Peripheral vascular disease
Atheromatous peripheral vascular disease
Atherothrombotic disease is by far the most important cause of peripheral vascular disease. Disease in peripheral arteries principally affects the aorta and renal and lower limb arteries. The risk factors for its development are similar to those for coronary artery and cerebrovascular disease (Chs 5 and 9). The strongest associations are with increasing age, smoking and a raised systolic blood pressure, and to a lesser extent with diabetes mellitus, a raised plasma low-density lipoprotein (LDL) cholesterol and lack of exercise. Not surprisingly, symptomatic ischaemic heart disease and cerebrovascular disease coexist in up to 50% of people with peripheral vascular disease and are responsible for about 70% of their excess mortality. Only about 50% of people with peripheral vascular disease are alive 10 years after diagnosis; this is three times the mortality of people of similar age without peripheral vascular disease.
Symptoms of peripheral vascular disease
Peripheral vascular disease is often asymptomatic until it produces a stenosis of more than 50% of the diameter of an arterial lumen. Symptoms usually arise as a consequence of atherosclerotic stenosis of a lower limb artery, and produce intermittent claudication. This is ischaemic pain in the muscles of the lower limb that is precipitated by walking and relieved by rest. Hypoxia of skeletal muscle occurs when blood flow through the diseased artery fails to increase sufficiently to meet the increased metabolic demand of the muscle during exercise. The metabolic changes that accompany the switch to anaerobic metabolism in the muscle trigger the pain. Depending on the site of the vascular narrowing, pain can be experienced in the calf, thigh or buttock. The severity of reduction in blood flow to the limb does not correlate well with symptoms, and an important factor is ischaemia–reperfusion injury to the muscle and altered oxidative metabolism. The development of a collateral arterial circulation (see also Ch. 5) will reduce the severity of the symptoms and influence the long-term outcome. In three-quarters of those with peripheral vascular disease the symptoms stabilise within a few months of presentation. The remaining 25% experience steady progression, but only 1% of symptomatic patients per year will develop critical ischaemia which causes pain at rest, trophic changes and ultimately distal gangrene (see below).
Drugs for peripheral vascular disease
Mechanism of action: Cilostazol appears to have several actions. It is a reversible inhibitor of the enzyme phosphodiesterase type 3 (PDE3), and therefore reduces breakdown of cAMP (Table 1.1). PDE3 is present in vascular smooth muscle cells and platelets, and cilostazol causes vasodilation, inhibits platelet activation and aggregation, and prevents release of prothrombotic inflammatory substances. Cilostazol also inhibits adenosine reuptake, which promotes vasodilation, has favourable effects on plasma lipids by increasing high-density lipoprotein (HDL) cholesterol, and inhibits cell proliferation in vascular smooth muscle.
Pharmacokinetics: Cilostazol is well absorbed orally, and undergoes hepatic metabolism via cytochrome P450 to two metabolites with antiplatelet activity, one of which is more active than cilostazol. Cilostazol has a half-life of about 12 h.
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.
Increased risk of bleeding when combined with aspirin and clopidogrel.
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.
Management of intermittent claudication
Stopping smoking slows the progression of peripheral atherosclerosis and may improve walking distance by improving blood oxygen transport. It will also have an impact on the risk of coronary and cerebrovascular events, and is therefore a cornerstone of long-term management.
Regular supervised exercise, up to the point of claudication, can improve maximum walking distance by 150% over 8–12 weeks.
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.
Cilostazol can improve maximum walking distance by up to 25% over 3–6 months of treatment, but the impact of this on quality of life is often minimal. It is not known whether cilostazol has any effect on long-term outcome or on the subsequent need for surgery.
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.
Other disorders of the peripheral circulation should also be considered in the differential diagnosis of Raynaud's phenomenon.
Acrocyanosis usually affects the hands and produces persistently cold, bluish fingers which are often sweaty or oedematous. The management of this condition is similar to that of Raynaud's phenomenon.
Chilblains are an inflammatory disorder with erythematous lesions on the feet, or less commonly the hands or face, that are precipitated by cold and humidity followed by rapid rewarming. The lesions are often painful or itchy. Treatments used for Raynaud's phenomenon may help, with the addition of topical non-steroidal anti-inflammatory agents (Ch. 29).
Erythromelalgia is a painful, burning condition often affecting the hands and feet that, unlike Raynaud's phenomenon, is usually provoked by heat. It sometimes responds to treatment with a calcium channel blocker (Ch. 5) or gabapentin (Ch. 23).
Vibration white finger is a patchy digital vasospasm associated with prolonged use of vibrating tools. If drug treatment is necessary, it is similar to that for Raynaud's phenomenon.
Management of Raynaud's phenomemon
Many people with Raynaud's phenomenon are only mildly inconvenienced by their symptoms and respond to simple measures. Drug treatment is usually reserved for those suffering from more intense vasospasm with pain, impairment of function or trophic changes. Responses to individual treatments are unpredictable, and are less satisfactory in secondary Raynaud's phenomenon because of structural changes to the vessel wall.
Non-pharmacological treatment
Often, minimising changes in ambient temperature with insulating clothing is enough to reduce the number of attacks, although electrically heated gloves or socks may be useful for more severely affected people.
Smoking should be strongly discouraged. Nicotine promotes vasospasm and may also reduce the threshold for other provoking factors.
Aggravating factors should be withdrawn or corrected whenever possible (see Box 10.1). Beta-adrenoceptor antagonists (Ch. 5) produce peripheral circulatory problems sufficient to necessitate stopping treatment in about 3–5% of people with hypertension.
Surgical sympathectomy is occasionally used for advanced disease.
Pharmacological treatment
Calcium channel blockers (Ch. 5): modified-release nifedipine is the drug of first choice for Raynaud's phenomenon, and reduces the frequency, duration and intensity of vasospastic episodes. Several other dihydropyridines are probably equally effective, but diltiazem is less effective and verapamil ineffective in this condition.
Naftidrofuryl oxalate may produce a modest reduction in the severity of attacks.
Alpha1-adrenoceptor antagonists (Ch. 6): moxisylyte is typically used and does not lower blood pressure, unlike other α-adrenoceptor antagonists.
Angiotensin II receptor antagonists (Ch. 6)
Sildenafil (Ch. 16) has been used successfully in secondary Raynaud's phenomenon that is resistant to other vasodilators.
Bosentan, an endothelin receptor antagonist (Ch. 6), has shown promise in severe Raynaud's phenomenon.
Fluoxetine (Ch. 22), a selective serotonin reuptake inhibitor (SSRI) antidepressant, is effective in some people.
Calcitonin gene-related peptide (CGRP) is effective for prolonged periods when given by short intravenous infusions over 5 or more consecutive days. It is a neurotransmitter for vasodilator cutaneous sensorimotor nerves in the fingers and toes. CGRP is usually reserved for failure to respond to epoprostenol (see below).
Drugs acting primarily on blood components:
Prostaglandins: short intravenous infusions of epoprostenol (prostacyclin (prostaglandin I2, PGI2); Ch. 11) over at least 5 consecutive days produces immediate vasodilation, but long-term improvement in symptoms and healing of ulcers over a period of 10–16 weeks. These effects are believed to be caused by actions on the flow properties of blood; that is, reduced platelet aggregation, increased red cell deformability and reduced neutrophil adhesiveness. Epoprostenol is rapidly inactivated in plasma by hydrolysis, and has a very short half-life of about 3 min. Unwanted effects are due to vasodilation, and include flushing, headache and hypotension.
Inositol nicotinate (a nicotinic acid derivative) produces a gradual onset of clinical response and only modest improvement. Its action may result more from fibrinolysis (reducing plasma viscosity) and reduction in platelet aggregation than from vasodilation.
True/false questions
1. Diabetes mellitus, hypertension and smoking confer an additive risk of developing peripheral vascular disease.
2. People with intermittent claudication do not have an increased risk of developing coronary artery disease.
3. Statin drugs are indicated in people with symptomatic atherosclerotic peripheral vascular disease.
4. Simvastatin increases the hepatic expression of low-density lipoprotein (LDL) receptors.
5. Drugs used in migraine treatment, such as ergotamine, can precipitate Raynaud's phenomenon.
6. Verapamil is the calcium channel blocker of choice in the treatment of Raynaud's phenomenon.
7. Epoprostenol mimics the actions of thromboxane A2.
8. Moxisylyte is metabolised to a compound with α1-adrenoceptor antagonist activity.
Case-based questions
Mr TH, aged 67 years, had type 1 diabetes mellitus and smoked 20 cigarettes a day. His plasma total cholesterol was raised at 7.2 mmol⋅L−1 and his blood pressure was 160/110 mmHg. After walking 50 m he developed pain in his left calf muscle, which was relieved by rest. He occasionally, but rarely, had rest pain at night. On examination, both popliteal and posterior tibial pulses were absent and femoropopliteal obstruction was diagnosed.
1. True. The risk factors for peripheral vascular disease are similar to those for coronary artery and cerebrovascular disease.
2. False. There is a two- to fourfold increase in risk of developing coronary disease, stroke or heart failure compared with age-matched subjects who do not have intermittent claudication.
3. True. Lowering serum LDL cholesterol can stabilise or regress atherosclerotic plaques.
4. True. By reducing cholesterol synthesis, simvastatin increases hepatic LDL receptors, which results in reduced LDL cholesterol in blood and a small accompanying increase in high-density lipoprotein (HDL) cholesterol (Ch. 48). The main potential benefit of lowered LDL cholesterol in these patients is a reduction in coronary artery disease events.
5. True. Ergotamine and other drugs including β-adrenoceptor antagonists can trigger Raynaud's phenomenon.
6. False. Verapamil is ineffective in the treatment of Raynaud's phenomenon, and the agent of choice is nifedipine.
7. False. Epoprostenol is prostacyclin (PGI2), which has opposing actions on vessels and platelets to thromboxane A2
OBA answer
A Correct. Cilostazol increases cAMP levels in vascular smooth muscle cells and platelets by inhibiting phosphodiesterase type 3.
B Incorrect. Unlike other phosphodiesterase 3 inhibitors such as milrinone, cilostazol does not increase the incidence of arrhythmias. However, cilostazol is not recommended in people with congestive heart failure and cardiac arrhythmia.
C Incorrect. Cilostazol is extensively metabolised by CYP3A4 and CYP2C19 isoenzymes in the liver.
Case-based answers
1. The usefulness and drawbacks of drugs A–F in treating Mr TH are as follows.
A Beta-adrenoceptor antagonists should probably be avoided in this man. They would not be the drug of choice in the initial treatment of his high blood pressure (Ch. 6), and by reducing cardiac output and inhibiting vasodilation they could further reduce blood flow in critical limb ischaemia.
B Cardioselective β-adrenoceptor antagonists such as atenolol do not cause deterioration in walking distance when used without a vasodilator.
C Vasodilators will lower blood pressure but do not improve walking distance. In some people, they may redirect blood from the maximally dilated ischaemic tissues to healthy tissues (vascular steal). This can be particularly troublesome in critical limb ischaemia, or when the cardiac output is also reduced by concurrent use of a β-adrenoceptor antagonist.
D Lowering LDL cholesterol can stabilise atherosclerotic plaques, perhaps reducing the consequences of coexistent heart disease; it is not known whether walking distance or limb survival are improved.
E Low-dose aspirin inhibits platelet aggregation and reduces future cardiac events, which are common in people with peripheral vascular disease.
2. Intensive management of blood pressure, control of diabetes and antiplatelet therapy will reduce the risk of cardiac events. An exercise programme can improve walking distance. Smoking is a major contributory factor to impaired walking distance and cardiac events.
3. An electric blanket should be discouraged as excessive warming of limbs may dilate normal arteries, ‘stealing’ blood from diseased arteries.
Compendium: drugs used to treat peripheral vascular disease
| Drug | Kinetics (half-life) | Comments |
| Cilostazol | Absorption increased by food; metabolised by CYP3A4 and CYP2C19 to active metabolites (12 h) | Reversibly inhibits phosphodiesterase (PDE) type 3 and blocks adenosine reuptake in vascular smooth muscle cells, causing vasodilation; also has antiplatelet activity and increases plasma HDL cholesterol |
| Cinnarizine | Slow oral absorption; eliminated largely by CYP2D6 (polymorphic) hepatic metabolism (24 h) | H1 antihistamine used primarily for vestibular disorders; at higher doses, cinnarizine has a vasodilator effect and may improve circulation in Raynaud's phenomenon and peripheral vascular disease |
| Epoprostenol | Must be freshly reconstituted from dry powder before intravenous infusion; eliminated very rapidly by hydrolysis (half-life <3 min) | A prostaglandin (PGI2, prostacyclin) with vasodilator and antiplatelet activity |
| Inositol nicotinate | Metabolised slowly into inositol and nicotinic acid (niacin); probably eliminated by hydrolysis | Nicotinic acid (niacin) has vasodilator activity; also used for hyperlipidaemias |
| Moxisylyte | Good oral bioavailability; prodrug rapidly converted in plasma to its active metabolite, deacetylmoxisylyte (1 h) | An α1-adrenoceptor antagonist used for the short-term treatment of primary Raynaud's phenomenon; formerly known as thymoxamine in UK |
| Naftidrofuryl oxalate | Good oral bioavailability; hepatic metabolism with some renal excretion (3–4 h) | Activates mitochondrial succinic dehydrogenase and is a 5-HT2 receptor antagonist |
| Pentoxifylline | Rapidly metabolised in liver and blood (1 h) | PDE inhibitor which increases erythrocyte flexibility and decreases blood viscosity, possibly by increasing erythrocyte cAMP |
All the drugs above are given orally, with the exception of epoprostenol (given intravenously).
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