Statins Lower but Don’t Erase the Excess Risk of Coronary Disease and Death in Familial Hypercholesterolemia

For primary prevention, moderate-to-high intensity statin therapy is associated with lower risks of both coronary disease events and mortality in patients with heterozygous familial hypercholesterolemia (FH), but the rates remain higher than those seen in unaffected individuals, an observational study shows.

Assuming the estimated relative risk reduction is accurate, statins would lower lifetime CAD risk in this patient population from 103 to 58 per 100,000 person-years in the Netherlands, where the study was conducted, Joost Besseling, MD (Academic Medical Center, Amsterdam, the Netherlands), and colleagues report in a study published online ahead of the July 19, 2016, issue of the Journal of the American College of Cardiology.

“This is certainly an improvement, but a substantial residual risk remains in these patients compared with CAD event rates in their unaffected family members (29 per 100,000 person-years),” they write.

The findings come at a time when payers are looking into whether reimbursement should be given to newer lipid-lowering approaches, including treatment with PCSK9 inhibitors, in patients with heterozygous FH, who have a very high risk of coronary events, they note. 

“An important aspect in this decision is the potential for the prevention of CAD events by statins at a population level; therefore, it is important to quantify the residual CAD risk in statin-treated patients,” Besseling et al write. “The relative risk reduction by statins is key information in this estimation. In fact, it is fundamental information in all cost-effectiveness studies in this disorder, such as when evaluating screening programs.”

For the study, the investigators looked at data on 1,559 adult patients with heterozygous FH who were identified by the Dutch screening program between January 1, 1994, and April 7, 2013, and were free of CAD at baseline.

After performing inverse-probability-for-treatment weighting and multivariate adjustment, the researchers found that statin users—compared with those who had never used statins—had a lower rate of a composite of CAD events or all-cause mortality during follow-up (7.5 vs 11.9 per 100,000 person-years; HR 0.56; 95% CI 0.33-0.96).

‘Underappreciated, Underdiagnosed, and Undertreated’

In an accompanying editorial, Joshua Knowles, MD, PhD (Stanford University, Stanford, CA), says that “more insight into the quantitative effects of LDL-C lowering on cardiovascular outcomes in FH is critical” because of evidence showing that there is room for improvement in treating this condition, which is more common than once thought, and because of questions about use of PCSK9 inhibitors.

He says that the 44% relative risk reduction observed in the study with statin use may underestimate the true effect because only about 30% of patients were receiving high-intensity regimens. Still, the number needed to treat (NNT) was 222 for 1 year of statin therapy to prevent a death, which is better than the NNT for either primary prevention (about 500) or secondary prevention (about 350) in patients without FH, he notes.

Knowles argues that “the evidence is now overwhelming that FH is highly morbid yet underappreciated, underdiagnosed, and undertreated. . . . As a community, we must turn our attention to the critical task of assuring that all individuals with FH have the opportunity for optimal care.”

That starts with finding undiagnosed and untreated patients and then involves appropriately classifying FH patients, educating providers and patients about FH, and combating misinformation.

“For instance, for all the negative press about statins, one of this study’s big conclusions is that, for FH patients, the most important potential ‘side effect’ of statins is increased longevity, and for those who cannot take statins or have elevated residual risk, we need to use other treatment modalities and work to remove barriers to care,” Knowles writes.

Furthermore, he says, “we must work with the knowledge that we never find an individual with FH, we only find families with FH. We know that systematic approaches to cascade screening can save lives yet, in many countries, are rarely implemented.

“If we can do these things,” he continues, “we will move from the current world where we refer to ‘patients with FH’ to a future where we refer to ‘individuals with FH.’”





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Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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  • Besseling J, Hovingh K, Huijgen R, et al. Statins in familial hypercholesterolemia: consequences for coronary artery disease and all-cause mortality. J Am Coll Cardiol. 2016;68:252-260.

  • Knowles JW. Statins in familial hypercholesterolemia: translating evidence to action. J Am Coll Cardiol. 2016;68:261-264.

  • Besseling reports no relevant conflicts of interest.
  • Knowles reports receiving support from an American Heart Association National Innovative Research grant and an Amgen Full Potential Initiative grant paid to his institution.