Canibais e Reis

Eur Heart J. 2008 Nov;29(21):2625-33. Epub 2008 Oct 7.

Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. (pdf)

Neil A, Cooper J, Betteridge J, Capps N, McDowell I, Durrington P, Seed M, Humphries SE.
NIHR School of Primary Care Research, Division Public Health and Primary Health Care, University of Oxford, Old Road Headington, Oxford, UK.
Comment in: Eur Heart J. 2008 Nov;29(21):2583-4.

AIMS: To examine the changes in coronary, all-cause, and cancer mortality in patients with heterozygous familial hypercholesterolaemia (FH) before and after lipid-lowering therapy with statins. METHODS AND RESULTS: A total of 3382 patients (1650 men) aged <80 years were recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2006 for 46 580 person-years. There were 370 deaths, including 190 from coronary heart disease (CHD) and 90 from cancer. The standardized mortality ratio (compared with the population in England and Wales) was calculated before and from 1 January 1992. In patients aged 20-79 years, CHD mortality fell significantly by 37% (95% CI = 7-56) from 3.4- to 2.1-fold excess. Primary prevention resulted in a 48% reduction in CHD mortality from 2.0-fold excess to none, with a smaller reduction of nearly 25% in patients with established disease. Coronary mortality was reduced more in women than in men. In patients without known CHD at registration, all-cause mortality from 1992 was 33% (21-43), lower than in the general population, mainly due to a 37% (21-50) lower risk of fatal cancer. CONCLUSION: The results emphasize the importance of early identification of FH and treatment with statins.

 

Eur Heart J. 2008 Nov;29(21):2583-4. Epub 2008 Oct 7.

Familial hypercholesterolaemia: underdiagnosed and undertreated. (pdf)

Rees A.
Comment on: Eur Heart J. 2008 Nov;29(21):2625-33.

 

BMJ. 2008 Nov 11;337:a2423. doi: 10.1136/bmj.a2423.

Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. (pdf)

Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DC, Liem AH, Heeringa J, Witteman JC, Lansberg PJ, Kastelein JJ, Sijbrands EJ.
Department of Internal Medicine, Erasmus University Medical Centre, PO box 2040, 3000 CA Rotterdam, Netherlands.
Comment in: BMJ. 2009;338:a3041.

OBJECTIVE: To determine the efficacy of statin treatment on risk of coronary heart disease in patients with familial hypercholesterolaemia. DESIGN: Cohort study with a mean follow-up of 8.5 years. SETTING: 27 outpatient lipid clinics. SUBJECTS: 2146 patients with familial hypercholesterolaemia without prevalent coronary heart disease before 1 January 1990. MAIN OUTCOME MEASURES: Risk of coronary heart disease in treated and "untreated" (delay in starting statin treatment) patients compared with a Cox regression model in which statin use was a time dependent variable. RESULTS: In January 1990, 413 (21%) of the patients had started statin treatment, and during follow-up another 1294 patients (66%) started after a mean delay of 4.3 years. Most patients received simvastatin (n=1167, 33 mg daily) or atorvastatin (n=211, 49 mg daily). We observed an overall risk reduction of 76% (hazard ratio 0.24 (95% confidence interval 0.18 to 0.30), P<0.001). In fact, the risk of myocardial infarction in these statin treated patients was not significantly greater than that in an age-matched sample from the general population (hazard ration 1.44 (0.80 to 2.60), P=0.23). CONCLUSION: Lower statin doses than those currently advised reduced the risk of coronary heart disease to a greater extent than anticipated in patients with familial hypercholesterolaemia. With statin treatment, such patients no longer have a risk of myocardial infarction significantly different from that of the general population.

 

BMJ. 2001 Apr 28;322(7293):1019-23.

Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study. (pdf)

Sijbrands EJ, Westendorp RG, Defesche JC, de Meier PH, Smelt AH, Kastelein JJ.
Department of Vascular Medicine and General Internal Medicine, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands.

OBJECTIVE: To estimate all cause mortality from untreated familial hypercholesterolaemia free from selection for coronary artery disease. DESIGN: Family tree mortality study. SETTING: Large pedigree in Netherlands traced back to a single pair of ancestors in the 19th century. Subjects: All members of pedigree aged over 20 years with 0.5 probability of carrying a mutation for familial hypercholesterolaemia. MAIN OUTCOME MEASURE: All cause mortality. RESULTS: A total of 70 deaths took place among 250 people analysed for 6950 person years. Mortality was not increased in carriers of the mutation during the 19th and early 20th century; it rose after 1915, reached its maximum between 1935 and 1964 (standardised mortality ratio 1.78, 95% confidence interval 1.13 to 2.76; P=0.003), and fell thereafter. Mortality differed significantly between two branches of the pedigree (relative risk 3.26, 95% confidence interval 1.74 to 6.11; P=0.001). CONCLUSIONS: Risk of death varies significantly among patients with familial hypercholesterolaemia. This large variability over time and between branches of the pedigree points to a strong interaction with environmental factors. Future research is required to identify patients with familial hypercholesterolaemia who are at extreme risk and need early and vigorous preventive measures.

 

Am J Epidemiol. 2004 Sep 1;160(5):430-5.

Familial hypercholesterolemia, peripheral arterial disease, and stroke: a HuGE minireview. (pdf)

Hutter CM, Austin MA, Humphries SE.
Institute for Public Health Genetics and Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, 1959 NE Pacific Avenue, Seattle, WA 98195, USA.

Heterozygous familial hypercholesterolemia (FH) is an autosomal dominant disorder known to be associated with elevated cholesterol levels and increased risk of premature coronary heart disease. Since increased cholesterol levels lead to atherosclerosis, FH has also been proposed as a risk factor for peripheral vascular and ischemic cerebrovascular disease. Currently, the association between clinical FH and risk of stroke is unclear: Two studies conducted in the 1980s indicated an increased risk of stroke in FH subjects; however, two others found no higher risk, and all had methodological limitations. A recent prospective study of familial hypercholesterolemia by the United Kingdom-based Simon Broome Register Group did not find an excess risk of stroke mortality for subjects with clinical FH. By contrast, the prevalence of peripheral arterial disease is increased from five- to 10-fold in FH subjects compared with non-FH controls. In addition, the intima-media thickness of the carotid and/or femoral artery is increased in FH subjects. Better understanding of the association between FH and the incidence of ischemic stroke events could have a public health impact by improving the diagnosis, prognosis, and treatment of individuals with FH and their relatives and by elucidating the relation between cholesterol levels and ischemic cerebrovascular disease.

 

Stroke. 2003 Jan;34(1):22-5.

Risk of fatal stroke in patients with treated familial hypercholesterolemia: a prospective registry study. (pdf)

Huxley RR, Hawkins MH, Humphries SE, Karpe F, Neil HA; Simon Broome Familial Hyperlipidaemia Register Group and Scientific Steering Committee.
Division Public Health and Primary Health Care, Institute of Health Sciences, University of Oxford, Oxford, UK.
Erratum in:  Stroke. 2003 Mar;34(3):826.
Comment in: Stroke. 2003 Jan;34(1):22-5.

BACKGROUND AND PURPOSE: Although it is recognized that in heterozygous familial hypercholesterolemia, large extracranial carotid vessels are affected by atherosclerosis, the risk of fatal stroke after treatment with cholesterol-lowering therapy remains uncertain. The goal of this study was to determine the risk of fatal stroke in patients with treated familial hypercholesterolemia. METHODS: A cohort of 1405 men and 1466 women with definite or possible heterozygous familial hypercholesterolemia was recruited from 21 outpatient lipid clinics in the United Kingdom. Patients were followed up prospectively from 1980 to 1998 for 22 992 person-years for a median duration of 7.9 years (interquartile range, 4.9 to 12.0 years). The mortality rate was calculated, and the standardized mortality ratio for men and women 20 to 79 years of age was derived from the ratio of the observed deaths to the number expected in the general population of England and Wales (standardized mortality ratio=100 for the standard population). RESULTS: A total of 169 deaths occurred; 9 (5.3%) were a result of stroke. The mortality rate from stroke was 0.39 per 1000 person-years (95% confidence interval, 0.18 to 0.74), and the standardized mortality ratio for fatal stroke was nonsignificantly lower than in the general population (79; 95% CI, 36 to 150). CONCLUSIONS: The results suggest that patients with treated familial hypercholesterolemia are not at increased risk of fatal stroke. However, the possibility cannot be excluded that untreated individuals are at increased risk, which would be consistent with the evidence that familial hypercholesterolemia is a panvascular disease.

 

Circulation. 2002 Dec 10;106(24):3031-6.

Low-density lipoprotein receptor gene mutations and cardiovascular risk in a large genetic cascade screening population. (pdf)

Umans-Eckenhausen MA, Sijbrands EJ, Kastelein JJ, Defesche JC.
Department of Vascular Medicine, Academic Medical Center at the University of Amsterdam, Amsterdam, The Netherlands.

BACKGROUND: A large cohort of patients with familial hypercholesterolemia (FH), free from selection for cardiovascular disease (CVD), and their unaffected relatives was collected by genetic cascade screening and examined for the influence of different mutations of the LDL receptor gene on lipoprotein levels and the risk of CVD. Multivariate analyses with adjustment for age, sex, and specific family ties were performed. METHODS AND RESULTS: Significant variation of LDL levels was observed among 399 patients with FH with different mutations. Null alleles were associated with more severely elevated LDL cholesterol, whereas the frequent N543H/2393del9 mutation led to less elevated LDL cholesterol. The type of mutation did not influence HDL cholesterol levels. Patients with FH had CVD 8.5 times more often compared with their unaffected relatives (RR, 8.54; 95% CI, 5.29 to 13.80). The N543H/2393del9 mutation was associated with a smaller increase of risk compared with other mutations (P<0.0001). After exclusion of families with the N543H/2393del9 mutation, null alleles and other allele mutations no longer differed with regard to LDL cholesterol levels and CVD risk. CONCLUSIONS: LDL receptor mutations only partly contributed to the variation of LDL cholesterol levels and cardiovascular burden in FH. Additional, so far unidentified, familial risk factors must underlie the differences of CVD risk, most likely independent of lipids and lipoproteins.

 

BMJ. 1991 Oct 12;303(6807):893-6.

Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. (pdf)

[No authors listed]
Comment in: BMJ. 2001 Apr 28;322(7293):1062.

OBJECTIVES–(a) To determine the excess mortality from all causes and from coronary heart disease in patients with familial hypercholesterolaemia; (b) to examine how useful various criteria for selective measurement of cholesterol concentration in cardiovascular screening programmes are in identifying these patients. DESIGN–Prospective cohort study. SETTING–Eleven hospital outpatient lipid clinics in the United Kingdom. PATIENTS–282 men and 244 women aged 20-74 with heterozygous familial hypercholesterolaemia. MAIN OUTCOME MEASURE–Standardised mortality ratio, all adults in England and Wales being taken as standard (standardised mortality ratio = 100 for standard population). RESULTS–The cohort was followed up for 2234 person years during 1980-9. Fifteen of the 24 deaths were due to coronary heart disease, giving a standardised mortality ratio of 386 (95% confidence interval 210 to 639). The excess mortality from this cause was highest at age 20-39 (standardised mortality ratio 9686; 3670 to 21,800) and decreased significantly with age. The standardised mortality ratio for all causes was 183 (117 to 273) and also was highest at age 20-39 (standardised mortality ratio 902; 329 to 1950). There was no significant difference between men and women. Criteria for measurement of cholesterol concentration in cardiovascular screening programmes (family history, presence of myocardial infarction, angina, stroke, corneal arcus, xanthelasma, obesity, hypertension, diabetes, or any of these) were present in 78% of patients. CONCLUSIONS–Familial hypercholesterolaemia is associated with a substantial excess mortality from coronary heart disease in young adults but may not be associated with a substantial excess mortality in older patients. Criteria for selective measurement of cholesterol concentration in cardiovascular screening programmes identify about three quarters of patients with the clinically overt condition.

 

Arteriosclerosis. 1988 Mar-Apr;8(2):163-7.

Mortality and cholesterol metabolism in familial hypercholesterolemia. Long-term follow-up of 96 patients. (pdf)

Miettinen TA, Gylling H.
Second Department of Medicine, University of Helsinki, Finland.

The aim of this prospective study was to explore the association of different prognostic factors including parameters of cholesterol metabolism with coronary morbidity and mortality in a study group of 96 patients who were heterozygous for familial hypercholesterolemia. During a 15-year follow-up period, 27% of the patients (44% of the men and 10% of the women, p less than 0.01) died from coronary disease, and an additional 4% died of noncoronary causes. Of the baseline characteristics, male gender, previous myocardial infarction, and smoking were the classical risk factors significantly associated with poor cardiac prognosis. In addition, a low bile acid synthesis predicted enhanced coronary mortality both in univariate and multivariate analysis, and in men bile acid synthesis was significantly correlated with cardiac mortality. Further analysis indicated that also in subjects without baseline myocardial infarction, low bile acid, cholesterol synthesis, or both predicted increased risk of coronary events. In multivariate analysis, male gender, previous myocardial infarction, and low bile acid synthesis at baseline explained 5%, 15%, and 5% (25%), respectively, of the variability of survival. Age, serum total cholesterol, and triglyceride values were unrelated to survival.

 

J R Soc Med. 1986 Jul;79(7):391-4.

Cardiovascular risk in patients with treated familial hypercholesterolaemia and patients with severe hypertriglyceridaemia. (pdf)

Way BP, Ball MJ, Thorogood M, Cobbe SM, Mann JI.

A study was performed to determine the morbidity and mortality from ischaemic heart disease (IHD) in patients with heterozygous familial hypercholesterolaemia (FH) and severe hypertriglyceridaemia (pretreatment plasma triglyceride greater than 5 mmol/l). Twenty-nine (38%) of 76 patients with FH and 8(44%) of 18 patients with hypertriglyceridaemia had evidence of IHD. Over a mean follow-up period of 5.5 years, 2 patients with hypertriglyceridaemia died but there were no deaths in patients with FH. This contrasts with earlier reports which showed a high mortality in FH patients. The lower mortality may be due to improved treatment and consequent lower levels of cholesterol.