CHD Mortality Significantly Elevated in Patients With Severe FH

MAASTRICHT, the Netherlands—While individuals with familial hypercholesterolemia (FH) are at an increased risk of dying from coronary heart disease (CHD), a new study confirms that it’s those with the severest phenotype who are in particular jeopardy.

In a new analysis of nearly 3,000 people with FH, the standard mortality ratio (SMR), which quantifies the observed versus expected number of deaths, was 2.20 (95% CI 1.84-2.61) for those with a severe form of the disease. In other words, the risk of CHD death was 2.2 times higher in those with severe FH than in the general population. Comparatively, the SMR for individuals with nonsevere FH was borderline significant at 1.44 (95% CI 0.98-2.03).

Overall, individuals with severe FH had a lifetime risk of coronary heart disease mortality that was 64% higher than those with nonsevere FH.

The new findings, which were presented this week at the European Atherosclerosis Society Congress 2019, suggest that patients with severe FH should be targeted with the most aggressive lipid-lowering therapies, including treatment with one of the expensive monoclonal antibodies, say investigators.

“There are clear guidelines for when a patient with FH should qualify for a PCSK9 inhibitor,” lead investigator Steve Humphries, PhD (University College London, England), told TCTMD. “In our registry, we estimated the proportion of FH patients likely to quality and we came up with 24%. Now, if we were to say we’re only going to treat the severe patients, that proportion comes down to 16%. That makes sense. You want to target your most expensive agent to the patient with the highest risk who is going to benefit the most.”

Severe FH and PCSK9 Inhibitors

Heterozygous FH is believed to affect roughly one in 200 individuals, while homozygous FH, the more severe form of the disease, affects roughly one in 300,000 people. In 2016, the International Atherosclerosis Society (IAS) proposed identifying individuals with severe FH because there is considerable overlap between the heterozygous and homozygous phenotypes.

Severe FH is defined by untreated LDL cholesterol greater than 400 mg/dL, untreated LDL cholesterol greater than 310 mg/dL plus one high-risk condition, or untreated LDL cholesterol greater than 190 mg/dL plus two high-risk conditions. The high-risk conditions include age greater than 40 years (to reflect lifetime burden of disease), smoking, male gender, lipoprotein(a) greater than 50 mg/dL, low HDL cholesterol, hypertension, diabetes, family history of premature atherosclerotic CVD in a first-degree relative, chronic kidney disease, and obesity.   

“I think the [IAS] is quite truthful around this in that this was a pharmacy-driven concept,” said Humphries, referring to the relatively new definition. “With the advent of these new PCSK9 inhibitors, which are more expensive, it would be appropriate to identify the patients at the highest risk who would benefit most. So, they identified ‘severe,’ as these are the ones who should be getting these agents.”

In the new study, the researchers identified 947 individuals with nonsevere and 1,982 individuals with severe FH in the UK Simon Broome FH Register. The nonsevere FH patients had less previous angina and were less likely to have diagnosed CHD. They were less likely to be smokers and had lower blood pressure and LDL cholesterol levels. Mean LDL cholesterol levels in the nonsevere and severe FH patients were 193 and 259 mg/dL, respectively.

In addition to calculating the SMR for nonsevere and severe FH patients, the researchers assessed 10-year CHD mortality in the two groups. For those diagnosed with FH at age 40, the 10-year mortality rate was fourfold greater in the severe FH patients compared with the nonsevere FH patients. For those ages 50 and 60 years at diagnosis, the 10-year mortality rates were threefold and twofold higher, respectively, in severe patients compared with nonsevere patients.

“Obviously, as you get older, you’re more likely to have heart disease, but the difference gets smaller,” said Humphries. “I think this is very important because having severe FH at a young age is associated with a much greater risk. We need to find patients at a young age and treat them.” 

In the men with severe FH, the researchers observed a statistically significant decline in CHD mortality over time. In 1992, before the introduction of statins, the SMR was 3.56. Between 1992 and 2008, when statins were available but before the advent of high-intensity statin therapy, the SMR declined to 2.55. Between 2008 and 2016, when high-intensity statins were more widely used to treat significantly elevated LDL cholesterol levels, the SMR declined further to 1.59. In women with severe FH, the SMR prior to 1992 was 4.98, which declined to 1.73 between 1992 and 2008 but climbed again to 3.50 between 2008 and 2016.

“With women, the increase [in CHD mortality] is counterintuitive, but it suggests that women are being somehow denied the benefits of high-intensity statins,” Humphries speculated. “It is possible women are being given the statins [and] they’re just deciding not to take them, but women tend to be much better than men in taking medication. I think it’s more likely that women are not being perceived as being as at a high risk by male cardiologists.”

Women’s symptoms, he added, are less likely to be recognized as cardiac in nature and as a result they are not being identified as having severe FH.

Heterogeneity of CVD Risk in FH Patients 

Raul Santos, MD, PhD (University of São Paulo Medical School Hospital, Brazil), the lead author of the 2016 IAS consensus statement on defining severe FH, confirmed that the writing committee was focused on pharmacotherapy for FH, particularly alirocumab (Praluent; Regeneron/Sanofi) and evolocumab (Repatha; Amgen), when they drafted the document.  

“We know the heterogeneity of cardiovascular disease risk in FH,” he said following Humphries’ presentation. “Those who have a higher burden of risk factors would have a greater risk and that is what this study showed.”

Santos said the IAS writing committee was criticized for their definition of severe FH, with some arguing that it would encapsulate the majority of FH patients. He noted that in the present study, the number of severe FH patients outnumbered those with nonsevere FH by two to one. However, it’s a selected sample, Humphries pointed out, as these patients were recruited by physicians running dedicated lipid clinics for the most severely affected patients. Santos said that in his own clinic, one in every three patients with FH has existing cardiovascular disease.  

In the United Kingdom, patients with cardiovascular disease and LDL cholesterol levels greater than 135 mg/dL while taking a maximally tolerated statin, as well as those without cardiovascular disease but with LDL cholesterol levels greater than 190 mg/dL on maximally tolerated statin therapy, are eligible for one of the PCSK9 inhibitors.