MANNHEIM — Half of patients who die from homozygous familial hypercholesterolemia (HoFH) do so by age 32 years, new registry data show.
The researchers looked at almost 40 patients from the HoFH International Clinical Collaborators (HICC) registry who had died before data entry, finding that they had a mean age of diagnosis of 12 years.
Even those who received treatment had high low-density lipoprotein (LDL) cholesterol levels, and 70% developed atherosclerotic cardiovascular disease (ASCVD) at a median age of 28 years.
Worryingly, the results showed that the median age at death was 32 years. Results were presented at the 91st European Atherosclerosis Society (EAS) Congress on May 22.
Patients with HoFH “have severe atherosclerotic cardiovascular disease risk,” said study presenter Janneke Mulder, a PhD candidate at the Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
“Therefore, early diagnosis and initiation of treatments, and also a combination of treatments, is really crucial,” she added.
Call to Action
Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland, and Secretary of the EAS, described the results as “terrifying.”
He told theheart.org | Medscape Cardiology that they are a “call to action,” especially given that so few patients in the study received intensive combination lipid-lowering therapy despite having a baseline LDL cholesterol level that was “very, very high.”
Banach underlined that patients who receive triple lipid-lowering therapy with a high-intensity statin, ezetimibe (Nustendi), and a PCSK9-inhibitor, could expect, based on current evidence, to see their LDL cholesterol levels reduced by 85% and be on target.
“Obviously, this is kind of academic,” because in the real-world “this 85% is not observed very often,” but it offers a target for steep reductions in cholesterol levels.
“This is something that we should focus on for these patients from the beginning,” said Banach, either with a stepwise approach “or for experts in pediatric HoFH, “maybe immediately.”
He emphasized that clinicians have everything to hand to “be both effective in the early diagnosis of HoFH, the earlier the better, and obviously to be effective with its treatment.”
“We should do something to prolong the lives of those people,” because the current results are “terrifying,” Banach added.
Rare Genetic Condition
Presenting her findings, Mulder began by highlighting that HoFH is a “rare genetic condition that occurs due to mutations in cholesterol metabolism.”
This, she continued, leads to “severely increased LDL cholesterol levels, and consequently to very premature cardiovascular disease,” with patients potentially experiencing their first cardiovascular event before age 20 years.
Mulder pointed out that although there have been case series in the literature on HoFH, they have had “limited numbers” and patients have typically spent decades being treated at the same lipid management clinic.
To broaden the understanding of the clinical characteristics and management of patients dying with HoFH, the team examined data from the HICC registry, which is “the largest contemporary database of homozygous FH patients,” Mulder said.
It includes 751 patients with HoFH from 88 centers in 38 countries who were alive in 2010 or later. Data entry was between 2016 and 2020. The current analysis focused on 37 patients who had already died by the time they were included on the registry.
Of those, 49% were women, 38% were of White ethnicity, and 43% were from high-income countries.
The median age at diagnosis was 12 years, Mulder showed, explaining that this is similar to that seen in other studies. The majority (86%) underwent genetic testing, and 92% presented with xanthomas.
Mulder also noted that at their final clinical evaluation, which was conducted a median age of 18 years after their initial diagnosis, 43% of patients were recorded as current or former smokers.
In terms of their lipid-lowering therapy, 94% were taking a statin, whereas 68% were on ezetimibe, and 23% were undergoing apheresis.
Mulder said that the median number of lipid-lowering therapies per patient was two, and that “sadly…26% of the deceased patients had only one or no treatment.”
Therefore, perhaps unsurprisingly even those patients who were receiving treatment had LDL cholesterol levels that were “too high,” at 9.4 mmol/L vs 15.6 mmol/L among those who were untreated.
There was a high prevalence of ASCVD, at 70% overall, or 41% for aortic stenosis, 30% for myocardial infarction, 30% for angina pectoris, and 22% each for aortic valve replacement and coronary artery bypass grafting. In addition, 19% underwent percutaneous coronary intervention.
The median age of onset for ASCVD was 28 years. Mulder pointed out, however, that, as data were not available for all patients, “this might be an underestimation.” Seventy percent of patients experienced recurrent ASCVD.
There was a wide range in the age at which patients with HoFH died, although the median was, “strikingly,” 32 years, Mulder said. Death was confirmed as due to cardiovascular causes in 76% of cases.
During the post-presentation discussion, session chair Antonio J. Vallejo-Vaz, PhD, from the Research Group of Clinical Epidemiology and Vascular Risk, Institute of Biomedicine of Seville, Spain, highlighted that if 38% of the patients were of White ethnicity, then the remainder must therefore be from other ethnic groups.
“There could be potential issues with accessibility to lipid centers” for these patients, which could affect the findings, noted Vallejo-Vaz, who is also chief scientist of the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC).
Mulder agreed, replying that their results, though already striking, may be an underestimation because the patients were all from either high or middle-income countries, “so it would be good to have some data on low-income countries.”
She was also asked about two patients who died at a much older age than did the others, at ages 70 years and 86 years, respectively, and whether they had, for example, a protective genetic mutation.
Mulder said that they do not yet know, but they are planning an extended case series on these and other long-lived patients so that they can be investigated further.
No funding declared. No relevant financial relationships declared.
European Atherosclerosis Society 2023. Presented May 22, 2023. Abstract SS081/658
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