10th June 2009
This retrospective cohort study found that statins significantly reduced the risk of coronary heart disease (CHD) in patients with familial hypercholesterolaemia (FH), even though they were used at lower doses and attained smaller reductions in low-density lipoprotein (LDL) cholesterol than is currently recommended.
Level of evidence
Level 2 (limited-quality patient-oriented evidence) according to the SORT criteria.
Healthcare professionals should follow NICE guidance when looking after people with FH. This includes using the maximum licensed or tolerated dose statins, plus ezetimibe▼ if necessary, to try to achieve at least a 50% reduction in LDL cholesterol from baseline. However, if a patient cannot tolerate or does not wish to take such intensive treatment, more moderate doses and reductions in LDL cholesterol may still be beneficial.
What is the background to this?
Patients with FH — an inborn error of lipid metabolism — have a greatly increased risk of CHD. Statins are the recommended first-line treatment for these patients by NICE, but they have never undergone placebo-controlled trials in this setting because it was considered unethical to withhold active treatment from patients at such high risk. These authors examined the records of 2,400 individuals with FH from 27 lipid clinics in the Netherlands between 1990 and 2002. Of these, 1,950 individuals for whom data on lipid-lowering therapy, including the date of initiation, were available for analysis. They compared the incidence of CHD in the people on treatment with statins with the incidence in those, not on treatment, to perform a statistical analysis that mimicked a clinical trial. They also compared the rates of CHD in the treated and untreated patients with those of an age- and sex-matched population aged over 55 years from the Rotterdam Heart Study — a large population based, prospective, follow-up study starting in 1990 assessing the disease burden in elderly people.
What does this study claim?
The absolute risk of first onset of CHD was 11/1000 person years in statin treated patients compared with 119/1000 person years in untreated patients. Incident CHD occurred at younger age in untreated patients (48.6 versus 50.9 years; P=0.05). After correction for age and sex, treated patients had a 76% reduction in the relative risk of CHD compared with untreated patients (hazard ratio [HR] 0.24; 95% confidence interval [CI] 0.18–0.30; P<0.001). After correction for further risk factors the reduction in relative risk was 82% (HR 0.18; 95% CI 0.13–0.25; P<0.001). However, most patients used simvastatin with a mean dose of 33mg (standard deviation [SD] 20mg), which produced a 44% (SD 16%) decrease in LDL cholesterol.
A further analysis for subjects aged >55 years found that the rate of myocardial infarction (MI) in treated FH patients was 6.7/1000 person-years; this was not significantly different from the reference population (the Rotterdam Heart Study): 4.1/1000 person-years; P=0.07. In untreated FH patients the rate of MI (60.5/1000 person-years) was significantly higher than in the reference group (P<0.001).
NICE guidance recommends that statins are first-line treatment for FH, and that the dose should be increased to the maximum tolerated or licensed dose, to achieve a recommended reduction in LDL cholesterol of greater than 50% from baseline. High-intensity statins should be considered, and ezetimibe▼ is an option if statins are not tolerated or if the desired degree of lipid lowering cannot be attained at the maximum tolerated or licensed dose. However, if a patient cannot tolerate or does not wish to take the intensive treatment recommended by NICE this study suggests that standard doses of statins (such as simvastatin 40mg) and moderate reductions in LDL cholesterol may still be beneficial and produce substantial reductions in CHD risk. When additional risks are also addressed (such as hypertension and smoking), it may be possible to reduce the risks of people with FH such that their risk is similar to that in the general population.
Design Retrospective cohort study from 1st January 1990, with a mean follow-up of 8.5 years.
Patients 1950 individuals with FH from 27 lipid clinics in the Netherlands, for whom data on lipid-lowering therapy, including the date of initiation, were available (of 2400 patient records initially examined). The time from starting therapy was used to perform a statistical analysis that mimicked a clinical trial, with corrections for confounding factors. The authors also compared the rates of CHD in subjects aged >55 years with a reference population from the Rotterdam Heart Study.
Intervention and comparison Statin therapy versus untreated patients.
Outcomes Risk of CHD (defined as MI, percutaneous coronary intervention or other invasive procedures, coronary artery bypass grafting, or confirmed angina pectoris) in treated versus ‘untreated’ (delay in starting treatment group) patients. Risk of incident MI in treated and untreated patients aged >55 years compared with an age- and sex- matched reference population.
Results 413 patients had started treatment by January 1990; 1294 started during follow-up and 243 did not receive statins.
Most patients (n=1167) used simvastatin at a mean dose of 33mg/day (SD 20mg), resulting in a 44% (SD 16%) reduction in LDL cholesterol. A further 211 patients used atorvastatin at a mean dose of 49mg/day resulting in a 49% (SD 15%) reduction. During statin treatment the mean LDL cholesterol level was 4.0mmol/L (SD 1.2mmol/L). The absolute risk of first occurrence of CHD was 11/1000 person-years in statin-treated FH patients and 119/1000 person-years in untreated patients. In subjects aged >55 years the rate of MI was 6.7/1000 person-years in statin-treated FH patients, 60.5/1000 person-years in the untreated FH patients and 4.1/1000 person-years in the reference population.
Sponsorship The study was funded by the Netherlands Heart Foundation and no competing interests were declared.
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