Long‐Term Cardiovascular Risk in Heterozygous Familial Hypercholesterolemia Relatives Identified by Cascade Screening

BACKGROUND Heterozygous familial hypercholesterolemia increases the risk of adverse cardiovascular events. Whether affected relatives of probands are at increased risk remains unknown. We aimed to evaluate the long-term cardiovascular risk in heterozygous familial hypercholesterolemia relatives with a low-density lipoprotein receptor (LDLR) mutation who were all recommended statin therapy. METHODS AND RESULTS Participants were identified by cascade screening at Aarhus University Hospital during 1992-1994. A comparison cohort from the Danish general population was matched 10:1 to relatives by birth year and sex. Using medical registries, participants were followed until the event of interest, migration, death, or end of follow-up on December 31, 2014. The primary end point was all-cause mortality and major adverse cardiovascular events comprising myocardial infarction, ischemic stroke, transient ischemic attack, peripheral artery disease, and coronary revascularization. We included 220 relatives. Median age was 37 years (interquartile range: 27-52 years) of which 118 (54%) had an LDLR mutation. By 2004, when prescription data became available, 89% of mutation-carrying participants were taking statins during their follow-up period. Despite frequent use of lipid-lowering medication, the adjusted hazard ratio of the primary end point was 1.65 (95% confidence interval, 1.17-2.33) in mutation-carrying relatives compared with the general population cohort. The risk in non-mutation-carrying relatives was not different from that of the general population cohort (adjusted hazard ratio: 0.85; 95% confidence interval, 0.56-1.29). Comparing mutation-carrying relatives with non-mutation-carrying relatives, the adjusted hazard ratio was 1.94 (95% confidence interval, 1.14-3.31). Results were driven by nonfatal events. CONCLUSION Heterozygous familial hypercholesterolemia relatives with an LDLR mutation had an increased long-term risk of adverse cardiovascular events.