Antithrombotic therapy in peripheral vascular disease

Atherosclerotic peripheral vascular disease is symptomatic as intermittent claudication in 2-3% of men and 1-2 % of women aged over 60 years. However, the prevalence of asymptomatic peripheral vascular disease, generally shown by a reduced ankle to brachial systolic pressure index, is three to four times greater. Peripheral vascular disease is also a significant cause of hospital admission, and is an important predicator of cardiovascular mortality. Pain at rest and critical ischaemia are usually the result of progression of atherosclerotic disease, leading to multilevel arterial occlusion. Other causes of arterial insufficiency—including fibromuscular dysplasia, inflammatory conditions, and congenital malformations—are much rarer.

Therapeutic objectives in peripheral vascular disease include relieving symptoms and preventing the disease, and any associated events, progressing.

Antithrombotic therapy in peripheral vascular disease

Clinical problem	Antithrombotic therapy of choice
Intermittent claudication	Aspirin (to reduce risk of stroke and myocardial infarction) Clopidogrel
Diabetes	Aspirin (to reduce risk of stroke and myocardial infarction) Clopidogrel
Embolic arterial occlusion	Intravenous heparin and emergency surgical intervention
Acute on chronic arterial occlusion	Heparin and angioplasty,intra-arterial thrombolysis or early surgery
Intraoperative anticoagulation during vascular surgery	Heparin
Infrainguinal vein bypass and infrainguinal prosthetic bypass	Aspirin (to reduce risk of stroke and myocardial infarction)Clopidogrel (if unable to take aspirin)
Infrainguinal bypass at high thrombotic risk	Aspirin or consider warfarin
Carotid endarterectomy	Aspirin or clopidogrel
Symptomatic carotid stenosis and too unwell for surgery	Consider warfarin or aspirin plus dipyridamole

The symptoms of peripheral vascular disease are progressive. A claudicating patient encouraged to exercise tends to report a symptomatic improvement. This effect is generally not accepted to be an improvement in the diseased segment of blood vessel, but the formation of collateral vessels perfusing the ischaemic tissue.

Vasodilating agents, such as naftidrofuryl, have little value in managing claudication and peripheral vascular disease as their effect is small and does not stop progression of the disease. Cilostazol has been shown to increase absolute walking distance in some patients by up to 47%. However, it has no clear antithrombotic effect and has not been shown to stop disease progression.

Unfortunately, not all progression is amenable to improvement and, without the appropriate risk factor management, progression to rest pain and necrosis can be rapid.

Intermittent claudication

The role of aspirin as an antiplatelet agent has been shown to be beneficial beyond doubt. In peripheral vascular disease it reduces the frequency of thrombotic events in the peripheral arteries and reduces overall cardiovascular mortality in claudicating patients. The dose of aspirin has been the subject of some debate, but 81-325 mg daily has been shown to be of value. Larger doses have no apparent additional benefit but increase the risk of adverse effects. Aspirin has been shown to reduce the progression of atherosclerosis in a few trials, but this remains unsubstantiated.

The role of dipyridamole remains controversial. Several small studies have shown the benefit of giving it in conjunction with aspirin, but it is uncertain if dipyridamole alone is superior to aspirin.

In aspirin intolerant patients there is now a clear role for clopidogrel 75 mg once a day. This is as effective as aspirin in preventing cardiovascular events. If a thrombotic event has occurred (whether the patient is taking aspirin or not) there may be an advantage in using clopidogrel to prevent further events, especially in peripheral vascular disease.

In non-critical peripheral ischaemia, there is no indication for warfarin treatment as the complexities of management and bleeding risks seem to far outweigh the benefits, unless the patient has concomitant problems needing anticoagulation such as atrial fibrillation.

Critical ischaemia

Rest pain and gangrene are markers of critical ischaemia. This is nearly always the result of extensive vessel occlusion with absent pedal pulses. The patient will almost certainly be immobile because of pain and arterial insufficiency making walking impossible. These patients need prophylaxis against venous thromboembolism.

Patients giving a short history of rest pain of sudden onset require full, immediate anticoagulation with low molecular weight heparin or intravenous unfractionated heparin (the latter with a target activated partial prothrombin time (APTT) ratio of 1.5-2.5). Warfarin should be avoided initially until investigations and possible interventions are complete.

Patients with chronic, progressive pain at rest also need full anticoagulation. Although the evidence is limited, these patients are often treated with warfarin to prevent progression, especially if remedial surgery is not possible. The international normalised ratio (INR) should be kept in the range of 2-3.

Acute thromboembolic occlusion of the peripheral arteries requires immediate anticoagulation with intravenous unfractionated heparin to prevent propagation of the thrombus and to guard against further embolism. Surgical intervention or, less commonly, thrombolytic therapy is indicated. Once the embolus has been cleared, the source needs to be investigated and this usually requires treatment with warfarin long term.

Peripheral artery revascularisation

When the ischaemia reaches a state where peripheral artery revascularisation or reconstruction is necessary, the requirements for antithrombotic therapy change.

Neointimal hyperplasia is a considerable problem in the long term survival of a graft as its consequences (reduced blood flow caused by reduced lumen) in some respects mimic those of the original disease. Hyperplasia of smooth muscle cells can occur along the entire length of a vein graft, but particularly does so at the anastomoses of prosthetic grafts.

Risk of thrombosis with different vein grafts

Site of proximal anastomosis	Site of distal anastomosis	Graft material	Other factors	Thrombotic risk	Recommended antithrombotic therapy
Aorta	Iliac or femoral	Prosthetic		Low	Antiplatelet*
Axilla	Femoral	Prosthetic		Medium	Antiplatelet
Femoral	Popliteal (above knee joint)	Vein		Low	Antiplatelet*
		Prosthetic		Low	Antiplatelet*
	Distal (below knee)	Vein	Good flow (>100 ml/min) and good distal arteries	Medium	Antiplatelet
			Poor flow (<50 ml/min) or poor distal arteries	High	Antiplatelet Consider warfarin
		Prosthetic		High	Antiplatelet Consider warfarin

*Antiplatelet therapy not indicated for graft survival but recommended as prophylaxis against cardiovascular events

Aspirin has no apparent effect on graft survival in humans. One trial showed that low molecular weight heparin had a profound beneficial effect on graft patency, when compared with aspirin and dipyridamole over three months, suggesting that early treatment with low molecular weight heparin suppresses neointimal hyperplasia. In the United Kingdom most low molecular weight heparins have licences only for 14 days' treatment, and, until more data are available, the prolonged use of low molecular weight heparin cannot be recommended.

Infrainguinal bypass

Antiplatelet treatment has no beneficial role for graft patency in short (femoral-popliteal) bypass with native vein grafts because these are high flow and non-thrombogenic. None the less, aspirin has been shown to reduce all cardiovascular end points in patients with peripheral vascular disease, and so should be continued. Anticoagulation with warfarin has not been shown to be of benefit.

Problems in patients undergoing infrainguinal bypass

• The thrombogenic characteristics of prosthetic graft materials

• The poor flow states associated with some grafts, for example, long bypasses passing over the knee joint

• The medium to long term complication of neointimal hyperplasia

Patients with prosthetic femoral-popliteal bypass are a different consideration. Taking aspirin with dipyridamole reduces platelet accumulation at the anastomosis. Starting antiplatelet treatment preoperatively leads to improved patency rates, especially in “high risk” (low flow, prosthetic) grafts once the increased complication rate of postoperative wound haematoma has passed. Again, aspirin (with or without dipyridamole) is recommended.

High risk grafts need to be dealt with cautiously. All patients should continue taking aspirin (or clopidogrel). The use of warfarin needs to be judged carefully. In cases of poor run off, marginal quality vein, and previous graft failure, oral anticoagulation has been shown to improve primary patency and limb salvage rates with a target INR of 2-3. If this is being considered then full heparinisation should begin immediately after the operation while oral anticoagulation is started. Naturally, older patients are more likely to have bleeding complications, including intracranial haemorrhage, and this should be considered.

Aortoiliac and aortofemoral grafts

Large aortoiliac and aortofemoral grafts are at low risk of thrombosis. Primary patency rates of 80-90% can be expected at five to ten years. Thus, specific antithrombotic therapy is not indicated. However, once again, the presence of peripheral vascular disease needs antiplatelet therapy to reduce all cardiovascular end points.

Among high risk patients, antiplatelet treatment reduces the combined outcome of any serious vascular event by about a quarter, non-fatal myocardial infarction by a third, non-fatal stroke by a quarter, and vascular mortality by a sixth (with no apparent adverse effect on other deaths)

Percutaneous transluminal angioplasty

Almost all patients undergoing percutaneous transluminal angioplasty have atherosclerotic peripheral vascular disease. As such, they should all be treated with aspirin or clopidogrel.

Studies with radiolabelled platelets have found substantial platelet accumulation at the sites of angioplasty, and antiplatelet treatment reduces this. In coronary angiography, this treatment has been shown to reduce the incidence of new thrombus at the site of the angioplasty. However, in similar coronary artery studies, antiplatelet treatment has no effect on restenosis compared with placebo. It is unclear how these results will extrapolate to peripheral angioplasty, and there are insufficient data to make recommendations in peripheral vascular disease.

Similarly there have not been enough studies to recommend the use of dipyridamole, ticlopidine, or clopidogrel as an adjunct to aspirin. Although the long term use of antiplatelet drugs is not known to have any long term effect on restenosis, the drug should be used to prevent cardiovascular mortality in patients undergoing percutaneous transluminal angioplasty.

Suggestions from the Antithrombotic Trialists' Collaboration

• Clopidogrel reduced serious vascular events by 10% compared with aspirin, which was similar to the 12% reduction observed with its analogue ticlopidine

• Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone

Carotid stenosis

Evidence for treatment of asymptomatic carotid stenosis of greater than 50% is unclear. One trial showed no reduction in stroke rate in patients treated with aspirin for two to three years. However, it is increasingly accepted that atherosclerosis affects all arteries to a greater or lesser extent. With this in mind, and the evidence for using aspirin in lower limb atherosclerosis, it is still recommended that these patients have antiplatelet treatment to prevent all cardiovascular events.

Treating patients who have had a transient ischaemic attack or known ischaemic stroke with aspirin has clear benefit as shown by the Antiplatelet Trialists' Collaboration. The dose is not clear, but 81-325 mg should be effective without unacceptable bleeding risk. Clopidogrel (75 mg daily) is recommended for aspirin intolerant patients. Limited evidence shows that the combination of aspirin and dipyridamole (400 mg daily) may be more beneficial to these patients than aspirin alone.

Further reading

• Jackson MR, Clagett GP. Antithrombotic therapy in peripheral arterial occlusive disease.

• CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39

• Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81-106

• Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy II: maintenance of vascular graft or arterial patency by antiplatelet therapy. BMJ 1994;308:159-68

• Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction and stroke in high risk patients. BMJ 2002;324:71-86

Inadequate data exist on the use of warfarin in symptomatic carotid stenosis, and so this cannot be recommended because of possible bleeding complications.

Carotid endarterectomy is the treatment of choice for all symptomatic carotid stenosis. Aspirin treatment should be continued in the perioperative period to prevent platelet deposition at the site of the endarterectomy and thus reduce intraoperative and postoperative stroke. Platelet deposition is known to start immediately after the operation, and aspirin started in the first few postoperative days seems to provide much less benefit. In patients with symptomatic disease who are not undergoing endarterectomy antiplatelet therapy is essential to reduce the incidence of ischaemic stroke. Again, warfarin should not be used as not enough evidence exists. In all patients with cerebrovascular or carotid disease, antiplatelet therapy is recommended at all stages to decrease the risk of cardiovascular events.

Figure.

Ischaemic ulcer on foot

Figure.

Survival curve from CAPRIE study showing the benefits of aspirin and clopidogrel on vascular events, with placebo rates from the Antiplatelet Trialists' Collaboration

Figure.

Gangrenous toe indicating critical ischaemia

Figure.

Peripheral angiogram showing chronic occlusions with multiple collateral vessels

Figure.

Meta-analysis from the Antithrombotic Trialists' Collaboration showing the benefits of antiplatelet treatment in patients with peripheral vascular disease