The primary initial goals of medical therapy in patients with PAD are to treat the systemic atherosclerosis by risk modification and antiplatelet drugs in an attempt to reduce cardiovascular morbidity and mortality. Once that has been accomplished, the physician can then address the relief of symptoms and limb preservation.
All patients with PAD should be referred to a smoking cessation program and prescribed nicotine replacement and antidepressants. Nicotine replacement therapies, in addition to behavior modification, are slightly more effective than behavior modification alone. A recent meta-analysis of several placebo-controlled trials revealed cessation rates of 23% to 27% over 6 to 12 months using a nicotine patch as compared to placebo, where the quit rates ranged from 13% to 18%. Also, in patients with medical diseases, transdermal nicotine patches have been shown to be safe even in high-risk populations. Thus, this is a strategy that should be considered for patients with PAD.
Patients with diabetes should first undergo intensive blood glucose control to target a hemoglobin A1C less than 7.0%. Obtaining this goal may have favorable effects on the risk of cardiovascular events in both type 1 and type 2 diabetes. However, intensive glycemic control had no effect on the risk of amputation from PAD. In addition to intensive blood sugar control, patients with atherosclerosis and diabetes also need aggressive risk factor modification; this may be particularly true in the treatment of hypertension when an angiotensin-converting enzyme (ACE) inhibitor may be a preferable agent. Given the lack of specific trials, drug therapy for patients with diabetes and PAD should follow general published recommendations.
Several effective therapies have been developed to treat patients with hyperlipidemia. Dietary restriction of cholesterol and saturated fats has only a modest effect on LDL cholesterol levels, but a more substantial decrease in triglyceride levels, important in the management of PAD. The statin drugs have become a well-established means of reducing LDL cholesterol levels. In addition to statin drugs, gemfibrozil has been shown to lower LDL cholesterol concentration, with the added benefit of increase in HDL cholesterol concentrations. Additional means to modify HDL cholesterol concentration is the use of niacin, which in a recent study was found to be safe in patients with PAD and diabetes.
In patients with PAD, a meta-analysis of randomized trials of lipid-lowering therapies showed a nonsignificant reduction in reducing mortality (odds ratio, 0.21; 95% CI, 0.03-1.17). This analysis also concluded that lipid reduction therapies favorably altered angiographic disease progression and symptoms of claudication. Limitations of the analysis were a relatively small sample size and the fact that there have been no clinical trials in PAD of lipid therapy to prevent ischemic events.
Patients with PAD are at high risk for systemic ischemic events but at less risk for progression of their leg arterial disease. Based on evidence from the lipid trials in coronary artery disease, the National Cholesterol Education Program guidelines include PAD as a patient population at the highest risk for future coronary heart disease events and therefore in need of aggressive secondary prevention therapies. The current recommendation for lipid therapy in the PAD population is to achieve an LDL cholesterol level less than 100 mg/dL and a triglyceride level less than 150 mg/dL. The LDL cholesterol goals often require the use of HMG-coenzyme A reductase inhibitors, and achieving the HDL cholesterol goals often requires the use of niacin.
All patients with PAD and hypertension should undergo aggressive lowering of their blood pressure according to the Joint National Committee VI guidelines. All classes of antihypertensive agents can be used in patients with PAD, including beta-adrenergic blockers, which are safe in patients with claudication. In addition, beta- adrenergic blockers are routinely used in the perioperative setting to decrease the risks of vascular surgery. Another class of drugs, the ACE inhibitors, may be protective against cardiovascular events in PAD patients. In the Heart Outcomes Prevention Evaluation Study, 44% of the population had evidence of PAD. The study demonstrated that ramipril was associated with a reduced risk for vascular death, nonfatal myocardial infarction, or stroke in patients with PAD. This study suggests that ACE inhibitors may be important agents in reducing the risk of ischemic events in the PAD population.
Additional Approaches to Risk Modification
Elevated homocysteine levels can be reduced by supplementing the diet with B vitamins and folate. Despite the ease of therapy with vitamin supplements, there are no clinical trials that demonstrate a clinical benefit in reducing homocysteine levels.
Estrogen therapy in postmenopausal women may also favorably influence several cardiovascular risk factors. However, the Heart and Estrogen/Progestin Replacement Study showed no overall benefit of hormone therapy for reduction of cardiovascular events or peripheral arterial endpoints. Thus, at the present time, there are no recommendations for this therapy in PAD patients.
Antioxidant vitamins such as vitamin E have been advocated to prevent ischemic events. However, the HOPE trial showed no benefit of vitamin E on prevention of cardiovascular events. Thus the use of antioxidant vitamins in patients with PAD may not result in any clinical benefits.