Atherosclerosis of the arteries of the extremities: how to recognize and treat it?

Peripheral Arterial Occlusive Disease (PAOD) is a chronic occlusive disease of the limbs caused by atherosclerosis. It affects approximately 12% of the general population and about 20% of individuals over 70 years of age.

Patients with PAOD who develop critical limb ischemia, manifested by rest pain, gangrene, or ulcers, have a poor prognosis, particularly in the presence of concomitant cardiovascular or cerebrovascular disease. Studies have shown that within 10 years, 95% of patients treated for leg gangrene and 80% of those treated for chronic ischemic pain die.

Risk factors that promote the progression of atherosclerosis and its complications include smoking, arterial hypertension, overweight, dyslipidemia, diabetes mellitus, elevated homocysteine levels, physical inactivity, and genetic predisposition. The combination of several risk factors, particularly smoking and diabetes, increases the risk of developing critical limb ischemia in patients with PAOD by up to eightfold.

Because atherosclerosis is a systemic disease, it frequently affects multiple vascular beds simultaneously.

Classification

In Lithuania, chronic limb ischemia is classified according to the Fontaine classification, which guides treatment decisions.

Stage I
Asymptomatic disease.

Stage II – Intermittent Claudication

• Stage IIa: Pain-free walking distance >200 m.
• Stage IIb: Pain-free walking distance <200 m.

Stage III

• Stage IIIa: Ankle systolic pressure >50 mmHg.
• Stage IIIb: Ankle systolic pressure <50 mmHg.

Stage IV

• Stage IVa: Necrosis limited to one toe.
• Stage IVb: Necrosis involving several toes or the entire foot.

Critical limb ischemia corresponds to Fontaine stages IIIb, IVa, and IVb.

Clinical Symptoms and Signs

The hallmark symptom of PAOD is intermittent claudication, characterized by pain, discomfort, or muscle weakness that develops during physical activity and resolves with rest.

Typically, after walking a certain distance, patients are forced to stop because of pain in the leg muscles, limiting their daily activities. The calf muscles are most commonly affected (calf claudication). Pain in the thighs is less common, while buttock and foot claudication occur even less frequently.

Calf claudication usually indicates obstruction of the iliac, femoral, or tibial arteries, whereas buttock and thigh claudication suggest aortic or iliac artery occlusion.

Patients with critical limb ischemia (Fontaine stages IIIb and IV) experience persistent pain at rest, usually during the night but often throughout the day. Elevating the affected limb aggravates pain, particularly in the toes. Lowering the leg often relieves symptoms because slower venous return allows tissues to extract more oxygen. However, prolonged dependency leads to edema, which further worsens ischemia and pain.

Patients may also report tingling sensations in the toes and feet as well as persistently cold feet.

Objective Findings and Diagnostic Evaluation

Loss of peripheral arterial pulses is one of the most important clinical signs of PAOD. Pulses should be palpated symmetrically at corresponding locations on both lower extremities.

Patients frequently exhibit trophic skin changes, including atrophic and scaly skin, reduced calf circumference, and trophic ulcers. Early in the disease, the skin appears pale; as ischemia progresses, it develops a bluish discoloration. In stage III disease, the skin often becomes red or bluish-red.

Skin temperature of the calves and feet is usually lower than on the contralateral side. Once gangrene develops and inflammation occurs, the skin temperature may increase. In stage IV disease, gangrene may involve one or more toes, part of the foot, or the entire foot.

The severity of impaired limb perfusion is assessed using the ankle-brachial index (ABI). The examination is performed with a Doppler ultrasound device by measuring systolic blood pressure at the ankles and both arms using appropriately placed blood pressure cuffs.

ABI is the primary non-invasive, simple, and inexpensive diagnostic test used both for the initial assessment of lower limb circulation and for postoperative follow-up after vascular reconstruction. It is calculated by dividing the ankle systolic blood pressure by the brachial systolic blood pressure.

ABI Interpretation

• 1.00–1.29: Normal
• 0.91–0.99: Borderline (suspected PAOD)
• 0.41–0.90: Mild to moderate PAOD
• 0.00–0.40: Severe PAOD

Further vascular assessment may include digital subtraction angiography, magnetic resonance angiography, or computed tomography angiography.

Principles of Conservative Treatment

Initial management should focus on eliminating modifiable risk factors, including smoking cessation and appropriate control of diabetes mellitus, dyslipidemia, and hypertension.

Treatment recommendations according to Fontaine stage are as follows.

Stage I (Asymptomatic Disease)

• Eliminate risk factors.
• Aspirin 75–100 mg once daily.

Stages IIa–IIb (Intermittent Claudication)

• Eliminate risk factors.
• Supervised exercise therapy (at least three times per week for 20–60 minutes, gradually increasing walking intensity until leg pain develops).
• Aspirin 75–100 mg once daily or clopidogrel 75 mg once daily.
• Cilostazol 100 mg twice daily.
• If symptoms fail to improve after three months of treatment or the patient remains dissatisfied with the outcome, referral to a vascular surgeon is recommended.

Stages III–IV (Critical Limb Ischemia: Rest Pain, Gangrene, or Ulcers)

• Eliminate risk factors.
• Conservative treatment alone is ineffective. Referral to a vascular surgeon is required for comprehensive evaluation and possible revascularization.
• If revascularization is not feasible, intravenous prostaglandins may be administered, and limb amputation should be considered when appropriate.

After Reconstructive Surgery

• Eliminate risk factors.
• Aspirin 75–100 mg once daily or clopidogrel 75 mg once daily (other anticoagulant combinations may be prescribed according to the vascular surgeon's recommendations).
• If intermittent claudication persists, exercise therapy and cilostazol 100 mg twice daily should be prescribed.

Cilostazol

As reflected in current treatment recommendations, cilostazol plays an important role in the management of intermittent claudication. Although previously unavailable in Lithuania, cilostazol is now registered under the trade name Dilsatan®.

Cilostazol is a phosphodiesterase III inhibitor that prevents degradation of cyclic adenosine monophosphate (cAMP), thereby increasing intracellular cAMP concentrations in platelets and vascular smooth muscle cells. As a result, it produces antiplatelet and vasodilatory effects, lowers plasma triglyceride levels, and increases high-density lipoprotein (HDL) cholesterol concentrations.

According to the 2012 American College of Chest Physicians (CHEST) guidelines, patients with intermittent claudication whose symptoms persist despite supervised exercise therapy should receive antiplatelet therapy together with cilostazol 100 mg twice daily. Pentoxifylline, heparins, and prostaglandins are not recommended for the treatment of intermittent claudication.

The efficacy of cilostazol has been demonstrated in two randomized, double-blind, controlled clinical trials.

In the study conducted by Dawson and colleagues, 698 patients with lower extremity arterial disease and intermittent claudication were randomized to receive cilostazol 100 mg twice daily (227 patients), pentoxifylline 400 mg three times daily (232 patients), or placebo (239 patients). Maximum walking distance was assessed after 4, 8, 12, 16, 20, and 24 weeks.

After 24 weeks, walking distance increased by an average of 107 m (54% above baseline) in the cilostazol group, compared with 64 m in the pentoxifylline group (P<0.001) and 65 m in the placebo group (P<0.001). A statistically significant benefit of cilostazol was already evident after four weeks of treatment, whereas pentoxifylline showed no advantage over placebo.

In another study, 239 patients were randomized to receive either cilostazol 100 mg twice daily (119 patients) or placebo (120 patients). Walking distance was evaluated after 8, 12, and 16 weeks.

After 16 weeks, walking distance increased by an average of 96.4 m (29% above baseline) in the cilostazol group, compared with 31.4 m in the placebo group (P<0.001).

The ankle-brachial index also improved significantly, increasing from 0.64 ± 0.02 to 0.70 ± 0.02 in the cilostazol group, whereas it changed only from 0.68 ± 0.02 to 0.69 ± 0.02 in the placebo group (P=0.0125).

Treatment with cilostazol also significantly improved patients' quality of life, as assessed using the SF-36 and Walking Impairment Questionnaire (WIQ).

Summary

Cilostazol (Dilsatan®) is indicated to increase the maximum pain-free walking distance in patients with intermittent claudication who do not experience rest pain and have no evidence of peripheral tissue necrosis (Fontaine stage II peripheral arterial disease).

It is recommended as second-line therapy for patients whose intermittent claudication symptoms have not improved sufficiently despite lifestyle modification, including smoking cessation and exercise therapy, together with other standard therapeutic interventions.

Cilostazol is contraindicated in patients with severe renal or hepatic impairment, congestive heart failure, or unstable angina. It should also not be used concomitantly with two or more additional antiplatelet or anticoagulant medications. Further prescribing information should be consulted in the official Summary of Product Characteristics.

The recommended dosage of cilostazol (Dilsatan®) is 100 mg twice daily. The medication should be taken 30 minutes before meals, in the morning and evening. Treatment efficacy should be reassessed after three months of therapy.

Prepared by Dr. Donatas Inčiūra
Clinic of Cardiac, Thoracic and Vascular Surgery, Hospital of the Lithuanian University of Health Sciences Kauno Klinikos