Liv Mundal

Mortality Among Patients With Familial Hypercholesterolemia: A Registry‐Based Study in Norway, 1992–2010

Background Untreated patients with familial hypercholesterolemia are at increased risk of premature cardiovascular death. The primary aim of this study was to investigate whether this is also the case in the statin era. Methods and Results In this registry‐based study, 4688 male and female patients from the Unit for Cardiac and Cardiovascular Genetics (UCCG) Registry with verified molecular genetic diagnosis of familial hypercholesterolemia in the period 1992–2010 were linked to the Norwegian Cause of Death Registry. Standardized mortality ratios and 95% CIs were estimated. There were 113 deaths. Mean age of death was 61.1 years. Cardiovascular disease was the most common cause of death (46.0%), followed by cancer (30.1%). Compared with the Norwegian population, cardiovascular disease mortality was significantly higher in the UCCG Registry in all age groups younger than 70 years (standardized mortality ratio 2.29, 95% CI 1.65 to 3.19 in men and women combined; standardized mortality ratio 2.00, 95% CI 1.32 to 3.04 in men; standardized mortality ratio 3.03, 95% CI 1.76 to 5.21 in women). No significant differences were found in all‐cause mortality or cancer mortality. Conclusions Despite prescription of lipid‐lowering drugs, familial hypercholesterolemia patients still had significantly increased cardiovascular disease mortality compared with the general Norwegian population.

Patients with familial hypercholesterolaemia are characterized by presence of cardiovascular disease at the time of death

AIMS Untreated familial hypercholesterolaemia (FH) increases the risk of premature atherosclerosis and cardiovascular disease (CVD). This study investigated the presence of CVD in FH patients at the time of death. METHODS AND RESULTS The presence of CVD, lipid profile, medical treatment, and cause of death was characterized in all deceased Norwegian FH patients, of whom we had access to medical records (n = 79, from 1989 to 2010). The mean age at first CVD event was 44 years. The mean age at the time of death was 60 years. Cardiovascular disease was the cause of 50% of the deaths. At the time of death, 93% of the FH patients had established CVD and 69% had experienced myocardial infarction. The FH patients were divided into two groups (cut-off 60 years); FH patients who died at a younger age (mean age 51 years) and at an older age (mean age 71 years). More of the younger FH patients received statins (98 vs. 81%, P = 0.038), and fewer received niacin (0 vs. 17%, P = 0.019) compared with the older patients. The last measured low-density lipoprotein cholesterol level was higher in the younger patients compared with the older FH patients (5.3 vs. 4.4 mmol/L, P = 0.033). There were more current smokers among the younger FH patients compared with the older patients (55 vs. 10%, P = 0.001). Interestingly, there were no sex differences in age at the first CVD event or age at the time of death. CONCLUSION Cardiovascular disease is present in most FH patients at the time of death, underscoring the severity of FH and the need for early diagnosis and treatment.

Cardiovascular disease mortality in patients with genetically verified familial hypercholesterolemia in Norway during 1992–2013

Background Patients with familial hypercholesterolemia have increased cardiovascular disease mortality but the magnitude of the increased risk is uncertain. The primary aim of this study was to investigate all causes of death and place and manner of deaths in a large sample of genotyped familial hypercholesterolemia patients. Design, methods and results In this registry study data on 5518 patients with genotyped familial hypercholesterolemia were linked to the Norwegian Cause of Death Registry during 1992–2013. Standardized mortality ratios and 95% confidence intervals (CIs) were estimated. There were in total 189 deaths. Cardiovascular disease was the most common cause of death (42.3%). Mean age at cardiovascular disease death was 64.5 years (range 33–91). Cardiovascular disease mortality including all cardiovascular disease deaths mentioning any place on the death certificate was significantly higher in familial hypercholesterolemia patients compared to the general Norwegian population under 70 years of age. Standardized mortality ratio (95% CI) was highest in the 20–39 years age group; 4.12 (1.85–9.18) decreasing to 0.77 (0.50–1.19) for those over 80 years. For total cardiovascular disease deaths occurring out of hospital, standardized mortality ratio was 12.35 (5.14–29.70) for those aged 20–39 years. Conclusion Familial hypercholesterolemia patients under 70 years of age have significantly higher cardiovascular disease mortality compared to the general Norwegian population. For those aged 20–39 years the risk of cardiovascular disease deaths occurring out of hospital was increased 12-fold. In spite of genotyped familial hypercholesterolemia and premature cardiovascular disease deaths, the majority of all death certificates did not include familial hypercholesterolemia among any of the contributing causes of death.

Cardiovascular disease in patients with genotyped familial hypercholesterolemia in Norway during 1994–2009, a registry study

Background Familial hypercholesterolaemia increases the risk for cardiovascular disease. The primary aim of the present study was to describe sex differences in incidence and prevalence of cardiovascular disease leading to hospitalisation in a complete cohort of genotyped familial hypercholesterolaemia patients. Design and methods In this registry study data on 5538 patients with verified genotyped familial hypercholesterolaemia were linked to data on all Norwegian cardiovascular disease hospitalisations, and hospitalisations due to pre-eclampsia/eclampsia, congenital heart defects and diabetes. Results During 1994–2009 a total of 1411 of familial hypercholesterolaemia patients were hospitalised, and ischaemic heart disease was reported in 90% of them. Mean (SD) age at first hospitalisation and first re-hospitalisation was 45.1 (16.5) and 47.6 (16.3) years, respectively, with no sex differences (P = 0.66 and P = 0.93, respectively). More men (26.9%) than women (24.1%) with familial hypercholesterolaemia were hospitalised (P = 0.02). The median (25th–75th percentile) number of hospital admissions was four (two to seven) per familial hypercholesterolaemia patient, with no sex differences (P = 0.87). Despite having familial hypercholesterolaemia at the time of hospitalisation, the diagnosis of familial hypercholesterolaemia was registered in only 45.7% of the patients at discharge. Conclusion Most cardiovascular disease hospitalisations were due to ischaemic heart disease. Familial hypercholesterolaemia patients were first time hospitalised at age 45.1 years, with no significant sex differences in age, which are important novel findings. The awareness and registration of the familial hypercholesterolaemia diagnosis during the hospital stays were disturbingly low.

A systematic review of current studies in patients with familial hypercholesterolemia by use of national familial hypercholesterolemia registries.

Purpose of review More than 25 million are expected to have familial hypercholesterolemia worldwide. The risk of cardiovascular disease (CVD) in familial hypercholesterolemia is not clear and register studies represent a valuable tool to get such data, which will be discussed in the present paper. Recent finding A systematic review of current familial hypercholesterolemia studies, by use of National familial hypercholesterolemia registries was performed from 1980 to 2016. This review shows that familial hypercholesterolemia patients have a high prevalence of CVD also in the time period after statins became available. The patient group does not reach recommended target values for lipids, and have a significantly higher CVD mortality as compared with the general population according to age and sex. Summary The review underscores the importance of establishing National familial hypercholesterolemia registries with complete datasets on familial hypercholesterolemia patients to improve early diagnostics, therapeutics and long-term follow-up to prevent the premature CVD events and deaths in this patient group.

Impact of age on excess risk of coronary heart disease in patients with familial hypercholesterolaemia

Objective The primary objective was to study the risk of acute myocardial infarction (AMI) and coronary heart disease (CHD) in patients with familial hypercholesterolaemia (FH) and compare with the risk in the general population. Methods Patients with an FH mutation but without prior AMI (n=3071) and without prior CHD (n=2795) were included in the study sample during 2001–2009. We obtained data on all AMI and CHD hospitalisations in Norway. We defined incident cases as first time hospitalisation or out-of-hospital death due to AMI or CHD. We estimated standardised incidence ratios (SIRs) with 95% CIs with indirect standardisation using incidence rates for the total Norwegian population stratified by sex, calendar year and 1 year age groups as reference rates. Results SIRs for AMI (95% CIs) were highest in the age group 25–39 years; 7.5 (3.7 to 14.9) in men and 13.6 (5.1 to 36.2) in women and decreased with age to 0.9 (0.4 to 2.1) in men and 1.8 (0.9 to 3.7) in women aged 70–79 years. Similarly, SIRs for CHD were highest among patients 25–39 years old; 11.1 (7.1–17.5) in men and 17.3 (9.6–31.2) in women and decreased 2.4 (1.4–4.2) in men and 3.2 (1.5–7.2) in women at age 70–79. For all age groups, combined SIRs for CHD were 4.2 (3.6–5.0) in men and 4.7 (3.9–5.7) in women. Conclusion Patients with FH are at severely increased risk of AMI and CHD compared with the general population. The highest excess risk was in the youngest group aged 25–39 years, in both sexes.

Increased risk of heart failure and atrial fibrillation in heterozygous familial hypercholesterolemia.

BACKGROUND AND AIMS Heart failure (HF) and atrial fibrillation/flutter (AF) are important causes of morbidity and mortality. Subjects with familial hypercholesterolemia (FH) carry a high risk of coronary artery disease (CAD) but it is not known if the risk of HF and AF is increased in FH. The present study investigated the incidence of hospitalization for HF and AF in a genetically verified FH cohort, age 25 years and older, compared to the general population. METHODS Incidence rates of hospitalization for HF and AF were estimated from national registry data. Standardized incidence ratios (SIRs) were calculated. RESULTS 4273 genotyped FH patients (51.7% women) with a total observation period of 18,300 patient years were studied. Overall, the expected number of FH patients with HF was 27.7 and the observed number of cases was 54 (SIR (95% CI) 2.0 (1.5-2.6)). The highest excess risk was observed in the age group 25-49 years, where SIRs were 3.8 (1.2-11.8) and 4.2 (2.0-8.8) in women and men, respectively. The total expected number of FH patients with AF was 39.4 while the observed number of cases was 77 (SIR 2.0 (1.6-2.4)). Among FH patients with an incident event of HF, nearly 90% had a previous diagnosis of CAD, and nearly 40% had suffered from a myocardial infarction. CONCLUSIONS We demonstrate a doubling of the risk of hospitalization for HF or AF in patients with FH. This is could have an important prognostic impact for patients and economic impact for the society.