FH Patients Derive Biggest Absolute Benefit From Statin Therapy: 4S Analysis

Digging into the landmark 4S study, researchers saw much larger reductions in hard clinical outcomes in the high-risk FH cohort.

FH Patients Derive Biggest Absolute Benefit From Statin Therapy: 4S Analysis

MAASTRICHT, the Netherlands—Individuals with elevated LDL cholesterol levels and clinical characteristics suggestive of familial hypercholesterolemia (FH) who are treated with statin therapy derive significantly larger absolute reductions in clinical events when compared with people who have elevated LDL cholesterol levels and existing coronary artery disease, according to a new analysis of the Scandinavian Simvastatin Survival Study (4S).

Presented this week at the European Atherosclerosis Society Congress 2019, the new data provide randomized trial evidence in secondary prevention showing that statins reduce cardiovascular events in patients with the FH phenotype, “however we chose to define it,” say researchers.

“The question here was whether the FH phenotype patients might benefit even more from therapy,” lead investigator Antonio Vallejo-Vaz, MD, PhD (Imperial College London, England), told TCTMD. “That’s what we have seen here, that the absolute benefit is greater in the particular patient who may have a genetic basis for FH.” 

While the gold standard for diagnosing FH is genetic testing, such tests are expensive and not widely used. In this new analysis, researchers focused on individuals with LDL cholesterol levels of 190 mg/dL or greater who met the Dutch Lipid Clinic Network (DLCN) criteria for FH. The 4S study, a secondary prevention trial, allowed them to compare the relative and absolute reductions in clinical outcomes among FH patients treated with simvastatin against other coronary heart disease (CHD) patients with elevated LDL cholesterol but not necessarily FH.

Using criteria from the DLCN, individuals were considered to have the FH phenotype if they had premature CAD (occurring before 55 years of age in men and 60 in women) and a family history of CAD in addition to significantly elevated LDL cholesterol and existing coronary heart disease.

The 4S study included 2,267 and 2,164 patients with LDL cholesterol less than and greater than 190 mg/dL, respectively. Focusing on those with LDL cholesterol levels greater than 190 mg/dL, the researchers stratified patients into four groups: those meeting the DLCN criteria of FH (n = 152), patients with a family history of CAD (n = 617), individuals with premature CAD (n = 469), and those without premature CAD or a family history disease (n = 926). Baseline LDL cholesterol was similar across the four groups—greater than 200 mg/dL in each—as was the achieved relative reduction in LDL cholesterol with simvastatin treatment.

“We wanted to identify patients who had a greater probability of having FH,” said Vallejo-Vaz. “We didn’t have DNA analysis so we applied a criteria for diagnosing FH to the 4S cohort. We tried to identify those who would have a genetic basis to explain the FH. Sometimes the FH phenotype is diagnosed with LDL cholesterol greater than 4.9 mmol/L [190 mg/dL], but this might only be primary severe hypercholesterolemia and not FH. We tried to go a bit farther with the additional features, such as premature CAD and having a family history of CAD.”

There was a trend toward larger relative reductions in clinical outcomes among patients with the FH phenotype compared with the other three groups, but the difference between groups was not statistically significant.

When investigators focused on the absolute reduction in clinical outcomes, those with FH phenotype had a significantly larger reduction in clinical events compared with the other patients. The absolute reductions in all-cause mortality, cardiovascular mortality, CHD mortality, and major CHD events were 6.6%, 5.3%, 5.3%, and 13.2%, respectively, in those with the FH phenotype. In contrast, the absolute reductions in these same endpoints among those with LDL cholesterol levels greater than 190 mg/dL only were 3.8%, 4.0%, 3.6%, and 8.3%, respectively.       

“We observed some significant relative risk reductions, but there was no interaction between the different groups in the cohort,” said Vallejo-Vaz. “We did see the absolute benefit was greater when we looked at the patients we defined as the FH phenotype.” He cautioned that the analysis is post hoc and limited by small numbers of patients, particularly those with FH. Nonetheless, the study suggests physicians need to seek out and identify FH patients for treatment, particularly early treatment, in order to lower their risk of cardiovascular events. 

In the original 4S trial, which was published in 1994, treatment with simvastatin lowered the risk of all-cause and CHD mortality in 4,444 men and women with established coronary artery disease and elevated LDL cholesterol levels. The landmark study established statin therapy as the cornerstone for the prevention of recurrent clinical outcomes in patients with existing CHD.

Michael O’Riordan is the Managing Editor for TCTMD. He completed his undergraduate degrees at Queen’s University in Kingston, ON, and…

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  • Vallejo-Vaz A, Packard CJ, Ference BA, et al. LDL cholesterol lowering among patients with LDL cholesterol above > 4.9 mmol/L and features suggesting a genetic vulnerability to cardiovascular disease: analysis from the 4S trial. Presented at: European Atherosclerosis Society Congress. May 27, 2019. Maastricht, the Netherlands.

  • The 4S Trial was originally funded by MSD.
  • Vallejo-Vaz reports receiving institutional research grants from Amgen, Sanofi, MSD, and Pfizer and honoraria from Amgen and Mylan.