Abstract

Background Sex differences in atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolaemia have been reported but are not fully established. We aimed to assess sex differences in the risk of ASCVD and life-time burden of ASCVD in patients with heterozygous familial hypercholesterolaemia. Methods SAFEHEART is a nationwide, multicentre, long-term prospective cohort study conducted in 25 tertiary care hospitals and one regional hospital in Spain. Participants in the SAFEHEART study aged 18 years or older with genetically confirmed familial hypercholesterolaemia were included in our analysis. Data were obtained between Jan 26, 2004, and Nov 30, 2022. ASCVD and age at onset were documented at enrolment and at follow-up. Our aim was to investigate the differences by sex in the risk and burden of ASCVD in patients with heterozygous familial hypercholesterolaemia, over the study follow-up and over the life course. The SAFEHEART study is registered with ClinicalTrials.gov, NCT02693548. Findings Of the 5262 participants in SAFEHEART at the time of analysis, 3506 (1898 [541%] female and 1608 [459%] male participants) met the inclusion criteria and were included in the current study. Mean age was 461 years (SD 155) and median follow-up was 103 years (IQR 64-130). Mean on-treatment LDL-cholesterol at follow-up was 31 mmol/L (SD 14) in females and 30 mmol/L (15) in males. LDL-cholesterol reductions over time were similar in both sexes (139 mmol/L [95% CI 130-147] absolute reduction in females vs 139 mmol/L [129-148] in males; p=098). At enrolment, 130 (68%) females and 304 (189%) males (p<00001) had cardiovascular disease. During follow-up, 134 (71%) females and 222 (138%) males (p<00001) had incident cardiovascular events. Median age at first ASCVD event (mostly due to coronary artery disease) was 616 years (IQR 500-714) in females and 506 years (420-586) in males (p<00001). The adjusted hazard ratio for ASCVD in males compared with females during follow-up was 190 (95% CI 149-242) and for cardiovascular death was 174 (111-273). Major adverse cardiovascular disease event (MACE)-free survival from birth was lower in males than females (hazard ratio 352 [95% CI 298-416]; p<00001). Median MACE-free survival time was 901 years (95% CI 865-not estimable) in females and 710 years (692-746) in males. The age at which 25% of female participants have had a MACE event was 749 years, this figure was 555 years in male participants. Interpretation Our findings suggest that the burden and risk of ASCVD are markedly lower in females than males with familial hypercholesterolaemia. The impact of sex needs to be considered to improve risk stratification and personalised management in patients with heterozygous familial hypercholesterolaemia. Funding Fundaci & oacute;n Hipercolesterolemia Familiar, the Instituto de Salud Carlos III, and Next Generation EU funds from the Recovery and Resilience Mechanism Program. Copyright (c) 2024 Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.