HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Guest Access | Sign In via User Name/Password

This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clagett, G. P. Articles by Verhaeghe, R. Search for Related Content PubMed PubMed Citation Articles by Clagett, G. P. Articles by Verhaeghe, R.

Antithrombotic Therapy in Peripheral Arterial Occlusive Disease

The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy

Correspondence to: G. Patrick Clagett, MD, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-9157; e-mail: patrick.clagett{at}utsouthwestern.edu

	Abstract

TOP Abstract Introduction 1.0 Chronic Limb Ischemia Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation 2.0 Acute Limb Ischemia Recommendation Recommendation 3.0 Vascular Grafts Recommendation Recommendation Recommendation Recommendation 4.0 Carotid Endarterectomy Recommendation 5.0 Asymptomatic and Recurrent... Recommendation 6.0 Lower-Extremity Endovascular... Recommendation 1.0 Chronic Limb Ischemia 2.0 Acute Limb Ischemia 3.0 Vascular Grafts 4.0 Carotid Endarterectomy 5.0 Asymptomatic and Recurrent... 6.0 Lower Extremity Endovascular... References

 
This chapter about antithrombotic therapy for peripheral arterial occlusive disease is part of the seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs, and Grade 2 suggests that individual patients’ values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004;126:179S–187S). Among the key recommendations in this chapter are the following: For patients with chronic limb ischemia, we recommend lifelong aspirin therapy in comparison to no antiplatelet therapy in patients with clinically manifest coronary or cerebrovascular disease (Grade 1A) and in those without clinically manifest coronary or cerebrovascular disease (Grade 1C+). We recommend clopidogrel over no antiplatelet therapy (Grade 1C+) but suggest that aspirin be used instead of clopidogrel (Grade 2A). For patients with disabling intermittent claudication who do not respond to conservative measures and who are not candidates for surgical or catheter-based intervention, we suggest cilostazol (Grade 2A). We suggest that clinicians not use cilostazol in patients with less-disabling claudication (Grade 2A). In these patients, we recommend against the use of pentoxifylline (Grade 1B). We suggest clinicians not use prostaglandins (Grade 2B). In patients with intermittent claudication, we recommend against the use of anticoagulants (Grade 1A). In patients with acute arterial emboli or thrombosis, we recommend treatment with immediate systemic anticoagulation with unfractionated heparin (UFH) [Grade 1C]. We also recommend systemic anticoagulation with UFH followed by long-term vitamin K antagonist (VKA) in patients with embolsim [Grade 1C]). For patients undergoing major vascular reconstructive procedures, we recommend UFH at the time of application of vascular cross-clamps (Grade 1A). In patients undergoing prosthetic infrainguinal bypass, we recommend aspirin (Grade 1A). In patients undergoing infrainguinal femoropopliteal or distal vein bypass, we suggest that clinicians do not routinely use a VKA (Grade 2A). For routine patients undergoing infrainguinal bypass without special risk factors for occlusion, we recommend against VKA plus aspirin (Grade 1A). For those at high risk of bypass occlusion and limb loss, we suggest VKA plus aspirin (Grade 2B). In patients undergoing carotid endarterectomy, we recommend aspirin preoperatively and continued indefinitely (Grade 1A). In nonoperative patients with asymptomatic or recurrent carotid stenosis, we recommend lifelong aspirin (Grade 1C+). For all patients undergoing extremity balloon angioplasty, we recommend long-term aspirin (Grade 1C+).

Key Words: anticoagulants • antithrombotic • occlusive artery disease • peripheral artery

	Introduction

TOP Abstract Introduction 1.0 Chronic Limb Ischemia Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation 2.0 Acute Limb Ischemia Recommendation Recommendation 3.0 Vascular Grafts Recommendation Recommendation Recommendation Recommendation 4.0 Carotid Endarterectomy Recommendation 5.0 Asymptomatic and Recurrent... Recommendation 6.0 Lower-Extremity Endovascular... Recommendation 1.0 Chronic Limb Ischemia 2.0 Acute Limb Ischemia 3.0 Vascular Grafts 4.0 Carotid Endarterectomy 5.0 Asymptomatic and Recurrent... 6.0 Lower Extremity Endovascular... References

 
Patient populations with peripheral arterial occlusive disease (PAOD) are summarized in Table 1 .

	1.0 Chronic Limb Ischemia

TOP Abstract Introduction 1.0 Chronic Limb Ischemia Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation 2.0 Acute Limb Ischemia Recommendation Recommendation 3.0 Vascular Grafts Recommendation Recommendation Recommendation Recommendation 4.0 Carotid Endarterectomy Recommendation 5.0 Asymptomatic and Recurrent... Recommendation 6.0 Lower-Extremity Endovascular... Recommendation 1.0 Chronic Limb Ischemia 2.0 Acute Limb Ischemia 3.0 Vascular Grafts 4.0 Carotid Endarterectomy 5.0 Asymptomatic and Recurrent... 6.0 Lower Extremity Endovascular... References

The prevalence of PAOD increases with age and is a significant cause of hospital admission and an important predicator of cardiovascular and stroke mortality, which is increased twofold to threefold.¹²⁸⁹ Rest pain and critical ischemia are usually the result of progression of atherosclerotic disease, leading to occlusion of the distal vessels such as the popliteal and tibial arteries. There is an inverse relationship between the ankle-to-brachial pressure index and clinically manifest cardiovascular disease.⁵ The lower the index, the greater the occurrence of adverse cardiac events, strokes, and cardiovascular deaths.

This chapter addresses antithrombotic therapy for patients with PAOD. We note, however, that a systematic review and metaanalysis¹⁰ of randomized trials of exercise therapy in patients with claudication suggests that exercise improves maximal walking time by 150%. One must judge symptomatic antithrombotic therapy in this context. Furthermore, while risk factor modification is not well studied in patients with PAOD, observational data and generalization from trials¹¹¹² in persons with other manifestations of cardiovascular disease support the importance of treating key risk factors such as smoking, diabetes, dyslipidemia, and hypertension.

1.1 Antiplatelet therapy
Antiplatelet therapy may modify the natural history of chronic lower-extremity arterial insufficiency, as well as lower the incidence of associated cardiovascular events. No convincing data from properly designed large trials demonstrate that antithrombotic therapy will delay or prevent progression of atherosclerosis.

A compelling reason to administer antiplatelet therapy to patients with PAOD is to prevent death and disability from stroke and myocardial infarction (MI). The Antithrombotic Trialists’ Collaboration metaanalysis¹³ found that among 9,214 patients with PAOD in 42 trials, there was a 23% reduction in serious vascular events (p = 0.004) in patients treated with antiplatelet therapy. Patients with intermittent claudication, those having peripheral bypass, endarterectomy, and those having peripheral angioplasty all benefited to a similar degree. For all conditions, aspirin at 80 to 325 mg/d was at least as effective as any other regimen, including higher-dose aspirin therapy, which is more prone to cause side effects and GI complications.

1.1.1 Aspirin
The antiplatelet trialists analysis¹³ showed that for all conditions, aspirin at 80 to 325 mg/d was at least as effective as any other regimen, including higher-dose aspirin therapy, which is more prone to cause side effects and GI complications. Data from a single randomized controlled trial (RCT)¹⁴ suggest that aspirin, alone or combined with dipyridamole, will delay the progression of established arterial occlusive disease as assessed by serial angiography. This may have been an effect on inhibiting thrombotic occlusion of stenotic vessels rather than retarding stenosis progression.

In another study of 54 patients with intermittent claudication, the combination of aspirin and dipyridamole was found to increase the pain-free walking distance and resting limb blood flow.¹⁵ An RCT¹⁶ of 296 patients with intermittent claudication found an improved coagulation profile and ankle/brachial index with therapy, but did not report if walking distance improved with combined therapy. The Physicians Health Study,¹⁷ a primary prevention study, found that aspirin, 325 mg every other day, decreased the need for peripheral arterial reconstructive surgery; however, no difference was noted between the aspirin and placebo groups in the development of intermittent claudication.

Other chapters in these guidelines describe the compelling evidence for aspirin in patients with coronary artery disease and stroke. This applies to many patients with chronic arterial insufficiency who also have clinically manifest coronary or cerebrovascular disease. Almost all patients with PAOD who do not have clinically manifest disease have occult coronary or cerebrovascular disease. Aspirin is less effective than ticlopidine and clopidogrel (see below). However, the marginal benefit of these other drugs is small, and aspirin is much less expensive. These are the rationales for our recommendation for aspirin over clopidogrel.

	Recommendation

TOP Abstract Introduction 1.0 Chronic Limb Ischemia Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation 2.0 Acute Limb Ischemia Recommendation Recommendation 3.0 Vascular Grafts Recommendation Recommendation Recommendation Recommendation 4.0 Carotid Endarterectomy Recommendation 5.0 Asymptomatic and Recurrent... Recommendation 6.0 Lower-Extremity Endovascular... Recommendation 1.0 Chronic Limb Ischemia 2.0 Acute Limb Ischemia 3.0 Vascular Grafts 4.0 Carotid Endarterectomy 5.0 Asymptomatic and Recurrent... 6.0 Lower Extremity Endovascular... References

 
1.1.1. We recommend lifelong aspirin therapy (75 to 325 mg/d) in comparison to no antiplatelet therapy in patients with clinically manifest coronary or cerebrovascular disease (Grade 1A) and in those without clinically manifest coronary or cerebrovascular disease (Grade 1C+).

1.1.2 Ticlopidine
One metaanalysis¹⁸ demonstrated that patients with intermittent claudication treated with ticlopidine had a significant reduction in fatal and nonfatal cardiovascular events in comparison with patients treated with placebo. Ticlopidine has also shown a modest beneficial effect for relieving symptoms, increasing walking distance, and improving lower-extremity ankle pressure indices in patients with intermittent claudication (see chapter by Patrono et al in this Supplement).¹⁹²⁰ In a multicenter, placebo-controlled RCT,²¹ ticlopidine, 250 mg/d, resulted in fewer vascular surgery procedures (relative risk, 0.49; p < 0.001) among patients with intermittent claudication. However, ticlopidine is associated with a substantial risk of leukopenia and thrombocytopenia, requiring close hematologic monitoring. Because of these side effects, clopidogrel has replaced ticlopidine as the thienopyridine of choice.

	Recommendation

TOP Abstract Introduction 1.0 Chronic Limb Ischemia Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation 2.0 Acute Limb Ischemia Recommendation Recommendation 3.0 Vascular Grafts Recommendation Recommendation Recommendation Recommendation 4.0 Carotid Endarterectomy Recommendation 5.0 Asymptomatic and Recurrent... Recommendation 6.0 Lower-Extremity Endovascular... Recommendation 1.0 Chronic Limb Ischemia 2.0 Acute Limb Ischemia 3.0 Vascular Grafts 4.0 Carotid Endarterectomy 5.0 Asymptomatic and Recurrent... 6.0 Lower Extremity Endovascular... References

 
1.1.2. We recommend clopidogrel over ticlopidine (Grade 1C+).

1.1.3 Clopidogrel
Clopidogrel is a thienopyridine, the chemical structure of which is similar to ticlopidine, that exerts an irreversible antiplatelet effect primarily directed against adenosine diphosphate-induced stimulation of platelet function (see chapter by Patrono et al in this Supplement). In a large, multicenter RCT²² of 19,185 patients, investigators compared the relative efficacy of clopidogrel and aspirin in reducing the risk of a composite end point of ischemic stroke, MI, or vascular death. The study population comprised patients with recent ischemic stroke, recent MI, or PAOD. The overall incidence of composite end points was lower in the group treated with clopidogrel (5.32%/yr) than with aspirin (5.83%; p = 0.043). A subgroup analysis suggested that a larger benefit of clopidogrel over aspirin in patients with symptomatic PAOD than those with cardiac or cerebrovascular disease. Subgroup analysis is often misleading, and we are inclined to trust the overall estimate of clopidogrel effectiveness in all patients with vascular disease.

	Recommendation

TOP Abstract Introduction 1.0 Chronic Limb Ischemia Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation 2.0 Acute Limb Ischemia Recommendation Recommendation 3.0 Vascular Grafts Recommendation Recommendation Recommendation Recommendation 4.0 Carotid Endarterectomy Recommendation 5.0 Asymptomatic and Recurrent... Recommendation 6.0 Lower-Extremity Endovascular... Recommendation 1.0 Chronic Limb Ischemia 2.0 Acute Limb Ischemia 3.0 Vascular Grafts 4.0 Carotid Endarterectomy 5.0 Asymptomatic and Recurrent... 6.0 Lower Extremity Endovascular... References

 
1.1.3. We recommend clopidogrel in comparison to no antiplatelet therapy (Grade 1C+) but suggest that aspirin be used instead of clopidogrel (Grade 2A).

Underlying values and preferences: This recommendation places a relatively high value on avoiding large expenditures to achieve small reductions in vascular events.

1.1.4 Cilostazol
Cilostazol is a type III phosphodiesterase inhibitor that suppresses platelet aggregation and is a direct arterial vasodilator. Its mechanism of action as a treatment for claudication is not fully understood. We found no systematic reviews on this drug for PAOD. Several published clinical trials that have evaluated the efficacy of cilostazol as a therapeutic agent for intermittent claudication.

In the first of these published trials,²³ 239 patients randomly assigned to receive a 16-week course of cilostazol or placebo, the cilostazol group showed an increase in absolute claudication distance (ACD) of 47%, while the control group improved by 13% (p < 0.001). Functional status assessment also showed improvement with cilostazol compared with control subjects, although there were significantly more side effects with cilostazol, most notably headache (30%) and diarrhea (12.6%).

In a smaller trial²⁴ of 12 weeks of cilostazol or placebo, the ACD increased 31% with cilostazol, vs a drop of 9% with placebo (p < 0.01). In another study,²⁵ 45 patients with claudication were randomly assigned to one of three groups, cilostazol, pentoxifylline, or placebo for 24 weeks; at 24 weeks, the treatment was changed to placebo for all groups, and follow-up was continued for 6 more weeks. There was a more significant decrease in ACD after cessation of cilostazol therapy than with either pentoxifylline or placebo. The increase in ACD from baseline was similar in both the cilostazol and pentoxifylline groups (109% and 94%, respectively).

In a trial²⁶ of 516 patients randomly assigned to cilostazol (100 mg bid or 50 mg bid) or placebo therapy for 24 weeks, those receiving 50 mg bid had a 38% and 48% mean improvement in maximal and pain-free walking distance, respectively, while with a dose of 100 mg bid showed a 51% and 59% improvement, respectively, compared to placebo. Benefit was noted as early as 4 weeks, with progressive improvement over the 24-week period of the trial. There was also a significant improvement in functional outcomes with cilostazol, and no difference in the incidence of adverse events in the three groups. Side effects noted in each of the studies included headache, loose and soft stools, diarrhea, dizziness, and palpitations.

Cilostazol is more effective than pentoxifylline, as illustrated in a study of 698 patients randomized to pentoxifylline (400 mg tid), cilostazol (100 mg bid), or placebo for 24 weeks.²⁷ In comparison to pentoxifylline, cilostazol produced a significant increase in walking distance for onset of claudication (218 m for cilostazol vs 202 m for pentoxifylline, p = 0.0001) and ACD (350 m for cilostazol vs 308 m for pentoxifylline, p = 0.0005). In addition, there were fewer patients who had no change or deterioration in walking distance (23% for cilostazol vs 34% with pentoxifylline).

Cilostazol thus appears to be an appropriate therapy for patients with disabling claudication who are not candidates for revascularization. However, its high cost, modest effect on walking distance, lack of demonstrated benefit in improving health-related quality of life, and the salutary effects of exercise therapy and risk factor modification argue against its routine use in patients with less-disabling intermittent claudication.

Cilostazol has weak platelet inhibitory effects, and there are no data to support its use as an antiplatelet agent. Antiplatelet therapy with aspirin or clopidogrel should be continued in patients receiving cilostazol.

	Recommendation

TOP Abstract Introduction 1.0 Chronic Limb Ischemia Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation 2.0 Acute Limb Ischemia Recommendation Recommendation 3.0 Vascular Grafts Recommendation Recommendation Recommendation Recommendation 4.0 Carotid Endarterectomy Recommendation 5.0 Asymptomatic and Recurrent... Recommendation 6.0 Lower-Extremity Endovascular... Recommendation 1.0 Chronic Limb Ischemia 2.0 Acute Limb Ischemia 3.0 Vascular Grafts 4.0 Carotid Endarterectomy 5.0 Asymptomatic and Recurrent... 6.0 Lower Extremity Endovascular... References

 
1.1.4. For patients with disabling intermittent claudication who do not respond to conservative measures (risk factor modification and exercise therapy) and who are not candidates for surgical or catheter-based intervention, we suggest cilostazol (Grade 2A). We suggest that clinicians notuse cilostazol in those with less-disabling claudication (Grade 2A).

Underlying values and preferences: The recommendation against cilostazol for those with less-disabling claudication places a relatively low value on small possible improvements in function in the absence of clear improvement in health-related quality of life.

1.1.5 Pentoxifylline
Pentoxifylline is a weak antithrombotic agent; its putative mechanisms of action include an increase in RBC deformity, and decreases in fibrinogen concentration, platelet adhesiveness, and whole-blood viscosity.²⁸²⁹³⁰ One metaanalysis³¹ suggests that pentoxifylline improves walking distance by 29 m compared with placebo, although the improvement was approximately 50% in the placebo group, and use of pentoxifylline improved walking distance by an additional 30%. Moreover, clinical trials have shown conflicting results. Some^323334353637 have concluded that pentoxifylline was significantly more effective than placebo in improving treadmill-walking distance, but others^383940414243 could not demonstrate consistent benefit. In many trials, patients treated with placebo also demonstrated significant improvement. Thus, the actual improvement in walking distance attributable to pentoxifylline is often unpredictable and may not be clinically important compared with the effects of placebo.⁴⁴ In summary, the evidence for a beneficial effect of pentoxifylline is not strong enough to suggest an important role in the treatment of patients with PAOD.⁴⁵⁴⁶

	Recommendation

TOP Abstract Introduction 1.0 Chronic Limb Ischemia Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation 2.0 Acute Limb Ischemia Recommendation Recommendation 3.0 Vascular Grafts Recommendation Recommendation Recommendation Recommendation 4.0 Carotid Endarterectomy Recommendation 5.0 Asymptomatic and Recurrent... Recommendation 6.0 Lower-Extremity Endovascular... Recommendation 1.0 Chronic Limb Ischemia 2.0 Acute Limb Ischemia 3.0 Vascular Grafts 4.0 Carotid Endarterectomy 5.0 Asymptomatic and Recurrent... 6.0 Lower Extremity Endovascular... References

 
1.1.5. We recommend againstthe use of pentoxifylline (Grade 1B).

1.1.6 Prostaglandins
Prostaglandins with antiplatelet and vasodilatory effects, such as prostaglandin E₁ (PGE₁) and prostaglandin I₂ (PGI₂), have been administered IV or intra-arterially to patients with advanced chronic arterial insufficiency in hopes of relieving rest pain and healing ischemic ulcers. In a study⁴⁷ of 80 patients with intermittent claudication, IV administration of a PGE₁ produced a dose-related improvement in walking distance and quality of life at 4 weeks and 8 weeks. In an older but larger randomized, blinded, multicenter trial⁴⁸ of patients with one to three ischemic ulcers not healing for 3 weeks with standard care who were randomized to receive either PGE₁ or a placebo for 72 h through a central venous catheter, PGE₁ was found to be ineffective. In a small, randomized open study,⁴⁹ PGE₁ administered IV and combined with an intensive exercise regimen produced dramatic and sustained improvement in symptom-free walking distance in comparison with exercise alone or exercise combined with IV-administered pentoxifylline. The largest data set comes from a multicenter RCT⁵⁰ in which 1,560 patients with chronic critical ischemia of the leg were randomly assigned to receive either a daily IV infusion of PGE₁ or nothing (open-label study) during their hospital stay. At discharge, there was a greater reduction in composite outcome events in the PGE₁ group than in the control subjects (63.9% vs 73.6%; relative risk, 0.87; p < 0.001), but this difference was not statistically significant at 6 months (52.6% vs 57.5%; relative risk, 0.92; p = 0.074). AS-013, a PGE₁ prodrug, was evaluated in a small randomized trial⁵¹ of 80 patients with claudication, and was associated with an increase of 35 m in maximal walking distance after 8 weeks of treatment, compared with a slight decrease in placebo-treated control subjects. This difference was statistically significant (p < 0.01), although the clinical significance of the increase was marginal.

A blinded trial that contained a high proportion of diabetics showed no beneficial effect of IV PGI₂ on ulcer healing or rest pain.⁵² However, selective intra-arterial PGI₂ was found to relieve rest pain and promote healing of ulcers to a significantly greater degree than did placebo treatment in 30 nondiabetic patients, half of whom had thromboangiitis obliterans (Buerger disease).⁵³ In another double-blind trial,⁵⁴ PGI₂ administered IV to nondiabetic patients with severe arterial insufficiency produced significantly greater relief (lasting up to 1 month) of rest pain than did placebo, but there was no correlation with changes in ankle-to-brachial pressure index, or ulcer healing.

Beraprost, an orally active PGI₂ analog, was evaluated in the Beraprost et Claudication Intermittente-2 trial⁵⁵ of 549 patients with a pain-free walking distance of 50 to 300 m. After 6 months, more patients receiving beraprost (40 µg tid) compared to placebo had an increase in walking distance on a treadmill (44% vs 33%), and pain-free walking distances (82% vs 53%), and maximum walking distances (60% vs 35%). These benefits were modest and probably not clinically significant. The incidence of cardiac death, MI, coronary revascularization, stroke, transient ischemic attack (TIA), or leg ischemia requiring intervention was similar in both groups.

	Recommendation

TOP Abstract Introduction 1.0 Chronic Limb Ischemia Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation 2.0 Acute Limb Ischemia Recommendation Recommendation 3.0 Vascular Grafts Recommendation Recommendation Recommendation Recommendation 4.0 Carotid Endarterectomy Recommendation 5.0 Asymptomatic and Recurrent... Recommendation 6.0 Lower-Extremity Endovascular... Recommendation 1.0 Chronic Limb Ischemia 2.0 Acute Limb Ischemia 3.0 Vascular Grafts 4.0 Carotid Endarterectomy 5.0 Asymptomatic and Recurrent... 6.0 Lower Extremity Endovascular... References

 
1.1.6. For limb ischemia, we suggest clinicians notuse prostaglandins (Grade 2B).

Underlying values and preferences: The recommendation places a low value on achieving small gains in walking distance in the absence of demonstrated improvement in quality of life.

1.1.7 Other agents
Other agents with putative antithrombotic activity that have been subjected to RCTs but were found to be ineffective in the treatment of intermittent claudication include the following: the antiserotonin agent ketanserin,⁵⁶ suloctidil,⁵⁷ fish oil supplementation,⁵⁸ and naftidrofuryl.⁵⁹⁶⁰ Other ineffective drugs for intermittent claudication (such as nifedipine, l-carnitine, etc) are not discussed, as there is little evidence for the role as antithrombotic agents.

Picotamide, an antiplatelet agent that inhibits thromboxane-A₂ synthase and antagonizes thromboxane-A₂ receptors, has been evaluated in one, small, blinded RCT⁶¹ in patients with PAOD. Treatment with picotamide significantly reduced the overall incidence of major and minor cardiovascular events. In a blinded, placebocontrolled RCT,⁶² patients treated with picotamide showed no progression of carotid atherosclerosis (as measured by B-mode ultrasound) compared with placebo-treated control subjects. There are no data on whether this agent is superior or equivalent to aspirin or other agents.⁶³ "Hemodilution therapy" for reducing the plasma viscosity involves the removal of blood and replacing it with a colloidal solution such as hydroxyethyl starch or a low molecular weight dextran one or twice weekly for several weeks, resulting in small improvement in pain-free walking distance in two studies.⁶⁴⁶⁵

A Cochrane review⁶⁶ assessed the effects of anticoagulant drugs (unfractionated heparin [UFH], low molecular weight heparin [LMWH], and vitamin K antagonists [VKAs]) in patients with PAOD. End points included walking capacity (pain-free walking distance or absolute walking distance), mortality, cardiovascular events, ankle/brachial pressure index, progression to surgery, amputation-free survival, and side effects. Thirteen trials were initially considered eligible for inclusion in the review. Only three studies (two evaluating VKA, one evaluating UFH) met the high quality methodologic inclusion criteria and were included in the primary analysis, while four other studies were included in the sensitivity analysis. No significant difference was observed between UFH treatment and control groups for pain-free walking distance or maximum walking distance at the end of treatment. The review found no data to indicate that LMWHs benefit walking distance. No study reported a significant effect on overall mortality or cardiovascular events, and the pooled odds ratios were not significant for these outcomes. Major and minor bleeding events were significantly more frequent in patients treated with VKAs compared to control, with a nonsignificant increase in fatal bleeding events. No major bleeding events were reported in the study evaluating UFH, while a nonsignificant increase in minor bleeding events was reported. In conclusion, no benefit of UFH, LMWH, or VKA has been established for intermittent claudication. An increased risk of major bleeding events has been observed especially with VKAs. The Cochrane review⁶⁶ concluded that the use of anticoagulants for intermittent claudication cannot be recommended.

	Recommendation

TOP Abstract Introduction 1.0 Chronic Limb Ischemia Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation 2.0 Acute Limb Ischemia Recommendation Recommendation 3.0 Vascular Grafts Recommendation Recommendation Recommendation Recommendation 4.0 Carotid Endarterectomy Recommendation 5.0 Asymptomatic and Recurrent... Recommendation 6.0 Lower-Extremity Endovascular... Recommendation 1.0 Chronic Limb Ischemia 2.0 Acute Limb Ischemia 3.0 Vascular Grafts 4.0 Carotid Endarterectomy 5.0 Asymptomatic and Recurrent... 6.0 Lower Extremity Endovascular... References

 
1.1.7. In patients with intermittent claudication, we recommend againstthe use of anticoagulants (Grade 1A).

	2.0 Acute Limb Ischemia

TOP Abstract Introduction 1.0 Chronic Limb Ischemia Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation 2.0 Acute Limb Ischemia Recommendation Recommendation 3.0 Vascular Grafts Recommendation Recommendation Recommendation Recommendation 4.0 Carotid Endarterectomy Recommendation 5.0 Asymptomatic and Recurrent... Recommendation 6.0 Lower-Extremity Endovascular... Recommendation 1.0 Chronic Limb Ischemia 2.0 Acute Limb Ischemia 3.0 Vascular Grafts 4.0 Carotid Endarterectomy 5.0 Asymptomatic and Recurrent... 6.0 Lower Extremity Endovascular... References

 
The major causes of acute arterial insufficiency are arterial thrombosis, embolus, and trauma. Extreme vasospasm (eg, ergot induced) and arterial dissection are unusual causes. Most traumatic occlusive events are associated with transection, laceration, or occlusion from external compression such as a fracture or dislocation; but in some instances, thrombosis occurs from blunt trauma. Iatrogenic vascular trauma, most often from diagnostic and therapeutic catheter placement, is a common cause of acute arterial occlusion. In most patients early surgery is required, with appropriate repair of the injured vessel. If thrombosis occurred, use of the Fogarty balloon catheter to remove thrombi is often required and is usually effective. Anticoagulation with UFH is variably used at the time of operation, but may be contraindicated because of other injuries. Outcome is related to the seriousness of associated injuries and duration of ischemia; successful vascular repair can be achieved in most cases.

Nontraumatic acute occlusion is mainly embolic or thrombotic. The large majority of emboli arise from the heart in patients with valvular disease and/or atrial fibrillation, with prosthetic valves, or with mural thrombi in an infarcted or dilated left ventricle. Noncardiac sources of embolism include arterial aneurysms, ulcerated atherosclerotic plaque, recent (endo)vascular procedures, paradoxic emboli from venous thrombi, and rarely arteritis or vascular trauma. Approximately two thirds of noncerebral emboli enter vessels of the lower extremity and half of these obstruct the iliofemoral segment, while the remainder involve the popliteal and tibial vessels. The upper-extremity and renal plus visceral vessels each receive approximately 15% of emboli.⁶⁷⁶⁸

Thrombotic occlusions of arteries are usually associated with advanced atherosclerosis, and arteries often have preexisting and developed collateral blood supply. For this reason, final occlusion may not be a dramatic event and is sometimes silent; it is not an emergent process in many patients. Thrombosis also occurs in vascular grafts and with other degenerative or inflammatory diseases or with trauma. The upper extremity better tolerates arterial occlusion because of rich collateral blood supply: gangrene or ischemic rest pain is rare in the absence of distal embolization. Hypovolemia, hyperviscosity, and hypercoagulability as observed in shock, thrombocytosis, polycythemia, and malignant disorders predispose to thrombotic arterial occlusion. Arterial thrombosis most frequently involves the lower extremities.

Therapeutic management will depend on whether the occlusion is caused by embolism in a healthy artery vs thromboembolism in an atheromatous artery. Prompt embolectomy through surgical intervention is the usual technique to remove emboli from healthy arteries. The introduction of the Fogarty balloon catheter 40 years ago dramatically decreased the mortality and the amputation rate from arterial embolism. Percutaneous thromboembolectomy with the aid of an aspiration catheter or of a thrombectomy device is a recent alternative. Literature on either of these new techniques is descriptive and was recently reviewed.⁶⁹⁷⁰ No randomized comparison between the different options is available. Traditionally, thromboembolism in a severely diseased artery or in a vascular graft causing acute ischemia symptoms has been the domain of the vascular surgeon as well, but optimal management needs to be determined.

2.1 Heparin
Patients presenting with acute limb ischemia secondary to thromboembolic arterial occlusion usually receive prompt anticoagulation with therapeutic dosages of UFH in order to prevent clot propagation and to obviate further embolism. The logic of this common clinical practice is not questioned, even though no formal studies have established unequivocally a beneficial role of any antithrombotic agent in patients with acute embolic occlusion. The expected adverse effect of perioperative anticoagulant therapy is an increased risk of wound complications, particularly hematomas. The major role for continued anticoagulant therapy (UFH followed by VKA) after embolization is to prevent embolic recurrence if the source of embolism cannot be eradicated or corrected.

	Recommendation

TOP Abstract Introduction 1.0 Chronic Limb Ischemia Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation 2.0 Acute Limb Ischemia Recommendation Recommendation 3.0 Vascular Grafts Recommendation Recommendation Recommendation Recommendation 4.0 Carotid Endarterectomy Recommendation 5.0 Asymptomatic and Recurrent... Recommendation 6.0 Lower-Extremity Endovascular... Recommendation 1.0 Chronic Limb Ischemia 2.0 Acute Limb Ischemia 3.0 Vascular Grafts 4.0 Carotid Endarterectomy 5.0 Asymptomatic and Recurrent... 6.0 Lower Extremity Endovascular... References

 
2.1. In patients with acute arterial emboli or thrombosis, we recommend treatment with immediate systemic anticoagulation with UFH to prevent thrombotic propagation (Grade 1C). We also recommend systemic anticoagulation with UFH followed by long-term VKA to prevent recurrent embolism in patients undergoing embolectomy (Grade 1C).

2.2 Thrombolysis
Initial intervention with thrombolysis with the aim of eliminating all thrombotic and embolic material and restore perfusion is a potential alternative to surgical revascularization in acute limb ischemia of thromboembolic origin. Systemic thrombolysis with IV administration of a thrombolytic agent was used in the 1960s and 1970s and has been completely abandoned and replaced by catheter-directed thrombolysis. With this technique, a catheter is positioned intra-arterially and advanced into the thrombus for local delivery of the thrombolytic agent. Several infusion methods can be used. Initially, streptokinase was the most widely used agent, but later it was superseded in clinical use by urokinase and recombinant tissue-type plasminogen activator (rt-PA). Dosages schemes vary considerably; an overview of reported dosages was published in a recent consensus document.⁷¹ rt-PA was mainly used in Europe, but since the suspension of urokinase sales in 1998, it has been administered in the United States as well. In addition, new agents are being investigated. For instance, reteplase, a nonglycosylated mutant of alteplase, was tested in a few small series:⁷²⁷³ doses of 0.5 up to 2 U/h produced thrombus dissolution rates and bleeding rates that appear comparable to published data with other thrombolytic agents, but a direct comparison is not available.

A new approach is the use of the platelet glycoprotein IIb-IIIa antagonist abciximab as adjuvant therapy to thrombolysis with the hope of improving lytic efficacy and clinical outcome. A pilot trial⁷⁴ randomized 70 patients to urokinase plus abciximab or to urokinase plus placebo. At 90 days, amputation-free survival was 96% in the urokinase-abciximab group vs 80% in the urokinase-placebo group. Thrombolysis occurred faster in the former group, but the rate of nonfatal major bleeding was also higher.⁷⁴

Only a few randomized studies compared thrombolytic agents directly. An open trial⁷⁵ compared intra-arterial streptokinase to intra-arterial and IV rt-PA in 60 patients with recent onset or deterioration of limb ischemia; initial angiographic success was superior with intra-arterial rt-PA (100%) than with intra-arterial streptokinase (80%; p < 0.04) or IV rt-PA (45%; p < 0.01), the 30-day limb salvage rates being 80%, 60%, and 45%, respectively. Another randomized trial⁷⁶ in 32 patients showed significantly faster lysis with rt-PA than with urokinase, but the 24-h lysis rate and the 30-day clinical success rate were similar. The Surgery vs Thrombolysis for Ischemia of the Lower Extremity (STILE) study⁷⁷ included a comparison of rt-PA and urokinase; patients assigned to thrombolytic treatment received at random one of the two drugs, and the main report mentions similar efficacy and safety for both agents.

A German study⁷⁸ randomized 120 patients with thrombotic infrainguinal arterial occlusion to treatment with urokinase or rt-PA, and noted a slight improvement in successful lysis in all segments treated with rt-PA(p < 0.05), but local hematomas were more common. The Prourokinase Versus Urokinase for Recanalization of Peripheral Occlusions, Safety and Efficacy trial⁷⁹ compared three doses of recombinant prourokinase to tissue culture urokinase with complete lysis as a primary end point; the highest lysis rate was obtained with the highest dose tested (8 mg/h for 8 h, then 0.5 mg/h), at the expense of a slightly increased frequency of bleeding and decrement in fibrinogen level. In assessing all of these data, there is at present no convincing scientific proof of superiority of any agent for catheter-directed thrombolysis in terms of efficacy and safety.

Although the extensive literature on catheter-directed thrombolysis is largely descriptive, five prospective randomized studies compared this treatment method to surgical intervention.^7780818485 Two meta-analyses⁸⁶⁸⁷ are available and conclude that there is a similar mortality and amputation rate for thrombolysis and surgery; thrombolysis reduces the need for open major surgical procedures but causes more bleeding and distal embolization.

In a small trial,⁸⁰ surgical thrombectomy was compared to an intra-arterial continuous infusion of 30 mg of alteplase over 3 h in 20 patients with acute (> 24 h but < 14 days) arterial occlusion and severe leg ischemia. Only patients with a need for intervention were included. Considerable lysis was obtained in six of nine patients treated with alteplase, and half of them subsequently underwent percutaneous transluminal angioplasty. Two early reocclusions occurred. Thrombectomy also resulted in an immediate restitution of blood flow in six of nine cases.

Ouriel et al⁸¹ compared initial thrombolysis complemented with percutaneous transluminal angioplasty or/and surgery vs immediate surgery in 114 patients with limb-threatening ischemia of < 7 days in duration, due to native artery or graft occlusion. Thrombolysis resulted in dissolution of the occluding thrombus in 70% of the patients. Limb salvage rate was similar in the two groups (82% at 1 year), but cumulative survival was significantly improved in patients randomized to thrombolysis due to fewer cardiopulmonary complications in hospital (84% vs 58% at 1 year, p = 0.01).

The STILE trial⁷⁷ randomized 393 patients with nonembolic native artery or bypass graft occlusion in the lower limbs within the past 6 months to either optimal surgical procedure or intra-arterial catheter-directed thrombolysis with rt-PA or urokinase. The primary end point was a composite outcome of death, major amputation, ongoing or recurrent ischemia, and major morbidity. At 1 month, the primary end point was reached for 36.1% of surgical patients and 61.7% of thrombolysis patients (p < 0.0001). This difference was primarily due to ongoing/recurrent ischemia (25.7% vs 54.0%; p < 0.0001); lysis was unsuccessful in 28% of the patients assigned to thrombolysis because of failure of proper catheter placement, an inexplicably high rate. However, in a secondary analysis that stratified patients by duration of ischemia, thrombolysis resulted in improved amputation-free survival at 6 months and shorter hospital stay in patients with acutely ischemic limbs (< 14 days), whereas surgical revascularization was more effective for more chronic ischemia (> 14 days).⁷⁷

Two additional publications⁸²⁸³ analyzed the STILE trial on an intention-to-treat basis for the 30-day, 6-month, and 1-year results in patients with native artery and graft occlusion separately. For 237 patients with native artery occlusion, the composite clinical outcome was in favor of surgery because of a lower incidence of major amputation (0% vs 10% at 1 year, p = 0.0024) and recurrent ischemia (35% vs 64% at 1 year, p < 0.0001). Factors predictive of a poor outcome with lysis were femoropopliteal occlusion, diabetes, and critical ischemia. Only 20% of those patients had an onset or progression of ischemic symptoms of < 14 days in duration; in these patients, the 1-year death/amputation rate was similar for surgery and thrombolysis. Overall, lysis failed to reestablish patency in 45% of patients, but 22% did not receive a lytic agent because of problems with catheter positioning.⁸² For 124 patients with bypass graft occlusion, there was also a better overall composite clinical outcome at 30 days and 1 year in the surgical group compared to lysis, predominantly due to a reduction in ongoing/recurrent ischemia. However, 39% randomized to lysis failed catheter placement and required surgery. Following successful catheter placement, patency was reestablished by lysis in 84%. A poststudy analysis indicated that limb loss at 1 year was significantly lower in patients with ischemia for < 14 days if treated with thrombolysis compared with those treated surgically (20% vs 48%; p = 0.026).⁸³

The Thrombolysis or Peripheral Arterial Surgery (TOPAS)⁸⁴⁸⁵ investigators prospectively compared recombinant urokinase vs surgery in acute arterial occlusion ( 14 days). In a first dose-ranging trial,⁸⁴ they evaluated the safety and efficacy of three doses of recombinant urokinase in comparison with surgery in 213 patients. The amputation-free survival rate at 1 year was 75% in 52 patients treated initially with recombinant urokinase at 4,000 IU/min, and 65% in 58 surgically treated patients, a nonsignificant difference. The 4,000 IU/min dosage appeared the most appropriate thrombolytic regimen (compared with 2,000 IU/min and 6,000 IU/min) for the first 4 h because it maximized lytic efficacy against the bleeding risk. This optimal dosage regimen (4,000 IU/min for the initial 4 h followed by 2,000 IU/min for up to 48 h) was next tested in a large multicenter trial⁸⁵ on 544 patients. Amputation-free survival rates in the urokinase group were 71.8% at 6 months and 65.0% at 1 year, as compared with respective rates of 74.8% and 69.9% in the surgery group; these differences between the two groups were not significant. Thrombolysis reduced the need for open surgical procedures (315 vs 551 at 6 months) without increased risk of amputation or death.

Overall, the randomized trials provide no clear-cut answer to the dilemma which of the two treatments (thrombolysis or surgical intervention) to prefer. They selected heterogeneous patient populations and studied complicated endpoints. The risk of intracranial bleeding remains a major burden for thrombolytic treatment in acute limb ischemia; in three American prospective randomized studies that compared thrombolysis to surgery, the intracranial bleeding rate with thrombolysis was 1.2% (STILE),⁷⁷ 2.1% (TOPAS-I),⁸⁴ and 1.6% (TOPAS-II).⁸⁵

A working party reached a consensus proposal on the use of thrombolysis in the management of lower-limb arterial occlusion.⁷¹ In native artery occlusion, a management strategy incorporating thrombolysis followed by correction of the causative lesion was proposed as an appropriate strategy in patients with ischemia of < 14 days in duration. Immediate surgical revascularization is to be preferred if thrombolysis would lead to an unacceptable delay in effective reperfusion. In patients with irreversible ischemia, primary amputation is indicated. For occluded bypass grafts, the therapeutic options are either surgical revision and thrombectomy, catheter-directed thrombolysis, or insertion of a new graft. Factors to consider in therapeutic decision making are the age and nature of the graft, the duration and degree of ischemia, and the availability of vein for a new distal bypass. In patients with a recent occlusion of a well-established graft, the working party proposed thrombolytic therapy as a primary treatment modality. Thrombolysis may eventually clear the thrombosed outflow vessels as well. However, the patency rate 1 year after successful lysis of thrombosed grafts is low (± 20%), and the question is whether the ultimate yield justifies the labor-intensive and expensive lytic procedure.⁸⁸

	Recommendation

TOP Abstract Introduction 1.0 Chronic Limb Ischemia Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation Recommendation 2.0 Acute Limb Ischemia Recommendation Recommendation 3.0 Vascular Grafts Recommendation Recommendation Recommendation Recommendation 4.0 Carotid Endarterectomy Recommendation 5.0 Asymptomatic and Recurrent... Recommendation 6.0 Lower-Extremity Endovascular... Recommendation 1.0 Chronic Limb Ischemia