Effectiveness of alternative strategies to define index case phenotypes to aid genetic diagnosis of familial hypercholesterolaemia.

OBJECTIVE: To determine the utility of secondary stratification measures to improve the ascertainment of index cases of familial hypercholesterolaemia (FH). DESIGN: A retrospective study of genotyped index patients with Simon Broome (SB) FH. SETTING: University teaching hospital. PATIENTS: 204 patients aged 55±14 years; 36% had tendon xanthoma (TX), 21% had coronary heart disease (CHD), low-density lipoprotein cholesterol (LDL-C) was 6.20±2.24 mmol/l and 55% had genetic FH. INTERVENTIONS: The effects of different staging systems (SB vs Dutch criteria), presence of TX, use of LDL-C level, personal history of CHD and imaging evidence of atheroma by carotid intima-media thickness or coronary artery calcium score to identify genetic FH was explored. OUTCOME MEASURES: Changes in C-statistic and net reclassification index (NRI). RESULTS: SB criteria gave a C-statistic of 0.64 comprising C=0.65 in TX(+) and C=0.5 in TX(-) patients. Genetic FH was present in 75% of TX(+) compared with 44% in TX(-) patients. The Dutch criteria gave C=0.72. Addition of imaging criteria to prior CHD raised C=0.64 to C=0.65 in all patients with a NRI of 19% (p=0.06). In TX(-) patients imaging raised C=0.50 to C=0.65 with a NRI of 0.38 (p=0.001) and a weighted comparison index of 0.28, implying the detection of 14 more FH cases per thousand. CONCLUSIONS: Patients with tendon xanthoma (definite FH) should be genotyped. In patients with possible FH, the presence of a personal history of CHD or imaging evidence of increased atheroma offers the best method of identifying index patients likely to have monogenic FH.

The effect of fibrate-statin combination therapy on cardiovascular events: a retrospective cohort analysis.

OBJECTIVE: To investigate the long-term efficacy of fibrate-statin combination therapy on cardiovascular events as opposed to lipid levels. RESEARCH DESIGN AND METHODS: A retrospective analysis was performed of patients attending metabolic clinics. Cardiovascular risk factor, baseline and final lipid data and details of concomitant drug therapies were gathered on all subjects. OUTCOME MEASURE: The occurrence of major adverse cardiovascular events (MACE) was recorded and major prognostic factors associated with outcome determined. RESULTS: A total of 318 patients with mixed dyslipidaemia were identified on fibrate-statin therapy. Follow-up comprised an average of 7.5 years totalling 2400 patient-years. Patients were 78% male aged 62 years and 68% had evidence of previous cardiovascular disease (CVD). Smoking was present in 17%, hypertension in 41% and 32% had established diabetes. Baseline lipid parameters were total cholesterol (TC) 6.84 mmol/L, triglycerides (TG) 6.09 mmol/L and HDL-C 1.09 mmol/L. Fibrate-statin combination reduced TC by 27% to 4.64 mmol/L, TG by a median 42% to 2.33 mmol/L and increased HDL-C by 21% to 1.22 mmol/L. Non-HDL-C was reduced by 35% and apolipoprotein B by 17%. MACE occurred in 25%. Logistic regression analysis showed that patients with MACE had higher initial TC (7.02 vs. 6.80 mmol/L; p = 0.002), established CVD (65 vs. 57%; p = 0.05) and a lesser atherogenic index response (31 vs. 38%; p = 0.008). Cox regression analysis showed that age (p = 0.002), and previous CVD (p < 0.001) were determinants of outcome allied either to reduction in TG (p = 0.009), TC (p = 0.04) and increase in HDL-C (p = 0.05) or change in TG (p = 0.002) and non-HDL-C (p = 0.01). CONCLUSION: Fibrate-statin therapy in a population with mixed dyslipidaemia resulted in an improved lipid profile with few side-effects. Consistent with its effects, decreases in TG allied with modest decrease in cholesterol and an increase in HDL-C, were associated with better prognosis.