Other PDE3 inhibitors such as milrinone have been shown to decrease survival in people with heart failure (Ch. 7); cilostazol does not appear to increase the risk of life-threatening arrhythmias, but is contraindicated in people with heart failure, cardiac arrhythmias and ischaemic heart disease due to an increase in heart rate.
Drug interactions: the pharmacokinetics of cilostazol will be altered by drugs that influence the liver cytochrome P450 CYP3A4 isoenzyme (Ch. 2).Naftidrofuryl oxalate
Mechanism of action and effects: Naftidrofuryl oxalate promotes the production of high-energy phosphates (ATP) in ischaemic tissue by activating the mitochondrial enzyme succinic dehydrogenase. It is also a 5-hydroxytryptamine type 2 (5-HT2) receptor antagonist, an action which leads to arterial vasodilation and reduced platelet aggregation. All these actions could improve blood flow to ischaemic tissues and tissue nutrition, but the effect on walking distance is modest.
Pharmacokinetics: Naftidrofuryl is well absorbed from the gut and metabolised in the liver. It has a half-life of 3–4 h.
Management of intermittent claudication
Pharmacological treatment
Low-dose aspirin inhibits platelet aggregation and reduces cardiac and cerebrovascular events (Chs 11 and 29).
Intensive management of hypertension reduces progression of atheroma. Conventional antihypertensive therapy is used (Ch. 6). Although β-adrenoceptor antagonists could theoretically exacerbate intermittent claudication by reducing cardiac output and impairing vasodilation of arteries supplying skeletal muscle (Ch. 5), there is little evidence that they are disadvantageous unless there is critical limb ischaemia.
Lowering serum LDL cholesterol (Ch. 48) can stabilise or regress atherosclerotic plaques. It is not known whether this improves limb survival or reduces the need for subsequent surgery. A greater benefit of lowering cholesterol may be reduced morbidity and mortality from coexistent ischaemic heart disease (Ch. 5).
Naftidrofuryl oxalate improves maximum walking distance by up to 60%. A trial of treatment may be justified for those who remain restricted by the disease after 6–12 months of conservative treatment, and for whom angioplasty is inappropriate or has failed. Withdrawal is advised after 3–6 months of treatment to assess whether spontaneous improvement has occurred.
Surgical treatment
Surgical treatment is usually considered if quality of life is significantly impaired by claudication or if tissue integrity is at risk. Percutaneous transluminal angioplasty, often with insertion of a stent, is used particularly for stenoses above the inguinal ligament, while bypass surgery is used for most other disease.
Acute and critical limb ischaemia
An arterial embolus is the usual cause of acute limb ischaemia, and can arise from an intracardiac site, usually associated with atrial fibrillation (Ch. 8) or following a myocardial infarction (Ch. 5), or from aortic or internal iliac artery thrombus. Emboli can occlude previously healthy vessels and presents with acute onset of severe pain at rest, associated with signs of critically impaired tissue perfusion.
Critical limb ischaemia results from chronic, severe, subtotal occlusion of an artery, and may be due to partial occlusion of the vessel from thrombus on a ruptured atherosclerotic plaque. The symptoms include rest pain, often worse at night and relieved by hanging the leg out of the bed.
Management of acute and critical limb ischaemia
Unless treatment of acute or acute-on-chronic critical limb ischaemia is rapid, the person may be left with a chronically ischaemic limb, or occasionally the limb may be lost through gangrene.
If the limb is still viable, then a peripheral arterial angiogram should be carried out. For acute embolic arterial occlusion, embolectomy is the treatment of choice. Intra-arterial thrombolysis, either with streptokinase or recombinant tissue plasminogen activator (rt-PA; alteplase) (Ch. 11), is used to dissolve an acute thrombus occluding a previously diseased vessel. Alteplase produces more rapid lysis, but there is no evidence that limb salvage is any better than with streptokinase. The fibrinolytic agent can be infused via a catheter for up to 24 h or given as repeated boluses. Reperfusion takes several hours and in about 25% of acute vascular occlusions lysis is not achieved, especially if there is embolic occlusion. The risk of intracerebral haemorrhage is also a concern. A surgical bypass may be considered if there is no time for thrombolysis.
Secondary prevention measures to reduce other cardiovascular events (see above) should also be started.
Raynaud’s phenomenon
Raynaud’s phenomenon is a profound and exaggerated vasospastic response of blood vessels in the extremities on exposure to cold, change in environmental temperature or during emotional upset. This leads to episodes of ischaemia that most commonly affect the fingers (occasionally also the toes, ear lobes or the nipples). A typical attack initially produces pallor of the affected part, followed by one or both of cyanosis then erythema. Each attack can last several minutes or up to a few hours. About two-thirds of cases occur in women (typically presenting under the age of 40 years), in whom the overall prevalence is about 15%. Common symptoms include discomfort, numbness and tingling, with loss of function and pain if the condition is severe. Rarely, digital ulceration can occur.
The majority of cases of Raynaud’s phenomenon are idiopathic (primary Raynaud’s phenomenon; also called Raynaud’s disease). The cause of the excessive vascular reactivity is unknown, although there is a genetic predispostion. Vascular function in other tissues is often abnormal in primary Raynaud’s phenomenon: for example, in the cerebral vessels (giving an association with migraine), the coronary circulation (producing variant angina) or, more rarely, in the pulmonary circulation (leading to pulmonary hypertension).
In about 10% of cases, Raynaud’s phenomenon is secondary to another disorder. This is most commonly scleroderma, but there are many other associated conditions (Box 10.1). Structural damage to arteries is common in secondary Raynaud’s phenomenon, and digital ulceration is much more common than in the primary type.
Box 10.1 Conditions associated with Raynaud’s phenomenon
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