higher untreated LDL-c was associated with a higher risk of MACE (with lowest tertile of untreated LDL-c as reference) (HR 3.60, 95%CI:2.22-5.84), with a stepwise attenuation of the HR after adjustment for age of diagnosis and income status (HR 1.60, 95%CI: 0.96-2.67).
This study on the largest global cohort of HoFH patients highlights that patients with HoFH require early diagnosis, and early and intensive treatment with lipid lowering drugs to prevent CV outcomes. Global disparities in diagnosis and treatment of HoFH patients result in differences in care and outcomes of these patients.
The authors conclude: “As the greatest global burden resides in non-high income countries, a critical reappraisal of health-care policy and funding is required at a global level to improve health outcomes for all patients with HoFH”.