Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia

ObjectivesTo assess the cost effectiveness of strategies to screen for and treat familial hypercholesterolaemia.DesignCost effectiveness analysis. A care pathway for each patient was delineated and the associated probabilities, benefits, and costs were calculated.ParticipantsSimulated population aged 16-54 years in England and Wales.InterventionsIdentification and treatment of patients with familial hypercholesterolaemia by universal screening, opportunistic screening in primary care, screening of people admitted to hospital with premature myocardial infarction, or tracing family members of affected patients.ResultsTracing of family members was the most cost effective strategy (£3097 (€5066, $4479) per life year gained) as 2.6 individuals need to be screened to identify one case at a cost of £133 per case detected. If the genetic mutation was known within the family then the cost per life year gained (£4914) was only slightly increased by genetic confirmation of the diagnosis. Universal population screening was least cost effective (£13 029 per life year gained) as 1365 individuals need to be screened at a cost of £9754 per case detected. For each strategy it was more cost effective to screen younger people and women. Targeted strategies were more expensive per person screened, but the cost per case detected was lower. Population screening of 16 year olds only was as cost effective as family tracing (£2777 with a clinical confirmation).ConclusionsScreening family members of people with familial hypercholesterolaemia is the most cost effective option for detecting cases across the whole population.

What is already known on this topic

In the United Kingdom there are an estimated 110 000 men and women with familial hypercholesterolaemia, only a small percentage of whom have been identified to dateWithout identification and treatment, over half of these people will have a fatal or non-fatal coronary heart disease event by the age of 50 (men) or 60 (women)Effective treatment of high cholesterol concentrations reduces total and coronary heart disease mortalityNo recommended screening strategy currently exists in the United Kingdom for familial hypercholesterolaemia

What this study adds

Computer modelling has shown that the earlier familial hypercholesterolaemia is diagnosed the more cost effective the screening strategy becomesIdentifying relatives of people with familial hypercholesterolaemia is the most cost effective screening option for all age groupsAs technology improves and the cost of statins falls all strategies will become more cost effective     

Combination treatment with cholestyramine and bezafibrate for heterozygous familial hypercholesterolaemia.

Cholestyramine and bezafibrate were compared individually and in combination in the treatment of 18 patients with heterozygous familial hypercholesterolaemia. The study used a double blind, placebo controlled block design with a placebo run in period of two months followed by three phases of active treatment, each of two months'' duration. Patients were randomly allocated to one of the six possible sequences of medication so that three patients would be treated with each sequence. Two patients withdrew from the study before completion. The median concentration of total cholesterol decreased from 9.65 mmol/l (interquartile range 8.62 to 8.72) to 7.24 mmol/l (6.70 to 7.52) with cholestyramine, to 8.09 mmol/l (7.18 to 8.68) with bezafibrate, and to 6.31 mmol/l (5.84 to 7.27) with the combination. This fall was due almost entirely to a decrease in the low density lipoprotein cholesterol concentration, and the combination was significantly more effective than either drug alone. The 98% confidence intervals for the median differences between the combination and cholestyramine and the combination and bezafibrate were 0.04 to 1.49 mmol/l and 0.51 to 2.18 mmol/l respectively. These results suggest that this combination is an effective and useful treatment in heterozygous familial hypercholesterolaemia.     

Diagnosing familial hypercholesterolaemia in childhood by measuring serum cholesterol.

The serum cholesterol concentrations of 134 children aged 1-16 years who had at least one first-degree relative with presumed familial hypercholesterolaemia showed a bimodal distribution, and, using the maximum likelihood technique, two overlapping curves could be fitted. The mean value of the affected children (heterozygotes) was 8-9 mmol/l and that of the unaffected 4-9 mmol/l. The two curves intersected at 6-77 mmol/l, and at this point 5% of the unaffected children had values over 6-77 mmol/l and 3-5% of the heterozygotes had values under 6-77 mmol/l. If this cholesterol concentration is used as a cut-off point 4-25% of cases would be misdiagnosed.     

Lipid concentrations and the use of lipid lowering drugs: evidence from a national cross sectional survey

ObjectiveTo evaluate the prevalence of the use of lipid lowering agents and its relation to blood lipid concentrations in English adults.DesignCross sectional survey.SettingEngland, 1998.ParticipantsNationally representative sample of 13 586 adults (aged ⩾16 years) living in non-institutional households.Results Mean total cholesterol concentrations were 5.47 (SE 0.02) mmol/l in men and 5.59 (0.02) mmol/l in women. Mean HDL cholesterol concentrations were 1.28 (0.01) mmol/l in men and 1.55 (0.01) mmol/l in women. Overall, of 10 569 adults who had a valid cholesterol measurement taken 7133 (67.5%; 95% confidence interval 66.5% to 68.4%) had a total cholesterol concentration ⩾5 mmol/l, 2804 (26.5%; 25.7% to 27.4%) had a ratio of total cholesterol to HDL cholesterol ⩾5 mmol/l, and 237 (2.2%; 1.9% to 2.5%) reported taking lipid lowering drugs. Of 117 participants with no history of cardiovascular disease but whose estimated 10 year risk of coronary heart disease was ⩾30% and whose total cholesterol concentration was ⩾5 mmol/l, four (3%) were taking lipid lowering drugs. Of 385 adults aged 16-75 with a history of coronary heart disease and eligible for lipid lowering treatment, 114 (30%; 25% to 34%) were taking lipid lowering drugs, of whom only 50 (44%; 35% to 53%) had a total cholesterol concentration <5 mmol/l.ConclusionsDespite the high prevalence of dyslipidaemia in English adults, the proportion of adults taking lipid lowering drugs in 1998 was only 2.2%. Rates of treatment were low among high risk patients eligible for primary prevention with lipid lowering drugs, and less than one third of patients with established cardiovascular disease received such treatment.     

What is the clinical utility of DNA testing in patients with familial hypercholesterolaemia?

PURPOSE OF REVIEW: Familial hypercholesterolaemia is a common genetic disorder of lipid metabolism in which patients have a significantly elevated risk of early coronary heart disease, which can be substantially lowered by treatment with the statin class of drugs. In many countries in Europe, tracing of relatives using DNA information, once the family mutation has been identified, is being actively carried out. The present review examines the specificity and clinical utility of DNA testing in patients with familial hypercholesterolaemia. RECENT FINDINGS: Technological progress has improved the detection rate in patients with the strongest clinical suspicion of familial hypercholesterolaemia to more than 70-80%. Patients carrying a mutation have, on average, higher low-density lipoprotein cholesterol levels and greater risk of early coronary heart disease, and studies have reported the utility of DNA information in the identification of affected relatives. More than 1000 different molecular causes of familial hypercholesterolaemia are documented in the University College London database, and although more than 90% of these clearly cause familial hypercholesterolaemia, the remainder require careful interpretation. SUMMARY: DNA testing, as an adjunct to the measurement of plasma low-density lipoprotein cholesterol levels, has clinical utility in providing an unequivocal diagnosis in patients and in identifying affected relatives at an early age so that they can be offered lifestyle advice and appropriate lipid-lowering therapies. Researchers and DNA diagnostic laboratories need to interpret novel sequence changes with caution in order to avoid a false positive diagnosis.     

Effectiveness of programme for reducing cardiovascular risk for men in one general practice.

OBJECTIVES--To assess the effectiveness of a programme for reducing cardiovascular risk in men in terms of clinical measurements and perceptions of patients. DESIGN--Collection of paired data on men attending well person clinics over three to five years. Questionnaire to determine changes in risk related habits. SETTING--Well person clinics in rural general practice with five partners in mid-Wales. SUBJECTS--The first 687 men seen in the clinic: analysable data obtained on 520. Initial age range 28-60 years. MAIN OUTCOME MEASURES--Analysis of serum cholesterol concentration (mmol/l) and blood pressure (mm Hg). Changes in diet, exercise, smoking, and drinking. RESULTS--Mean (SD) cholesterol concentration for all subjects increased from 5.8 (1.0) to 6.0 (1.0), p < 0.001. Overall percentage of ideal weight and mean systolic blood pressure also increased. Mean diastolic blood pressure was unchanged at 84 mm Hg. Professed dietary change, age, and number of visits all had significant effects on final cholesterol concentration. Those seen more often showed a significant decrease in cholesterol concentrations (in those seen more than twice mean (SD) initial value 6.7 (0.9) mmol/l v final value 6.5 (1.0) mmol/l, p < 0.001). Those over 45 years at start of study showed a significant decrease in diastolic blood pressure (mean (SD) initial value 89 (9) mm Hg v final value 86 (7) mm Hg, p < 0.001). CONCLUSIONS--These clinics are not effective in achieving a reduction in mean cholesterol concentration or blood pressure, despite evidence that the message of reduction in risk had been successfully transmitted. Success was achieved in older patients and those in whom a definite problem was identified. Identification of high risk groups and clinical case finding with appropriate long term follow up may be more cost effective in reducing cardiovascular risk than non-specific screening of the whole population.     

Case-control study of whether subfertility in men is familial.

OBJECTIVE--To test the hypothesis that subfertility in men is familial and to examine the distribution of subfertility within families for consistency with a genetic cause. DESIGN--Case-control study and segregation analysis. SETTING--Two teaching hospitals in Leeds. SUBJECTS--Cases (probands) were men with an abnormal sperm count who attended a subfertility clinic and whose partners had no major factor contravening fertility. Controls were fathers of two or more children recruited through vasectomy clinics or a maternity department. MAIN OUTCOME MEASURES--The incidence of involuntary childlessness among brothers with partners and among sisters and second and third degree male relatives. When possible clinical and laboratory details were obtained from involuntarily childless brothers. RESULTS--Seventeen of the 148 (11.5%) brothers of probands but none of the 169 brothers of controls had sought medical advice for childlessness (P < 0.0005). Four probands had more than one involuntarily childless brother. There were six further brothers whose childlessness was thought to be involuntary bringing the total prevalence of subfertility among brothers of probands to 16%. Segregation analysis was consistent with an autosomal recessive mode of inheritance accounting for 60% of subfertility in men. Seventeen of the 346 (4.9%) uncles of probands and 10 of 420 (2.8%) uncles of controls were reported to be involuntarily childless (P = 0.09), but there was no difference in childlessness among sisters. In three families sperm counts from "affected" brothers confirmed the diagnosis and showed considerable similarities within but not between families. CONCLUSION--Subfertility in men has a familial component, and the observations are consistent with an autosomal recessive mode of inheritance in over half the cases. Several different genes are probably involved.     

Endpiece: A chameleon

ObjectivesTo examine the relation between self reported eating frequency and serum lipid concentrations in a free living population.Design Cross sectional population based study.Setting Norfolk, England.Participants 14 666 men and women aged 45-75 years from the Norfolk cohort of the European prospective investigation into cancer (EPIC-Norfolk).Results Mean concentrations of total cholesterol and low density lipoprotein cholesterol decreased in a continuous relation with increasing daily frequency of eating in men and women. No consistent relation was observed for high density lipoprotein cholesterol, body mass index, waist to hip ratio, or blood pressure. Mean cholesterol concentrations differed by about 0.25 mmol/l between people eating more than six times a day and those eating once or twice daily; this difference was reduced to 0.15 mmol/l after adjustment for possible confounding variables, including age, obesity, cigarette smoking, physical activity, and intake of energy and nutrients (alcohol, fat, fatty acids, protein, and carbohydrate).Conclusions Concentrations of total cholesterol and low density lipoprotein cholesterol are negatively and consistently associated with frequency of eating in a general population. The effects of eating frequency on lipid concentrations induced in short term trials in animals and human volunteers under controlled laboratory conditions can be observed in a free living general population. We need to consider not just what we eat but how often we eat.

What is already known on this topic

Studies in animals and small human trials indicate that eating frequency is inversely related to serum lipid concentrationsFew studies have examined this in a free living population under no dietary restrictions

What this study adds

In a free living population increased eating frequency was negatively and significantly associated with concentrations of total cholesterol and low density lipoprotein cholesterolThis association was still present after adjustment for body mass index, physical activity, cigarette smoking, and dietary intakeMean age adjusted cholesterol concentrations differed by 0.25 mmol/l between people eating more than six times a day and those eating less than twice daily     

Sex difference in the regulation of plasma high density lipoprotein cholesterol by genetic and environmental factors

Association between high density lipoprotein (HDL) cholesterol concentration and restriction fragment length polymorphisms at the cholesteryl ester transfer protein (CETP) gene locus was studied in a random population-based cohort of 526 Caucasian subjects (259 men, mean age 50.9 years, and 267 women, mean age 51.8 years). HDL cholesterol concentration was adjusted for age, body mass index, alcohol consumption, smoking and plasma triglyceride and low density lipoprotein cholesterol levels. In females, the HDL cholesterol levels were associated withTagIB polymorphism (1.46 mmol/1 in the B1B1 genotype, 1.56 mmol/l in B 1B2 and 1.72 mmol/1 in B2B2,P = 0.0001 for the trend). In contrast, this was not observed in men (1.24, 1.20, 1.27 mmol/l, NS). The association was seen even in women who were current smokers (1.41, 1.56, 1.75 mmol/l,n = 72,P = 0.007), but not in male smokers (1.26, 1.19, 1.14 mmol/l,n = 102, NS). In male non-smokers the association was weak (1.22, 1.20, 1.32 mmol/l,n = 157,P = 0.05). In postmenopausal women not receiving hormone replacement therapy (n = 108), the association continued to be present, although weaker (1.50, 1.58, 1.70 mmol/l,P = 0.06). CETP activity (n = 101) tended to be lower in subjects with the 132132 genotype. In conclusion, a clear-cut sex difference was observed in the genotype effect on plasma HDL cholesterol levels. The slight attenuation of the gene dosage effect after menopause suggests that the gender difference may be, at least in part, due to sex hormones. A genetic subgroup (men with the 132132 genotype) particularly susceptible to the HDL cholesterol decreasing effect of smoking could be demonstrated.Part of this work was presented at the 67th Scientific Sessions of the American Heart Association, Dallas, Texas, USA, 14–17 November, 1994     

Lipid screening: is it enough to measure total cholesterol concentration?

OBJECTIVES--To determine whether measurement of total cholesterol concentration is sufficient to identify most patients at lipoprotein mediated risk of coronary heart disease without measurement of triglyceride and high density lipoprotein (HDL) cholesterol concentrations. DESIGN--Cross sectional screening programme. SETTING--Six general practices in Oxfordshire. PATIENTS--1901 Men and 2068 women aged 25-59. MAIN OUTCOME MEASURE--Cardiovascular risk as assessed by fasting venous plasma concentrations of total cholesterol, triglyceride, and HDL cholesterol. RESULTS--2931 Patients (74% of those screened) had a total cholesterol concentration of less than 6.5 mmol/l. If the triglyceride concentration had not been measured in these patients isolated hypertriglyceridaemia (greater than or equal to 2.3 mmol/l) would have remained undetected in 185. Among these 185 patients, however, 123 were overweight or obese and only 18 (0.6% of those screened) had an increased risk associated with both a raised triglyceride concentration (greater than or equal to 2.3 mmol/l) and a low HDL cholesterol concentration (less than 0.9 mmol/l). Conversely, in the 790 patients with predominant hypercholesterolaemia (cholesterol concentration greater than or equal to 6.5 mmol/l and triglyceride concentration less than 2.3 mmol/l) measurement of HDL cholesterol concentration showed that 348 (9% of those screened) had only a moderately increased risk with a ratio of total to HDL cholesterol of less than 4.5 and 104 had a low risk with a ratio of less than 3.5. CONCLUSIONS--Fasting triglyceride and HDL cholesterol concentrations identify few patients at increased risk of coronary heart disease if the total cholesterol concentration is less than 6.5 mmol/l. HDL cholesterol and triglyceride concentrations should, however, be measured in patients with a total cholesterol concentration exceeding this value. Total cholesterol concentration alone may overestimate risk in a considerable number of these patients, and measurement of HDL cholesterol concentration allows a more precise estimate of risk. Measurement of the triglyceride concentration is required to characterise the lipoprotein abnormality. A patient should not be started on a drug that lowers lipid concentrations without having had a full lipoprotein assessment including measurement of HDL cholesterol concentration.     

Contrasting patterns of coronary atherosclerosis in normocholesterolaemic smokers and patients with familial hypercholesterolaemia.

An angiographic comparison was made of the extent and severity of coronary artery disease in 25 patients with heterozygous familial hypercholesterolaemia and 25 normocholesterolaemic patients with coronary artery disease in whom heavy cigarette consumption was the chief risk factor. The patients with familial hypercholesterolaemia were younger and included a much higher proportion of women than the smokers. Significantly more patients with familial hypercholesterolaemia had disease of the main stem of the left coronary artery (eight v none, p less than 0.05) and triple-vessel disease (18 v four, p less than 0.05). Disease affecting only distal vessels occurred in five smokers, whereas all the patients with familial hypercholesterolaemia showed a combination of proximal and distal lesions. These findings suggest that cigarette smoking and familial hypercholesterolaemia predispose to different patterns of coronary atheroma. Early coronary angiography with a view to coronary artery bypass surgery seems desirable in symptomatic patients with familial hypercholesterolaemia because of the common association of this disorder with life-threatening left main-stem disease.     

Fall in total cholesterol concentration over five years in association with changes in fatty acid composition of cooking oil in Mauritius: cross sectional survey.

OBJECTIVE: To determine the extent to which reducing the saturated fatty acid composition of a ubiquitously used cooking oil influenced changes in cholesterol concentration in the population during a five year intervention programme in Mauritius. DESIGN: Cross sectional surveys in 1987 and 1992 determined mean total cholesterol concentrations in the population. A random sample of respondents in the 1992 survey completed a nutrition questionnaire that included questions on diet in the previous 24 hours. SETTING: Mauritius. INTERVENTION: In 1987 the government of Mauritius changed the composition of the commonly used cooking oil from being mostly palm oil (high in saturated fatty acids) to being wholly soya bean oil (high in unsaturated fatty acids). SUBJECTS: 5080 and 5162 subjects in 1987 and 1992 cross sectional surveys. 2059 subjects aged 30-64 years were randomly selected from the respondents of the 1992 survey to take part in the nutrition survey. MAIN OUTCOME MEASURES: Fatty acid composition of phospholipids in pooled serum samples from men and women from the two surveys; measured and predicted change in serum cholesterol concentration. RESULTS: From 1987 to 1992 total cholesterol concentrations fell significantly by 0.79 mmol/l (P < 0.001) in men and 0.82 mmol/l (P < 0.001) in women. The estimated intake of saturated fatty acids decreased by 3.5% of energy intake in men and by 3.6% in women, and the intake of polyunsaturated fatty acids increased by 5.5% and 5.6% of energy intake, respectively. These changes were reflected in changes in the fatty acid composition of serum phospholipids, and according to Keys'' formula these changes explained much of the decrease in serum cholesterol concentrations (predicted decrease of 0.38 mmol/l in men and by 0.40 mmol/l in women). CONCLUSION: Dietary changes that entailed a reduction in the saturated fat content of a ubiquitous cooking oil explained most of the observed decrease in serum cholesterol concentration over five years in the population of Mauritius.     

High prevalence of low HDL cholesterol concentrations and mixed hyperlipidemia in a Mexican nationwide survey

The prevalence of lipid abnormalities revealed in a survey done in 417 Mexican cities is described. Information was obtained on 15,607 subjects, aged 20 to 69 years. In this report, only samples obtained after a 9- to 12-h fast were included (2,256 cases: 953 men and 1,303 women). The population is representative of Mexican urban adults. Mean lipid concentrations were: cholesterol, 4.80 mmol/l; triglycerides, 2.39 mmol/l; HDL cholesterol, 1.00 mmol/l; and LDL cholesterol, 3.06 mmol/l. The most prevalent abnormality was HDL cholesterol below 0.9 mmol/l (46.2% for men and 28.7% for women). Hypertriglyceridemia (>2.26 mmol/l) was the second most prevalent abnormality (24.3%). Severe hypertriglyceridemia (>11.2 mmol/l) was observed in 0.42% of the population. Increased LDL cholesterol (> or =4.21 mmol/l) was observed in 11.2% of the sample. Half of the hypertriglyceridemic subjects had a mixed dyslipidemia or low HDL cholesterol. More than 50% of the low HDL cholesterol cases were not related to hypertriglyceridemia. Insulin resistance was found in 59% of them. In conclusion, the prevalence of hypoalphalipoproteinemia and other forms of dyslipidemia in Mexican adults is very high and it is among the highest previously reported worldwide.     

Carotid artery plaque in women with rheumatoid arthritis and low estimated cardiovascular disease risk: a cross-sectional study

IntroductionWe previously reported that most patients with rheumatoid arthritis (RA) and moderate cardiovascular disease (CVD) risk according to the Systematic COronary Evaluation score (SCORE) experience carotid artery plaque. In this study, we aimed to identify patient characteristics that can potentially predict carotid plaque presence in women with RA and a concurrent low CVD risk according to the SCORE.MethodsA cohort of 144 women with an evaluated low risk of CVD (SCORE value of zero) was assembled amongst 550 consecutive patients with RA that underwent CVD risk factor recording and carotid artery ultrasound. Participants had no established CVD, moderate or severe chronic kidney disease, or diabetes. We assessed carotid plaque(s) presence and its associated patient characteristics.ResultsCarotid artery plaque was present in 35 (24.3%) of women with RA. Age, the number of synthetic disease-modifying agents (DMARDs) and total cholesterol concentrations were independently associated with plaque in multivariable stepwise backward regression analysis (odds ratio (95% confidence interval) = 1.15 (1.07 to 1.24), P <0.0001, 1.51 (1.05 to 2.17), P = 0.03 and 1.66 (1.00 to 2.73) P = 0.04), respectively). The area under the curve (AUC) of the receiver operating curve (ROC) for the association with plaque was 0.807 (P <0.0001), 0.679 (P = 0.001) and 0.599 (P = 0.08) for age, total cholesterol concentrations and number of synthetic DMARDs used, respectively. The optimal cutoff value in predicting plaque presence for age was 49.5 years with a sensitivity and specificity of 74% and 75%, respectively, and for total cholesterol concentration, it was 5.4 mmol/l with a sensitivity and specificity of 63% and 70%, respectively. The plaque prevalence was 37.5% in patients (n = 80; 55.6%) with age >49.5 years or/and total cholesterol concentration of >5.4 mmol/l, respectively, compared to only 7.8% in those (n = 64; 44.4%) with age ≤49.5 years or/and total cholesterol concentration of ≤5.4 mmol/l, respectively.ConclusionsApproximately one-third of women with RA who experience a low SCORE value and are aged >49.5 years or/and have a total cholesterol concentration of >5.4 mmol/l, experience high-risk atherosclerosis, which requires intensive CVD risk management.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0576-7) contains supplementary material, which is available to authorized users.     

Do Abnormal Serum Lipid Levels Increase the Risk of Chronic Low Back Pain? The Nord-Tr?ndelag Health Study

Background

Cross-sectional studies suggest associations between abnormal lipid levels and prevalence of low back pain (LBP), but it is not known if there is any causal relationship.

Objective

The objective was to determine, in a population-based prospective cohort study, whether there is any relation between levels of total cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides and the probability of experiencing subsequent chronic (LBP), both among individuals with and without LBP at baseline.

Methods

Information was collected in the community-based HUNT 2 (1995–1997) and HUNT 3 (2006–2008) surveys of an entire Norwegian county. Participants were 10,151 women and 8731 men aged 30–69 years, not affected by chronic LBP at baseline, and 3902 women and 2666 men with LBP at baseline. Eleven years later the participants indicated whether they currently suffered from chronic LBP.

Results

Among women without LBP at baseline, HDL cholesterol levels were inversely associated and triglyceride levels positively associated with the risk of chronic LBP at end of follow-up in analyses adjusted for age only. Adjustment for the baseline factors education, work status, physical activity, smoking, blood pressure and in particular BMI largely removed these associations (RR: 0.96, 95% CI: 0.85–1.07 per mmol/l of HDL cholesterol; RR: 1.16, 95% CI: 0.94–1.42 per unit of lg(triglycerides)). Total cholesterol levels showed no associations. In women with LBP at baseline and men without LBP at baseline weaker relationships were observed. In men with LBP at baseline, an inverse association with HDL cholesterol remained after complete adjustment (RR: 0.83, 95% CI: 0.72–0.95 per mmol/l).

Conclusion

Crude associations between lipid levels and risk of subsequent LBP in individuals without current LBP are mainly caused by confounding with body mass. However, an association with low HDL levels may still remain in men who are already affected and possibly experience a higher pain intensity.     

Treatment of familial hypercholesterolaemia. United Kingdom lipid clinics study of pravastatin and cholestyramine.

OBJECTIVE--To compare the efficacy and safety of cholestyramine, an anion exchange resin, and pravastatin, a new hydrophilic specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, in the treatment of heterozygous familial hypercholesterolaemia. DESIGN--Double blind, double dummy, placebo controlled study with three parallel groups. SETTING--Six specialist lipid clinics in the United Kingdom. PATIENTS--128 patients aged 18-70 with heterozygous familial hypercholesterolaemia diagnosed on strict biochemical and clinical findings. MAIN OUTCOME MEASURES--Total plasma cholesterol, triglyceride, and lipoprotein subfractions and biochemical and haematological safety parameters. RESULTS--Pravastatin (40 mg/day) led to a 25% reduction in total plasma cholesterol concentration and a reduction in low density lipoprotein cholesterol concentration of 30%. Cholestyramine (24 g/day) led to similar reductions in concentrations of total cholesterol (23%) and low density lipoprotein cholesterol (31%). No consistent changes occurred in high density lipoprotein cholesterol values with either compound. Plasma triglyceride concentrations showed a small rise (18%) on resin therapy. No serious adverse drug reactions occurred during the study. CONCLUSIONS--Pravastatin seems to be a highly effective, well tolerated drug for severe hypercholesterolaemia. Patients chosen for this study were recruited on the basis that they could tolerate a full dose of cholestyramine, and in this situation cholestyramine was also highly effective in lowering plasma low density lipoprotein cholesterol concentrations.     

Effect of pectin on cholesterol distribution in the lipoproteins of streptozotocin-diabetic rats fed cholesterol diet

In rats fed a semisynthetic diet, streptozotocin-induced diabetes [45 mg/kg, 17 days] led to hypertriglyceridaemia [6.4 mmol/l], to a marked increase in the proportion of plasma cholesterol present in the very low density lipoproteins [VLDL] [to 40 %] and to a decrease in the amount present in the high density lipoproteins [HDL] [to 34 %]. The addition of 0.25 % cholesterol to the above diet led in healthy rats to hypercholesterolaemia [4.3 mmol/l] and to similar changes in the distribution of cholesterol in the lipoproteins. In diabetic rats, the same diet led to pronounced hypertriglyceridaemia [13.8 mmol/l] and hypercholesterolaemia [18.9 mmol/l], while the proportion of HDL-borne plasma cholesterol fell still further to 6 % and rose in the VLDL to 70 %. The addition of pectin to the diet in 6 % concentration markedly inhibited triglyceridaemia [3.3 mmol/l] and cholesterolaemia [4.4 mmol/l] and raised the proportion of HDL plasma cholesterol to 47 %.     

Long term metabolic effects of two dietary methods of treating hyperlipidaemia.

OBJECTIVES--To compare the long term metabolic effects of two diets for treating hyperlipidaemia. DESIGN--Randomised controlled study: after three weeks of normal (control) diet, subjects were randomly allocated to one of two test diets and followed up for six months. SETTING--Lipid clinic of tertiary referral centre in Naples. SUBJECTS--63 subjects with primary type IIa and IIb hyperlipoproteinaemia entered the study, and 44 completed it. Exclusion criteria were taking drugs known to influence lipid metabolism, evidence of cardiovascular disease, homozygous familial hypercholesterolaemia, and body mass index over 30. INTERVENTIONS--Two test diets with reduced saturated fat (8%) and cholesterol (approximately 200 mg/day): one was also low in total fat and rich in carbohydrate and fibre, and the other was low in carbohydrate and fibre and rich in polyunsaturated and monounsaturated fats. MAIN OUTCOME MEASURES--Fasting plasma lipid and lipoprotein concentrations; blood glucose, insulin, and triglyceride concentrations before and after a test meal. RESULTS--In comparison with the control diet, both test diets induced significant and similar decreases in low density lipoprotein cholesterol concentrations (by a mean of 0.72 (SE 0.15) mmol/l, P < 0.001, for low total fat diet; by 0.49 (0.18) mmol/l, P < 0.05, for high unsaturated fat diet) and plasma triglyceride concentrations (by 0.21 (0.09) mmol/l, P < 0.05, for low total fat diet; by 0.39 (0.15) mmol/l, P < 0.05, for high unsaturated fat diet), while high density lipoprotein cholesterol concentrations after fasting and plasma glucose and insulin concentrations during test meals were not modified by either diet. CONCLUSIONS--Both test diets are suitable (alone or in combination) for treatment of hypercholesterolaemia.     

Explaining Poorer Stroke Outcomes in Women: Women Surviving 3 Months Have More Severe Strokes Than Men Despite a Lower 3-Month Case Fatality

BackgroundWomen who survive stroke are more disabled and more often institutionalized than men.ObjectiveWe explore this phenomenon by studying case fatality and stroke severity in stroke survivors separately for men and women.MethodsA Danish stroke registry (2000−2007) contains information about 26,818 patients with first-ever ischemic stroke, including stroke severity (Scandinavian Stroke Scale, 0 worst to 58 best), computed tomography scan, cardiovascular risk factors, and death 3 months after stroke. We modeled stroke severity by generalized additive linear model and 3-month case fatality with logistic model adjusting for age and cardiovascular risk factors.ResultsMale to female ratio was 51.5% to 48.5%. Mean age was 68.8 (SD 12.6) years in men; 73.7 (13.8) years in women. Stroke was more severe in women (mean [SD] Scandinavian Stroke Scale, 42.2 [16.0]) than in men (mean [SD] Scandinavian Stroke Scale, 45.6 [14.2]) also after adjustment for age and cardiovascular risk factors; significant in patients older than 75 years. In survivors at 3 months, stroke was more severe in women than men, given same age and cardiovascular risk factor profile; significant in patients older than 75 years. More women (11.9%) had died within 3 months than men (8.6%). However, adjusting for age, stroke severity, and risk factor profile, 3-month case fatality was lower in women than men; significant in patients older than 78 years.ConclusionsAlthough 3-month case fatality was lower in women than men, strokes were more severe among survivors at 3 months in women than in men. In addition, strokes were more severe in women. Our data help elucidate why women survive stroke better but have poorer functional outcomes that require more care than men.