Arterial Disease Multifactorial Intervention Trial (ADMIT)

BACKGROUND:

Multiple mechanisms are involved in the deposition of LDL-C into the arterial wall, and the prevention of such deposition as well as the removal of the LDL-particles. Further, there remain questions regarding what causes an existing plaque that has been stable for a long period of time to become occlusive or ulcerating and what may prevent it from doing so. Prevention and treatment are almost certain to become multifaceted and more complex when using several complementary interventions or preventive measures concomitantly.

Multifactorial prevention and treatment may be particularly useful in people with peripheral arterial disease. PAD as manifested by intermittent claudication affects about 0.5 to 1.0 percent of individuals above age 35, with a twofold predominance in men. There is a strikingly increased incidence with age in both sexes, particularly in those above age 50. Mortality in patients with intermittent claudication has been shown to be six times higher than in other people of similar age and gender. The excess in mortality is primarily due to a ninefold increase in cardiovascular disease (CVD) deaths. Those who have asymptomatic but measurable PAD (two to two-and-a-half times as many as have intermittent claudication), have relative risks of about 3 and 4 for total and CVD mortality, respectively. Therefore, interventions that prevent the development or progression of atherosclerotic disease or reduce arterial thrombosis should reduce mortality and morbidity due to myocardial infarction and stroke while favorably affecting the morbidity directly associated with PAD.

The National Cholesterol Education Program (NCEP) has included peripheral vascular disease (PVD) in its guidelines as a risk factor in the Classification and Decision for Treatment Algorithm. This means that patients who have PVD and elevated LDL-C and one other risk factor such as male gender, family history, cigarette smoking, or hypertension, should have appropriate dietary intervention followed by drug therapy as needed. Even with the guidelines in place since the end of 1987, a survey of PVD patients referred to a major medical center clinic found that very few patients were on lipid lowering therapy, either diet or drug. The reason for the primary care community not modifying lipids in these high risk patients may be related to lack of studies demonstrating benefit of lipid modification in those who have PVD. It is anticipated that many patients with PAD will require treatment for elevated LDL-C. It is not as clear whether interventions aimed at raising HDL-C will result in a slowing of progression of atherosclerosis in this population.

Platelets have been shown to have a key role in the development of occlusive atherosclerosis and thrombosis related to coronary heart disease. Inhibition of platelet function has been postulated to slow progression of atherosclerosis; specifically, aspirin has been demonstrated to reduce lipoprotein deposition in the arterial wall of nonhuman primates. This deposition is even further reduced by the addition of a lipid lowering regimen to the antiplatelet regimen. It remains unclear whether mini-dose, less intense anticoagulation is the most appropriate antithrombotic therapy in people with PAD who are also receiving lipid modifying agents.