Hypercholesterolemia primary prevention

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [mailto:mgibson@perfuse.org] Phone:617-632-7753; Associate Editor(s)-In-Chief: Kashish Goel, M.D.

Overview
Primary prevention is the most effective means of reducing the global burden of cardiovascular disease. NCEP recommends population-based and clinical-based approaches for primary prevention. Physicians should establish short-term and long-term goals for their patients based on risk factors and 10-year CHD risk. Therapeutic lifestyle changes and LDL lowering are both advocated.

Therapeutic lifestyle changes
Therapeutic lifestyle changes should be recommended to every individual to reduce long-term risk. These include cessation of smoking, dietary modifications, weight control and physical inactivity. A previous meta-analysis showed that dietary lowering of cholesterol was associated with CHD risk reduction similar to drug therapy. A recent randomized controlled trial by Jenkins et al. showed that cholesterol lowering diets were associated with a significant reduction in LDL and 10-year CHD risk at 6 monhts, as compared to control diet. ATP III recommends a multifaceted lifestyle approach to reduce risk for CHD. The essential features of this approach designated as therapeutic lifestyle changes are: 1. Reduced intakes of saturated fats (<7% of total calories) and cholesterol (<200 mg per day).

2. Therapeutic options for enhancing LDL lowering such as plant stanols/sterols (2 g/day) and increased viscous (soluble) fiber (10-25 g/day)

3. Weight reduction

4. Increased physical activity



LDL lowering drug therapy
LDL lowering therapy for primary prevention has been evaluated in numerous trials. If therapeutic lifestyle changes do not achieve the desired LDL goal, then drug therapy should be considered. Statins are usually the 'first choice' medications. Trials evaluating the role of statin therapy in primary prevention are detailed here.

Meta-analyses

 * A recently published Cochrane meta-analysis including 14 randomized controlled trials (34,272 participants) showed a significant reduction in all-cause mortality, combined fatal and non-fatal CVD endpoints and revascularizations with statin therapy in subjects without cardiovascular disease. However, they reported heterogeneity of effects between studies.


 * Another meta-analysis evaluating the role of statins in primary prevention of cardiovascular disease showed a significant reduction in major coronary events, major cerebrovascular events and revascularizations in 42, 848 participants, however no change in coronary heart disease mortality or overall mortality was noted.

WOSCOPS (1995)
Treatment with pravastatin 40 mg daily in 6595 men with hypercholesterolemia resulted in a significant reduction in the incidence of fatal and non-fatal myocardial infarction and death from cardiovascular causes, without a difference in the deaths due to non-cardiovascular causes in a follow-up period of 4.9 years.

AFCAPS/TexCAPS (1998)
Lovastatin 20-40 mg daily (in addition to low-saturated ad low-colesterol diet) reduced the incidence of first major acute cardiovascular event (MACE) during a follow-up of 5.2 years, in this study involving 5608 men and 997 women with average total cholesterol and LDL levels and low HDL levels.

PROSPER (2002)
Pravastatin 40 mg daily reduced the incidence of non-fatal MI and CHD death during a follow-up of 3.2 years, in this trial involving the 2804 elderly men and 3000 women with a history of, or risk factors for vascular disease. This trial extended the treatment strategies to elderly population.

ALLHAT-LLT (2002)
No significant difference was observed on CHD mortality in the group treated with pravastatin 40 mg daily as compared to the usual care group with well controlled hypertension and moderately elevated LDL. Possible explanations for failure to observe a significant reduction included a modest reduction in total cholesterol, unblinded study with no placebo group and a large crossover of high risk subjects

ASCOT-LLA (2003)
Hypertensive patients (n=10305) with total cholesterol < 251 mg/dL were randomly assigned to atorvastatin 10 mg daily and a significant reduction in non-fatal MI, fatal CHD and stoke (fatal and non-fatal) was noticed. No significant difference was observed on all-cause mortality. The trial was stopped earlier than expected of 5 years because of beneficial treatment.

HPS (2003)
In the sub-group of 5963 patients with diabetes without known occlusive vascular disease, simvastatin 40 mg daily significantly reduced the rate of first major vascular events during a follow-up period of 4.8 years.

CARDS (2004)
Atorvastatin 10 mg daily significantly reduced the occurrence of primary end-point of MACE and secondary end-points of CHD events, coronary revascularizations and stroke during a median follow-up of 3.9 years in 2838 patients with type 2 diabetes and LDL < 160 mg/dL. Trial was stopped 2 years earlier than expected.

ASPEN (2006)
In 1905 patients with diabetes and no prior CHD, the composite/primary end-point and secondary end-points of CV mortality, fatal/non-fatal MI, revascularizations, strokes or hospitalization for angina were similar in the treatment group (atorvastatin 10 mg daily) and placebo.

MEGA (2006)
A total of 3966 Japanese subjects with hypercholesterolemia were randomized to diet alone or diet plus pravastatin 10-20 mg daily during a mean follow-up of 5.3 years. Low dose pravastatin significantly reduced the occurence of CHD in this ethnicity-specific study.

JUPITER (2008)
This most recent trial randomly assigned 17,802 healthy subjects with LDL < 130 mg/dL and high-sensitivity CRP > 2 g/L to Rosuvastatin 20 mg daily or placebo. A significant reduction in the composite and individual components of the primary end-point of myocardial infarction, stroke, arterial revascularization hospitalization for unstable angina or death from cardiovascular causes and all-cause mortality was noted and trial was stopped earlier at 1.9 years (maximum of 5 years).