Lipid lowering in peripheral arterial disease

The studies of lipid lowering in PAD are heterogeneous in terms of the type of drugs used, inclusion criteria, and outcome measures. An advantage of lipid lowering in patients with intermittent claudication, but without symptomatic CAD is that such therapy would also be expected to reduce mortality from heart disease. In addition, it might improve local symptoms such as intermittent claudication, and reduce the need for reconstructive surgery. Several studies have validated the benefits of lipid lowering on femoral atherosclerosis. These studies included symptomatic patients with intermittent claudication, as well as asymptomatic patients with critical limb ischemia identified by abnormal ankle-bra-chial index (ABI) or peripheral angiogram. Disease progression was assessed by ultrasound, angiography, ABI, and exercise capacity evaluated by treadmill testing. Additional end points evaluated were fatal and nonfatal clinical events and subjective measures such as symptom improvement.

The Saint Thomas's Trial was the first randomized controlled trial evaluating the effect of lipid lowering therapy on the course of femoral atherosclerosis in hyperlipidemic patients with intermittent claudication (40). The patients were randomized to receive diet, cholestyramine, nicotinic acid, or clofibrate depending upon their lipoprotein phenotype. Total cholesterol (TC) decreased by 25%, LDL cholesterol by 28%, and TG by 45% following therapeutic intervention. Femoral atherosclerosis was studied by arteriography. In patients receiving lipid-lowering therapy, progression of atherosclerosis was reduced by 60% compared to the placebo group. The rate of increase in the cross-sectional area of the plaque in the treated group was one-third that of the placebo group. Change in edge irregularity was 2.5-fold greater in the placebo group, whereas twice as many arterial segments showed improvement in the therapy group.

The CLAS study (41) included 188 men with previous CABG and PAD, diagnosed by femoral angiograms, treated with colestipol and niacin for two years. The effect of therapy on femoral atherosclerosis was evaluated by estimating lumen abnormality measured by a computer-estimated atherosclerosis scale. Although a significant therapeutic benefit was observed in both femoral and coronary arteries, the effect was less marked on the femoral arteries. The HDL levels and the ratio of TC/HDL correlated with regression or progression of femoral atherosclerosis. Subjects who demonstrated regression of femoral atherosclerosis had higher HDL levels and a lower ratio of TC/ HDL, than subjects who had no change in femoral atherosclerosis. Of particular interest, statistical significance was obtained for HDL levels only for femoral atherosclerosis and not for coronary atherosclerosis. A significant therapy effect was found in segments with moderately severe atherosclerosis and in proximal femoral segments. The POSCH trial (42) was a randomized single-blind controlled trial with a mean follow-up of 10 years. Patients with established CAD were assigned to diet only vs diet and partial ileal bypass surgery. LDL reduction of 38% was noted in the surgical group with an absolute risk reduction of 10%, and relative risk reduction of 35% for fatal and nonfatal CAD events. The POSCH trial also reported a reduction in symptoms of intermittent claudication in patients with PAD in the surgical group.

The Probucol Quantitative Regression Swedish Trial (43) (PQRST) was a 3-year study performed to investigate the effects of probucol, cholestyramine, and diet on atherosclerosis in the femoral arteries in patients with hypercholesterolemia, with or without clinical signs and symptoms of PAD. The primary endpoint was the change in atheroma volume of the femoral artery as estimated by annual measurements of angiograms of 20 cm segments of the femoral artery. Clinical events such as MI, silent MI, new onset angina, and other events were also noted. At the end of 3 years, the lumen volume of femoral arteries, cardiovascular event rates, and ABI were the same in both groups. It has been speculated that the benefit of LDL lowering by probucol was negated by the concomitant lowering of HDL level induced by this drug.

The 4S trial (44), in addition to CAD data, also reported the effects of therapy with simvastatin on noncoronary signs and symptoms during a median follow-up of 5.4 years. Patient assessment for these included a history of symptoms suggestive of intermittent claudication and a physical examination for carotid and femoral bruits that was done at baseline and followed annually. Risk of a new or worsening carotid bruit was substantially reduced by treatment, consistent with a reduction in cere-

brovascular events. Even though there was no statistically significant effect on femoral bruits, there was a 38% reduction in the incidence of new or worsening intermittent claudication.

In a nonrandomized trial Olsson et al.(45) evaluated the development of femoral atherosclerosis after one year of treatment with diet, nicotinic acid, and fenofibrate in 45 middle-aged men with asymptomatic hyperlipidemia. Disease progression was demonstrated in 24% of the treatment group compared to 40% in controls, whereas regression occurred in 29% and 0%, respectively.

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